*5.3.3. Microbiological studies*

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

**•** the data reflect the afore mentioned age group only, in more heterogenous groups both sensitivity and specificity have to be (down)-corrected to 95 % and 90 % respectively [22,

**•** the results strictly apply to high TB prevalence settings only and do not allow for different

**•** also immune suppression like in AIDS endemic areas may interfere with inflammatory

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

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

) [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,

effusions) resulting in a sensitivity and specificity of 92 % and 90 % respectively [52].

ADA-release and invalidate diagnostic conclusions [3, 51].

of these results and their clinical relevance:

276 Tuberculosis - Current Issues in Diagnosis and Management

49, 50].

pre-test prohabilities [3].

*5.3.2. Cytological analysis*

mm3

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 with CD4 cell counts < 200 x 106 /l significantly higher yields are being reported amounting in 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 [57].

#### *5.3.4. Immunological and molecular studies*

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‐ ques.

Molecular mycobacterial identification methods employing a variety of *nucleic acid amplifica‐ tion techniques (NAAT)* have been applied in TB pleurisy with considerable enthusiasm and expectations ever since their first application in TB in 1989 [62]. The techniques that have been used include target amplification (polymerase chain reaction, PCR), strand displacement amplification (SDA), transcription mediated amplification (TMA), probe/primer amplification (ligand chain reaction, LCR) and Q-Beta replicase amplification mostly with the IS 6110, 16S recombinant ribonucleic acid (rRNA) and 65 XD target sequence [63-66]. So far published data, both biopsy- and pleural fluid-based have shown considerable variance of diagnostic yield, which ranged from 20-81 % as to sensitivity with an expectedly high specificity in the order of 98-100 % (table 1). When analyzing the sources of this high variance, apart from technical factors like contamination-related "carry over" or amplification inhibitors, the most important determinant appeared to be the number of bacilli in the pleura fluid or specimen sample [31]. Although theoretically requiring the presence of merely one microorganism to trigger amplification, similar to sputum anlysis, failed to detect pleural MTB in particular when the pleurisy was paucibacillar, correlating with cultural negativity. In addition to fluid samples numerous studies have evaluated the value of various nucleic acid extraction and amplifica‐ tions techniques in formalin-fixed and paraffin-embedded pleural tissue specimen [67-71]. With the use of commercial kits of both DNA amplicons (ligand chain MTB assay, LCxMTB or AMPLICOR MTB) or RNA amplicons (amplified MTB direct test, AMTDT) according to the latest currently available sources, the sensitivity of each single technique did not exceed 63.2 % albeit at an expected 100 % specificity [71]. The so far largest meta-analysis including 40 studies and featuring commercial as well as in-house ("home-brew") tests, confirms a low and heterogeneous sensitivity (in the mean 62 %) and high specificity of 98 % [72]. Thus there is no convincing evidence, that generally and especially in the critical issue of paucibacillar (cultural negative) pleurisy, NAATs perform substantially better in tissue than in effusion specimens (table 1). Although in-house assays have been reported to be slightly superior [73], there remain significant sensitivity set backs both in liquid- and tissue-derived specimen. In summary NAATs may offer certain advantages like quick results within hours or added specificity. They may also improve sensitivity in combined and parallel use with conventional methods and multiple amplicors (diagnostic confirmation), but can certainly not replace or obviate the need for conventional tools in the diagnosis of TB pleurisy.

ly contain a representative parietal pleural sample [74]. With this premise and the expected yield of at least two valid samples closed needle biopsy should be diagnostic in tubercu‐ lous pleurisy in ~ 60 % of cases, when histology and tissue-, as well as fluid-culture are being combined. In a major series (n=100 %) a 61 % positive yield was composed of 51 % biopsy yield and 28 % positive fluid culture (figure 4) [18, 55]. Distinctly higher yields have also been reported in the literature, leading in a collective review to an average sensitivity of 69 % (range 28-88 %) [75]. The difference and wide range is likely to be due to technical disparities and inclusion of data originating from largely different prevalence areas. In one study from a high prevalence area (South Africa) comprising 51 patients with undiagnosed pleurisy the positive closed needle yield in tuberculous pleurisy (histology+AFB-stain+culture) was 79%, when combined with pleural fluid ADA-determination and a lymphocyte/neutrophil ratio > 0.75 sensitivity increased to 93% at a specificity of 100% [76]. Thus with the parallel use of less invasive parameters needle biopsy approaches the diagnostic potency of more inva‐ sive techniques and would appear the second best diagnostic option in areas with limited

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 279

**Table 1.** Role of Nucleic-Acid-Amplification-Techniques (NAAT) in the Diagnosis of Tuberculous Pleuritis

*Medical thoracoscopy* as a *"window to the pleural space"* [77] is the gold standard procedure in the evaluation of exudative pleural effusion, hence also pleural pleurisy. The current and future role of thoracoscopy needs to be redefined for its diagnostic and interventional efficacy in the light of its close historical affiliation with TB. In fact tuberculosis was already a major focus of medical thoracoscopy or *"pleuroscopy"* as referred to and initiated by JACOBAEUS back in

medical logistics and resources.

#### *5.3.5. Invasive bioptic and endoscopic studies*

Bioptic techniques in the evaluation of tuberculous effusions incorporate closed blind or imaging guided needle biopsy and medical (video)-thoracoscopy. Only exceptionally, if ever, surgical diagnostic efforts including video-assisted surgical thoracoscopy (VATS) would appear appropriate. Invasive techniques are indicated when clinical investigation and pleural fluid analysis provide only ambiguous or conflicting results and this is particularly true if relevant differential diagnoses like malignancy need to be reliably excluded. *Needle biopsy* may be considered a first step. There are no clear preferences as to the type of needle to be used, although in the author´s opinion the Tru-Cut or Raja-system may be preferable to the older Abrams- or Ramel-needle by providing a larger specimen along with easier han‐ dling. It is recommended, that at least six biopsies are obtained, since they will not regular‐


Molecular mycobacterial identification methods employing a variety of *nucleic acid amplifica‐ tion techniques (NAAT)* have been applied in TB pleurisy with considerable enthusiasm and expectations ever since their first application in TB in 1989 [62]. The techniques that have been used include target amplification (polymerase chain reaction, PCR), strand displacement amplification (SDA), transcription mediated amplification (TMA), probe/primer amplification (ligand chain reaction, LCR) and Q-Beta replicase amplification mostly with the IS 6110, 16S recombinant ribonucleic acid (rRNA) and 65 XD target sequence [63-66]. So far published data, both biopsy- and pleural fluid-based have shown considerable variance of diagnostic yield, which ranged from 20-81 % as to sensitivity with an expectedly high specificity in the order of 98-100 % (table 1). When analyzing the sources of this high variance, apart from technical factors like contamination-related "carry over" or amplification inhibitors, the most important determinant appeared to be the number of bacilli in the pleura fluid or specimen sample [31]. Although theoretically requiring the presence of merely one microorganism to trigger amplification, similar to sputum anlysis, failed to detect pleural MTB in particular when the pleurisy was paucibacillar, correlating with cultural negativity. In addition to fluid samples numerous studies have evaluated the value of various nucleic acid extraction and amplifica‐ tions techniques in formalin-fixed and paraffin-embedded pleural tissue specimen [67-71]. With the use of commercial kits of both DNA amplicons (ligand chain MTB assay, LCxMTB or AMPLICOR MTB) or RNA amplicons (amplified MTB direct test, AMTDT) according to the latest currently available sources, the sensitivity of each single technique did not exceed 63.2 % albeit at an expected 100 % specificity [71]. The so far largest meta-analysis including 40 studies and featuring commercial as well as in-house ("home-brew") tests, confirms a low and heterogeneous sensitivity (in the mean 62 %) and high specificity of 98 % [72]. Thus there is no convincing evidence, that generally and especially in the critical issue of paucibacillar (cultural negative) pleurisy, NAATs perform substantially better in tissue than in effusion specimens (table 1). Although in-house assays have been reported to be slightly superior [73], there remain significant sensitivity set backs both in liquid- and tissue-derived specimen. In summary NAATs may offer certain advantages like quick results within hours or added specificity. They may also improve sensitivity in combined and parallel use with conventional methods and multiple amplicors (diagnostic confirmation), but can certainly not replace or

obviate the need for conventional tools in the diagnosis of TB pleurisy.

Bioptic techniques in the evaluation of tuberculous effusions incorporate closed blind or imaging guided needle biopsy and medical (video)-thoracoscopy. Only exceptionally, if ever, surgical diagnostic efforts including video-assisted surgical thoracoscopy (VATS) would appear appropriate. Invasive techniques are indicated when clinical investigation and pleural fluid analysis provide only ambiguous or conflicting results and this is particularly true if relevant differential diagnoses like malignancy need to be reliably excluded. *Needle biopsy* may be considered a first step. There are no clear preferences as to the type of needle to be used, although in the author´s opinion the Tru-Cut or Raja-system may be preferable to the older Abrams- or Ramel-needle by providing a larger specimen along with easier han‐ dling. It is recommended, that at least six biopsies are obtained, since they will not regular‐

*5.3.5. Invasive bioptic and endoscopic studies*

278 Tuberculosis - Current Issues in Diagnosis and Management

**Table 1.** Role of Nucleic-Acid-Amplification-Techniques (NAAT) in the Diagnosis of Tuberculous Pleuritis

ly contain a representative parietal pleural sample [74]. With this premise and the expected yield of at least two valid samples closed needle biopsy should be diagnostic in tubercu‐ lous pleurisy in ~ 60 % of cases, when histology and tissue-, as well as fluid-culture are being combined. In a major series (n=100 %) a 61 % positive yield was composed of 51 % biopsy yield and 28 % positive fluid culture (figure 4) [18, 55]. Distinctly higher yields have also been reported in the literature, leading in a collective review to an average sensitivity of 69 % (range 28-88 %) [75]. The difference and wide range is likely to be due to technical disparities and inclusion of data originating from largely different prevalence areas. In one study from a high prevalence area (South Africa) comprising 51 patients with undiagnosed pleurisy the positive closed needle yield in tuberculous pleurisy (histology+AFB-stain+culture) was 79%, when combined with pleural fluid ADA-determination and a lymphocyte/neutrophil ratio > 0.75 sensitivity increased to 93% at a specificity of 100% [76]. Thus with the parallel use of less invasive parameters needle biopsy approaches the diagnostic potency of more inva‐ sive techniques and would appear the second best diagnostic option in areas with limited medical logistics and resources.

*Medical thoracoscopy* as a *"window to the pleural space"* [77] is the gold standard procedure in the evaluation of exudative pleural effusion, hence also pleural pleurisy. The current and future role of thoracoscopy needs to be redefined for its diagnostic and interventional efficacy in the light of its close historical affiliation with TB. In fact tuberculosis was already a major focus of medical thoracoscopy or *"pleuroscopy"* as referred to and initiated by JACOBAEUS back in

**Figure 4**: Single and cumulated yield (%) of various microbiological and

bioptical investigations in tuberculous pleurisy

According to Loddenkemer et al. **Figure 4.** Single and cumulated yield (%) of various microbiological and bioptical investigations in tuberculous pleurisy

1910 [78]. Anticipating modern minimally invasive surgical techniques, now all included under the heading *video-assisted thoracic surgery (VATS),* his pioneering approach to thoraco‐ scopy was basically interventional with the intention to optimize pneumolysis and to break strands for artificial pneumothorax induction in pulmonary TB *("Jacobaeus operation")*. However the ability to visualize major portions of the pleural surface, to intervene in the presence of membranes, adhesions and septae with the option of numerous dedicated biopsies also ensures optimum diagnostic results that are reflected in a yield of 94-99 % as confirmed in decades of clinical experience [18, 77-81]. At thoracoscopy tuberculous pleurisy usually appeals to the experienced investigator with characteristic and fairly diagnostic inflammatory patterns. Reference 55

**•** One may present with abundant fibrinous membranes, septae, loculations and diffuse inflammatory thickening of the parietal and visceral pleura as the prevailing pattern. An example of this endoscopic pattern is shown in figure 5.

scopic results are combined with aforementioned techniques positive results may be aug‐

**Figure 5.** Typical thoracoscopic aspect of fibrin-type multi-loculated effusion including septae and chambers in tuber‐

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 281

**•** With the reasonable diagnostic certainty of visual findings combined with an immedi‐ ate histological yield of > 90 % it allows instant implementation of antituberculous

**•** The percentage of positive TB-cultures obtained from biopsies and fibrous membranes may be twice as high (78 %) as from needle biopsies and pleural fluid combined (39 %) [77]. This

**•** Complete removal and subsequent drainage of pleural fluid with pulmonary re-expansion provides instant relief to the patients and warrants better healing and outcome options (see

mented to virtually 100 % (fig. 2) [18].

Male 48 years, pleuritis tuberculosa exsudativa

chemotherapy

culous pleurisy

section on therapy).

Thoracoscopy also provides a number of additional advantages:

in turn provides superior opportunity for drug susceptibility testing.


Similarly to closed needle biopsy a sufficient number of biopsies – at least three- should be obtained to warrant optimum and representative results. This may often require mechanical debridement of membranes and septae to gain access to the inflamed pleura. When thoraco‐

Male 48 years, pleuritis tuberculosa exsudativa

1910 [78]. Anticipating modern minimally invasive surgical techniques, now all included under the heading *video-assisted thoracic surgery (VATS),* his pioneering approach to thoraco‐ scopy was basically interventional with the intention to optimize pneumolysis and to break strands for artificial pneumothorax induction in pulmonary TB *("Jacobaeus operation")*. However the ability to visualize major portions of the pleural surface, to intervene in the presence of membranes, adhesions and septae with the option of numerous dedicated biopsies also ensures optimum diagnostic results that are reflected in a yield of 94-99 % as confirmed in decades of clinical experience [18, 77-81]. At thoracoscopy tuberculous pleurisy usually appeals to the experienced investigator with characteristic and fairly diagnostic inflammatory

**Figure 4.** Single and cumulated yield (%) of various microbiological and bioptical investigations in tuberculous pleurisy

Reference 55

**Figure 4**: Single and cumulated yield (%) of various microbiological and

**Medical** 

**28 99**

**100**

According to Loddenkemer et al.

**thoracoscopy**

bioptical investigations in tuberculous pleurisy

**Pleural fluid thoracentesis**

**•** One may present with abundant fibrinous membranes, septae, loculations and diffuse inflammatory thickening of the parietal and visceral pleura as the prevailing pattern. An

**•** A second characteristic feature is a more or less intensive seeding of the pleural surface with solid or caseous, sago-like nodules and only scanty fibrin deposits as shown in figure 6. Although usually fairly small, major nodules as also shown in figure 6 may easily be

**•** *Tuberculous empyema* as exemplified in figure 7 may be visually indistinguishable from nonspecific bacterial empyema unless calcifications, irreversible lung trapping or suspect

Similarly to closed needle biopsy a sufficient number of biopsies – at least three- should be obtained to warrant optimum and representative results. This may often require mechanical debridement of membranes and septae to gain access to the inflamed pleura. When thoraco‐

example of this endoscopic pattern is shown in figure 5.

**61**

pulmonary lesions suggest a tuberculous origin.

confused with malignant lesions.

patterns.

**Closed needle** 

280 Tuberculosis - Current Issues in Diagnosis and Management

**51** 

According to Loddenkemer et al. [55]

**biopsy**

**Figure 5.** Typical thoracoscopic aspect of fibrin-type multi-loculated effusion including septae and chambers in tuber‐ culous pleurisy

scopic results are combined with aforementioned techniques positive results may be aug‐ mented to virtually 100 % (fig. 2) [18].

Thoracoscopy also provides a number of additional advantages:


Male 24 years, pleuritis exsudativa tuberculosa

**Figure 6.** Typical thoracoscopic aspect of sago-type disseminated small and larger nodules both of the parietal and visceral pleura giving rise to confusion with malignancy

**6. Therapy options**

ing bioptic lesion and circumscript coin-like pleural thickening

Male patient, 48 yrs

**6.1. Systemic therapy**

Basically systemic therapy of tuberculous pleurisy in the moderately ill patient neither differs in intensity nor duration from antituberculous chemotherapy of pulmonary and other organ tuberculosis in general. Current short term recommendations for non-complicated pulmonary and extrapulmonary organ tuberculosis call for a quadruple drug therapy in the 2-month acute phase in the combination of 5 mg/kg Isoniacid (INH), 10 mg/kg Rifampicin (RMP), 30-35 mg/ kg Pyrazinamid (PZA) and 20-25 mg/kg Ethambutol (EMB) or 15 mg/kg Streptomycin (SM), where daily alternation of the SM and EMB component may be preferable [82]. In the second 4-month stabilizing phase a INH/RMP dual therapy is recommended. Until the 1990-years a triple therapy in the initial phase for Tb was considered safe enough in view of a low incidence of primary drug resistance. The quadruple therapy recommendation is therefore an amend‐ ment to a meanwhile globally changed drug susceptibility situation. Thus in an un-clarified clinical setting the extent of drug resistance expectation will modify treatment strategies. The

**Figure 7.** Typical thoracoscopic aspect of tuberculous ("specific") empyema showing putrid parietal coverings includ‐

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 283

**•** In addition thoracoscopy may be easily expanded to an adjuvant therapeutic intervention by breaking adhesions and debridement of membranes as also discussed in the section on therapy.

In the overall assessment of biopsy techniques the experienced investigator will therefore bypass closed needle biopsy and prefer thoracoscopy. Closed needle biopsy however will remain the second best alternative if


In summary, for the diagnosis of tuberculous pleurisy it appears and remains a well-founded clinical policy to push for the recovery of biopsy specimens whenever possible and to combine these with less invasive test results to ensure optimum management of the condition.

#### Male patient, 48 yrs

**Figure 7.** Typical thoracoscopic aspect of tuberculous ("specific") empyema showing putrid parietal coverings includ‐ ing bioptic lesion and circumscript coin-like pleural thickening

#### **6. Therapy options**

#### **6.1. Systemic therapy**

**•** In addition thoracoscopy may be easily expanded to an adjuvant therapeutic intervention by breaking adhesions and debridement of membranes as also discussed in the section on

**Figure 6.** Typical thoracoscopic aspect of sago-type disseminated small and larger nodules both of the parietal and

In the overall assessment of biopsy techniques the experienced investigator will therefore bypass closed needle biopsy and prefer thoracoscopy. Closed needle biopsy however will

**•** in the presence of clinical obstacles such as contraindications or mal-detachment of the lung

In summary, for the diagnosis of tuberculous pleurisy it appears and remains a well-founded clinical policy to push for the recovery of biopsy specimens whenever possible and to combine

these with less invasive test results to ensure optimum management of the condition.

therapy.

remain the second best alternative if

Male 24 years, pleuritis exsudativa tuberculosa

282 Tuberculosis - Current Issues in Diagnosis and Management

visceral pleura giving rise to confusion with malignancy

**•** there is no logistic option for thoracoscopy or

due to adhesions or advanced obliteration of the pleural space.

Basically systemic therapy of tuberculous pleurisy in the moderately ill patient neither differs in intensity nor duration from antituberculous chemotherapy of pulmonary and other organ tuberculosis in general. Current short term recommendations for non-complicated pulmonary and extrapulmonary organ tuberculosis call for a quadruple drug therapy in the 2-month acute phase in the combination of 5 mg/kg Isoniacid (INH), 10 mg/kg Rifampicin (RMP), 30-35 mg/ kg Pyrazinamid (PZA) and 20-25 mg/kg Ethambutol (EMB) or 15 mg/kg Streptomycin (SM), where daily alternation of the SM and EMB component may be preferable [82]. In the second 4-month stabilizing phase a INH/RMP dual therapy is recommended. Until the 1990-years a triple therapy in the initial phase for Tb was considered safe enough in view of a low incidence of primary drug resistance. The quadruple therapy recommendation is therefore an amend‐ ment to a meanwhile globally changed drug susceptibility situation. Thus in an un-clarified clinical setting the extent of drug resistance expectation will modify treatment strategies. The current policy in the case of tuberculous pleurisy therefore holds, that in lone and paucibacillar pleurisy (without lung parenchymal lesions) after immediate quadruple therapy a downgrading to a historical triple scheme is safe enough, provided full drug susceptibility is warranted. In the presence of lung parenchymal involvement the full standard scheme would however apply. The current average drug resistance probability is reflected in one major series (n=78) with a rate of 6.4 %, being probably representative for Middle Europe [55].

catheter technique and comparing a loculated streptokinase group (n=22) with a loculated normal saline irrigation group (n=22), reported significantly better outcome both in clinical terms of imaging and functional criteria [86]. Additional future evidence provided, this would seem an encouraging step towards further improvement in acute tuberculous pleurisy

Tuberculous Pleural Effusion http://dx.doi.org/10.5772/54955 285

*Surgery* in the era of antituberculous chemotherapy is only exceptionally required in the management of tuberculous involvement of the pleura. Remaining indications refer to rare instances of previously mentioned tuberculous empyema and in particular its complications. Specific issues in this context would be excessive membrane formation with trapped lung and significant long term pulmonary encasement due to fibrothorax. Due to the scarcity of pertinent cases and studies (at least in the western hemisphere) there are no generally accepted surgical guidelines for the management of these conditions. Surgical decisions must be created in an individual case-determined approach. A reasonable policy would appear to perform lone or combined empyemectomy/pleurectomy, also termed *early decortication* in clinically severe and functionally disabling conditions refractory to medical efforts. These indications may be amenable to video-assisted thoracic surgery (VATS)-based interventions. Formal thoracotomy would however be required if it comes to additional lung parenchymal resection or thoraco‐ plasty in rare complicated cases e.g. with persisting pyopneumothorax with or without

A different issue is severe, chronically trapped lung due to fibrothorax. A reserved approach to surgical strategies is generally advised because unexpected long term remission of inflammato‐ rypeelsissometimesimpressing.Althoughdecorticationhasbeenperformedasearlyas6weeks after the precipitating insult (empyema), the indication to *late decortication* is basically dis‐ cussed in the context of definitely and irreversibly trapped lung (fibrothorax) i.e. when at least 6monthshaveelapsed.Withafocusonrepairoflungfunctionandpreventionof chestdeformity most investigators agree that the indication requires a significant decrement of lung function (TLC<60%pred.,reductionofperfusion>50%)andlevelofdeformityintheabsenceofsignificant calcifications (*pleuritis calcarea*). Even then with extensive fibrotic fusion of both pleural sheaths not only will surgery be fraught with considerable technical problems but also the certainty and

There are largely diverging data as to the prevalence of fibrothorax and permanent pleural thickening as the most important sequel of pleural TB. In one source based on standard radiographs in pleuritis exudative tuberculosa a percentage as high as 49 % has been given [32]. With the strict definition of fibrothorax as a pleural membrane of at least 5 mm thickness extending across major portions of the hemithorax and persisting > 8 weeks after initiation of therapy a figure of ~ 5 % is a more likely and widely accepted rate of this complication. The intensity of pleural inflammation expressed as interleukin levels and derangement of bio‐ chemical parameters is assumed to be to some extent predictive for this complication. In one study residual pleural thickening was indeed significantly correlated with the magnitude of

trapped lung due to a large, medically intractable broncho-pleural fistula.

extent of functional improvement may not be predictable and warranted.

the intitial change of inflammatory glucose-, pH- and TNF-α-levels [87].

**6.3. Sequels and prognosis**

management.

The addition of an oral or parenteral steroid regimen to antituberculous drug therapy has been discussed controversially. The rationale put forward for this approach focuses on


Three valid clinical studies employing a randomized, double-blind controlled design may be considered to have basically settled the issue [83, 84, 85]. These studies consistently showed, that a tapering steroid therapy for 4 and up to 12 weeks starting with 0.5, 0.75 and 1.0 mg/kg/ day prednisone added to a standard antituberculous drug regimen, although mitigating and shortening the clinical course to a moderate extent in two studies, did not alter any of the outcome endpoints (clinical status, effusion resolution, pleural sequelae, lung volume and gas exchange). In conclusion from these data, steroids would generally not appear indicated in TB-pleurisy, a reasonable practice however would be a temporary use in the presence of a severe febrile and consumptive clinical course. Their long term use for the prevention of fibrotic sequels would appear obsolete.

#### **6.2. Local therapy**

Local therapy is an option, which is usually directly derived from a thoracoscopic approach to the management of the condition. First of all it needs to be emphasized that the (possibly complete) evacuation of pleural effusion is already an important topic treatment approach. While this can basically be achieved by non-endoscopic techniques like simple thoracentesis and small bore catheters as well, there is no doubt, that thoracoscopy will be disparately more effective due to the ability of visual guided optimum positioning and the use of large bore drains. In addition there is ample clinical evidence, that expert medical thoracoscopy can open intrapleural loculations and chambers, completely evacuate sequestrated effusion compart‐ ments and also to some extent produce effective debridement of membranes. Although no controlled study has so far proven the value of such efforts, from the view of the expert endoscopist it would appear a straightforward and convincing approach. Together with the early induction of antituberculous chemotherapy it might be responsible for the fact that in our institution over more than two decades of experience none of the patients needed decor‐ tication subsequently.

Another more recently discussed approach in topical therapy would be, by a rationale analogue to non-specific bacterial empyema, the use of fibrinolysis (streptokinase) which even need not necessarily be linked to an endoscopic protocol. There is so far only scanty experience [85]. However one fairly comprehensive study from Taiwan using a non-endoscopic pigtail catheter technique and comparing a loculated streptokinase group (n=22) with a loculated normal saline irrigation group (n=22), reported significantly better outcome both in clinical terms of imaging and functional criteria [86]. Additional future evidence provided, this would seem an encouraging step towards further improvement in acute tuberculous pleurisy management.

*Surgery* in the era of antituberculous chemotherapy is only exceptionally required in the management of tuberculous involvement of the pleura. Remaining indications refer to rare instances of previously mentioned tuberculous empyema and in particular its complications. Specific issues in this context would be excessive membrane formation with trapped lung and significant long term pulmonary encasement due to fibrothorax. Due to the scarcity of pertinent cases and studies (at least in the western hemisphere) there are no generally accepted surgical guidelines for the management of these conditions. Surgical decisions must be created in an individual case-determined approach. A reasonable policy would appear to perform lone or combined empyemectomy/pleurectomy, also termed *early decortication* in clinically severe and functionally disabling conditions refractory to medical efforts. These indications may be amenable to video-assisted thoracic surgery (VATS)-based interventions. Formal thoracotomy would however be required if it comes to additional lung parenchymal resection or thoraco‐ plasty in rare complicated cases e.g. with persisting pyopneumothorax with or without trapped lung due to a large, medically intractable broncho-pleural fistula.

A different issue is severe, chronically trapped lung due to fibrothorax. A reserved approach to surgical strategies is generally advised because unexpected long term remission of inflammato‐ rypeelsissometimesimpressing.Althoughdecorticationhasbeenperformedasearlyas6weeks after the precipitating insult (empyema), the indication to *late decortication* is basically dis‐ cussed in the context of definitely and irreversibly trapped lung (fibrothorax) i.e. when at least 6monthshaveelapsed.Withafocusonrepairoflungfunctionandpreventionof chestdeformity most investigators agree that the indication requires a significant decrement of lung function (TLC<60%pred.,reductionofperfusion>50%)andlevelofdeformityintheabsenceofsignificant calcifications (*pleuritis calcarea*). Even then with extensive fibrotic fusion of both pleural sheaths not only will surgery be fraught with considerable technical problems but also the certainty and extent of functional improvement may not be predictable and warranted.

#### **6.3. Sequels and prognosis**

current policy in the case of tuberculous pleurisy therefore holds, that in lone and paucibacillar pleurisy (without lung parenchymal lesions) after immediate quadruple therapy a downgrading to a historical triple scheme is safe enough, provided full drug susceptibility is warranted. In the presence of lung parenchymal involvement the full standard scheme would however apply. The current average drug resistance probability is reflected in one major series

The addition of an oral or parenteral steroid regimen to antituberculous drug therapy has been

**•** improved outcome by prevention of sequels in terms of pulmonary encasement and

Three valid clinical studies employing a randomized, double-blind controlled design may be considered to have basically settled the issue [83, 84, 85]. These studies consistently showed, that a tapering steroid therapy for 4 and up to 12 weeks starting with 0.5, 0.75 and 1.0 mg/kg/ day prednisone added to a standard antituberculous drug regimen, although mitigating and shortening the clinical course to a moderate extent in two studies, did not alter any of the outcome endpoints (clinical status, effusion resolution, pleural sequelae, lung volume and gas exchange). In conclusion from these data, steroids would generally not appear indicated in TB-pleurisy, a reasonable practice however would be a temporary use in the presence of a severe febrile and consumptive clinical course. Their long term use for the prevention of fibrotic

Local therapy is an option, which is usually directly derived from a thoracoscopic approach to the management of the condition. First of all it needs to be emphasized that the (possibly complete) evacuation of pleural effusion is already an important topic treatment approach. While this can basically be achieved by non-endoscopic techniques like simple thoracentesis and small bore catheters as well, there is no doubt, that thoracoscopy will be disparately more effective due to the ability of visual guided optimum positioning and the use of large bore drains. In addition there is ample clinical evidence, that expert medical thoracoscopy can open intrapleural loculations and chambers, completely evacuate sequestrated effusion compart‐ ments and also to some extent produce effective debridement of membranes. Although no controlled study has so far proven the value of such efforts, from the view of the expert endoscopist it would appear a straightforward and convincing approach. Together with the early induction of antituberculous chemotherapy it might be responsible for the fact that in our institution over more than two decades of experience none of the patients needed decor‐

Another more recently discussed approach in topical therapy would be, by a rationale analogue to non-specific bacterial empyema, the use of fibrinolysis (streptokinase) which even need not necessarily be linked to an endoscopic protocol. There is so far only scanty experience [85]. However one fairly comprehensive study from Taiwan using a non-endoscopic pigtail

(n=78) with a rate of 6.4 %, being probably representative for Middle Europe [55].

discussed controversially. The rationale put forward for this approach focuses on **•** the assumption of a shorter, attenuated clinical course in the severely ill patient,

fibrothorax.

sequels would appear obsolete.

284 Tuberculosis - Current Issues in Diagnosis and Management

**6.2. Local therapy**

tication subsequently.

There are largely diverging data as to the prevalence of fibrothorax and permanent pleural thickening as the most important sequel of pleural TB. In one source based on standard radiographs in pleuritis exudative tuberculosa a percentage as high as 49 % has been given [32]. With the strict definition of fibrothorax as a pleural membrane of at least 5 mm thickness extending across major portions of the hemithorax and persisting > 8 weeks after initiation of therapy a figure of ~ 5 % is a more likely and widely accepted rate of this complication. The intensity of pleural inflammation expressed as interleukin levels and derangement of bio‐ chemical parameters is assumed to be to some extent predictive for this complication. In one study residual pleural thickening was indeed significantly correlated with the magnitude of the intitial change of inflammatory glucose-, pH- and TNF-α-levels [87].

Caseous tubercus pleurisy and specific empyema respectively is in its natural course and in prognostic terms an entirely different entity. These patients will invariably and typically develop an extensive calcified fibrothorax (pleuritis calcarea) with or without concomitant chest deformity. Also chronic non-specific lung disease (COPD) with or without bronchiecta‐ sis, late TB-exacerbations and internal or external fistulisation (specific empyema necessitans) may develop. Anecdotical occurrence of non-HODGKIN lymphomas arising from long term smouldering encasements has also been described.

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