In the name of God
Shiraz E-Medical Journal
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Resident, Department of Internal Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Pleural tuberculosis (TB) is a major treatable cause of exudative pleural effusions. The frequency of pleural effusion in TB patients was approximately 31%. Pleural involvement may be primary, secondary to pulmonary TB (e.g., miliary TB) or post primary (reactivation) TB pleurisy. TB empayema is a chronic active pleural infection that is a more complicated form of the pleural TB. Clinical presentation of the pleural TB may be subtle or severe, with pleuritic chest pain, nonproductive cough, fever, dyspnea, night sweat and weight loss. Diagnostic tests include thoracocenthesis, sputum smear and culture, pleural biopsy, Tuberculostearic acid, ADA, PCR and d-INF. Pleural TB should be treated with standard anti-TB regimen. Thoracocenthesis is needed just for symptom relief and has no therapeutic effect. Corticosteroids, although may help in faster recovery, may cause pleural adhesions. For TB empayema, in addition to standard chemotherapy, surgical drainage is also mandatory.
Pleural tuberculosis (TB) is a major treatable cause of exudative pleural effusions(1). Among the extrapulmonary presentations of TB, pleural TB is second only after TB lymphadenitis (2). In one study, the frequency of pleural effusion in TB patients was approximately 31% (3). Pleural reaction in HIV patients with TB is seen in up to 37% of cases(4). A recent study from South Carolina found a higher incidence of pleural effusion in HIV (11%) than in non-HIV patients (6%) with TB. In another study in sub-Saharan region, four fifth of patients with pleural TB were HIV positive.
data suggest that HIV patients tend to develop TB pleurisy in the early stages
of immunosuppression (3). The prevalence of pleural effusion in TB
HIV patients with CD4+ T lymphocyte count >200 cell/ml was 27% while it was
only 10% in patients with CD+4 T-lymphocyte <200 cell/ml (3,5).
Pleural TB is more common among men. Incidence increases with increasing age between ages 5 and 45 years(6). The mean age of occurrence of TB pleurisy has been reported to be 34.1± 18.1 years(7).
Mechanism of pleural involvement:
pleura may be affected in three different ways:
1- Effusion which develops within a few months of primary infection in children and young adults.
2- Effusion developing as a result of lung disease in older adults. Rarely may this go on to purulent effusion. (empayema)
3- Rupture of a tuberculous cavity and escape of air into the pleural space, with resultant pynopneumothorax.
Primary pleural TB:
pleural TB has been considered a manifestation of primary TB seen largely in
children (1,2,9) even some authors used this finding as a criterion
for primary TB(1). In
recent years, the mean age of these patients has gradually risen(7).
The increased prevalence of pulmonary TB in young adults is thought to be related to healthy susceptible individuals living or working in crowded environments or under poor socioeconomic conditions(1).
Primary TB in the elderly may be related to some poor living conditions, with increased susceptibility caused by chronic debilitating diseases and resulting immunosuppression.
The current hypothesis for the pathogenesis of primary TB pleural effusion is that a subpleural caseouse focus in the lunge ruptures into the pleural space (1,3,7,8,9) within 6-12 weeks after a primary infection(3,7). Mycobacterial antigens enter the pleural space and interact with T-cells previously sensitized to mycobacteria, resulting in a delayed hypersensitivity reaction and accumulation of fluid(3). The fluid is generaly exudate but may be serousanguineous and usually contains few tubercle bacilli(1).
criteria refer to primary TB pleurisy(1):
a) Documentation of a newly positive PPD test
b) Chest roentgenogram within one year showing no evidence of paranchymal tuberculosis
c) Hilar adenopathy with or without pranchymal disease.
In 30% of patients there is no radiologic evidence of involvement of the lunge paranchyma; however, paranchymal disease is nearly always present in pathology(6). The effusions in primary pleural TB are generally small. There is no tendency for TB pleural effusion (TPE) to occur preferntially on either the right or left side(7), but one study from Edinburgh showed that TPE had a right sided preferance(11). Bilateral effusions are rare(6,7). About one fifth of patients suffer massive effusion(7). Commonly, effusions in primary TB pleuritis goes unnoticed and the process resolves spontaneously in 90% of cases(1,6,9). 65% of untreated patients develop active pulmonary or extrapulmonary disease within five years, if not treated(1,7,9,12).
Post-primary (reactivation) TB pleurisy:
pleurisy can occur from reactivation at any time after infection(13).
may occur if the patient's immunity is lowered(8). In recent years,
some authors reported that mean patients age with pleural TB has gradually
risen.(7) In one study, the mean age of patients with reactivation TB
was 44.6 years(10). The
diagnosis of TB pleurisy in older patients is more problematic because many of
these patients are deabilated or immunosuppressed(1,3,7). Coexisting
underlying diseases such as pleural malignancy which can commonly produce
pleural effusion may hamper establishment of the correct diagnosis(1).
These chext x ray show a unilateral, small to moderate pleural effusion, although
massive effusion have been noted(13). Paranchymal disease can be
detected radiographically by CT Scan in most patients.
Infiltration may be seen in the upper lobes or superior segments of the lower lobe(10). Paranchymal scarring may exist in the upper lobes, that is typical of TB reactivation. The effusion is almost always ipsilateral to the infiltrate and is a mark of active paranchymal disease(13).
Pleurisy with effusion complicating miliary TB:
Hematogenous dissemination occurs in miliary TB(8). TB pleural effusion may be rarely the result of hematogenous dissemination or contamination by adjacent infected lymph node(1). TB spreads to the blood stream from a recent primary infection or by reactivation of an old tuberculous lesions(8). Sometimes it enters the blood after a surgical operation on an organ containing a tuberculous lesion. It occurs in patients whose immunity is supposed. Pleural effusions occur in 10 to 30% of cases of miliary TB(9). These may be associated with other progressive extrapulmonary foci and involvement of other serous membranes. There is a history of gradual onset of fever, malaise and weight loss, usually over weeks(8). It may follow some other illness. There may be evidence of tuberculous lesion somewhere in the body. Sometimes there is enlargement of the liver or spleen. Chest x ray may show diffuse, evenly distributed, small shadows. They vary from vague shadows 1-2mm in diameter to large dense shadows 5-10mm in diameter. The effusions may be massive or bilateral in miliary TB(9).TB skin test may be negative and sputum smear is usually negative too(8).
empymea represents a chronic, active infection of the pleural space(14).
The inflammatory process may be present for years with a paucity of clinical
symptoms. It is a rare complication of TB and characterized by the presence of
thick pus, and visceral pleura is usually calcified(3). It
results from a large number of organisms spilling into the pleural space,
usually from rupture of a cavity or an adjacent paranchymal focus via a
bronchopleural fistula(6,14). TB
empyema is usually associated with evidence of pulmonary paranchymal disease on
chest films(6). On CT tumography show, a thick, calcified pleural and
rib thickening surrounding loculated pleural fluid. Patients often come to
attention at the time of a routine chest radiograph or after the development of
bronchopleural fistula or empyema necessitatis. The fluid is thick and cloudy
and may contain cholesterol, causing the fluid to look like chyle. (Pseudochylous
is a rare complication of patients with chronic TB pleuritis(3).
Analysis of pleural fluid usually demonstrates triglyceride level below 110mg/dl but the cholestrol level is usually elevated about 200mg/dl and frequently there are cholestrol crystals. TB chylothorax should be treated with the anti TB regimen even if there is no evidence of active TB. The pleural fluid is grossly purulent(14) and usually has a high WBC count, nearly all of them lymphocyte(6). Acid fast smear and mycobacterial cultures are usually positive(3,4,6,14) which makes pleural biopsy unnecessary(6).
Before anti TB drugs were available, TB empyema was almost always rapidly fatal(9). Death virtually never occurs in patients being treated with antituberculous therapy.
clinical presentation of TB pleurisy may be subtle or abrupt and severe(9).
one study, the disease began abruptly in 63% of patients as an acute illness
with fever and pleuretic chest pain, often mimicking acute pneumonea(4,6,15).
The symptoms most commonly reported in published series are: cough (71-94%),
fever (71-100%), chest pain (78-82%) and dyspnea(4). The
cough is usually nonproductive particularly when active pulmonary lesions are
not present(15). Night
sweats, chill sensation, dyspnea, weakness and weight loss are common
and chest pain were observed mainly in younger patients, and production cough
and dyspnea in older patients(16). Median duration of symptoms before
presentation is about 14 days for primary TB and 60 days in reactive disease(10).
effusions are thought to be rare(4).
The patients with TB pleural effusion and HIV have been symptomatic for a longer period and have additional symptoms such as tachypnea, night sweats, fatigue, diarrhea and have more chance for hepatomegaly, splenomegaly and lymphodenopathy. Negative skin test has been reported in up to 30% of immunocompetent and in up to 50% of HIV infected patients. Tuberculin skin test is ultimately positive in most nonanergic patients if repetitive tests are used(4). Physical examination reveals findings related to pleural involvement including splinting due to pain and reduced breath sounds and percussion dullness overlying the effusion. Pleural friction rub is reported in 10% of patients.
pleural effusions are not always easy to diagnose,(1,7) because the
typical features such as presence of a lymphocyte rich exudative pleural
effusion associated with caseous necrotic granuloma in pleural biopsy, positive
Ziehl Neelsen stains or lowenstein cultures of effusions or tissue samples, and
cutaneous sensitivity to PPD are not invariably present(7).
The diagnosis of pleural TB is generally established by analysis of pleural fluid and pleural biopsy(6). In recent years, numerous studies investigated possible biochemical markers such as ADA, ADA isoenzyme, lysozyme, INF- d and other lymphokines to improve diagnostic efficiency, but diagnosis is still sometimes difficult(7).
An initial diagnostic thoracocentesis is always indicated(8). The fluid is nearly always straw-colored exudative, although it may be slightly bloody(6). Cell counts are usually in range of 100 to 5000 per mililiter with more than 90% lymphocyte in two thirds of cases(3,6,9). However, 38% of cases in one series had predominantly PMN, and 15% had more than 90% PMN on the first tap(9). Repeated taps demonestrated a shift to lymphocytes. The effusions have high protein level (above 5g/dl) on greater than 50% of the serum protein concentration(1,6,9). The glucose is usually moderately low compared with serum values(1,9). It is generally greater than 60mg/dl and rarely less than 20mg/dl. The PH is always 7.3 or lower and may be as low as 7(9). LDH is more than 200U/dl(4). Direct examination of pleural fluid with Ziehl-Neelsen staining requires bacillar concentration of 10000/ml to be positive. There are usually only a few organisms present in the pleural space of cases with primary TB so smears of the pleural fluid are rarely positive (0 to 1%) (2,6,9). Mycobacterium tuberculosis is isolated by culture of pleural fluid in only 20 to 40% of patients with proved TB pleuritis(6,9)
Cultures require 2 to 6 weeks but the use of radiometric mycobactrium culture system (BACTEC) could overcome the problem of delay of the culture results and positive culture can be obtained in 18 days(3). As previously noted, acid fast smear and culture of fluid in TB empyema are usually positive. Cases complicating chronic pulmonary TB have positive pleural acid fast smear in 50% cases and positive culture in 60%, but it is less likely to see granuloma on pleural biopsy (25%) in these cases(9).
Sputom smear and culture:
Smears of sputum are rarely positive in primary cases and cultures are positive in primary cases only 25 to 33% of patients(9). In contrast, sputum smear is positive in 50% and culture is positive in 60% of reactivation cases.
The role of pleural biopsy in rapid diagnosis of TB pleurisy is well established(17). Finding acid fast bacilli by stains of biopsy specimen has been reported useful, but false positive has been recorded, so it has not proved reliable. Culture of pleural biopsy is superior for the detection of TB bacilli to culture of any other material available. At least 4 separate biopsy specimen of the pleura should be obtained(3). Three should be sent for histological studies and the last one should be cultured for M.Tuberculosis, since the pleural biopsy culture is sometimes positive when there are no granulomas in the pleura. With both histological and microbiological studies of the pleura, diagnostic yields as high as 86% have been reported for pleural TB. Repeated biopsy might be done if the first is negative and TB is suspected(18). It increases the yield to 80-90%(6).
Tuberculostearic acid (TBSA) is a structural component of M.Tuberculosis and other members of the actinomycetals organisms.(19) However, detection of TBSA in pleural aspirate is not a very useful diagnostic test, with many false positive and false negative. It is sensitivity and specificity is 69.6% and 52.3%, respectively. The detection of TBSA in pleural biopsies might be more useful.
ADAP "total pleural ADA level" is an enzyme which is typically found at high concentrations in pleural TB(20). Pleural activity of ADA is dependent on two principal isoenzymes, ADA1, and ADA2. ADA1 is found in all cells and ADA2 reflects monocyte/macrophage activation(3). Patients with TB pleurisy have predominantly ADA2, whilst those with empyema and parainfective effusions have mainly ADA1. Level of ADA p>40 IU may indicate pleural TB with sensitivity of (81-100%) and specificity of (83-100%)(20).
The usefulness of ADA in the diagnosis of TB pleurisy d1epends on the prevalance of TB (3). In populations with a high prevalence, the sensitivity and specificity of ADA are 95 and 90% respectively, but in populations with low prevalance, its specificity can be considerably lower.
The sensitivity and robustness of ADA activity in the diagnosis of pleural TB, together with its simplicity, speed, and low cost, urge the widespread implementation and routine utilization of this method in populations with a high prevalence of TB(2).
Anti TB therapy can reasonably be started in patients less than 3 years old with a pleural exudate and ADA higher than 47 U/L, if empyema is ruled out(3). The false positive cases are due to lymphoma, empyema, malignant neoplasms, and with rare instances of parapneumonic effusion and collagen vascular disease(2,20).
Stimulation of monocyte by phagocytosis of micro-organisms (M.Tuberculosis) allows the release of ADA2, which will consequently reduce the ADA1/ADAp ratio(7,20). A proportion of ADA1/ADAp <0.42 is a good indicator of TB pleurisy, with an accuracy of 99%, a sensitivity of 100%, and a specificity of 98.6%, thus correcting all ADAp false positive except for a single melanoma(20). So in cases of suspected false positive or negative ADAp levels, confirmation by the more efficacious ADA1/ADAp ratio is advocated.
PCR, which is based on the amplification of a specific genomic sequence of M. Tuberculosis, is theoretically highly specific(2). PCR has a sensitivity of (20-80%) (depending on genomic sequence amplified and the procedure used in extraction of DNA) and a specificity of 78-100% for pleural TB(3). A recent Spanish study using a 126-bp segment of M. Tuberculosis complex specific insertion sequence in evaluation of pleural effusion, revealed a sensitivity and specificity of 81% and 98%, respectively for PCR(2). PCR is positive in 100% of culture positive TB pleural fluids and only in 30-60% of culture negative pleural fluids(3). However, the high biological sensitivity and specificity of PCR suggest that this method, when used in combination with ADA or INF-d levels, could improve the accuracy of the laboratory diagnosis of pleural TB(2). But routine use of PCR cannot be recommended at this time(3,21).
INF-d, a cytokine associated with T. helper, one type of cell mediated immunity, proved to be highly associated with a TB etiology of pleural effusion(2). It is the only test with a yield comparable to ADA in the diagnosis of TB pleurisy(3,4). But, since determining d-INF is more expensive than ADA, there is no reason to recommend its routine application(3). INF-d has a sensitivity of 85.7% and a specificity of 97.1.% for pleural TB, which has been confirmed by either culture or pleural biopsy(2). The sensitivity of test did not differ in HIV-positive and negative patietns(22).
Treatment of TB pleurisy:
pleural effusion may resolve over a period of several months (2-4m) without
treatment(2,9). Chemotherapy does not hasten resolution but failure
to diagnose and treat pleural TB can result in progressive disease and the
involvement of other organs in as many as 65% of patients.
Treatment of the hypersensitive variety of TB pleural effusion consists of a standard anti TB drug regimens(6). The current recommendation for all pulmonary and extrapulmonary TB is a 6 months regimen with a first phase of isoniazid (INH), rifampicin (R) and pyrazinamide (2) for the first 2 months, and a second phase of INH and R. for the next 4 months. (2HRZ/4HR)(3,21). Some investigators have shown that because of the low organism load, INH and R. for 6 months is adequate(13). Also some authors recommended 4 months treatment with 2HRZ/2HR for isolated TB pleurisy(23). Multiple thoracocentesis is not necessary once the diagnosis is established and treatment initiated(9), but it may be required to relieve symptoms(6).
Tube thoracostomy is rarely necessary. The use of corticosteoids may relieve symptoms more rapidly and increase absorption of pleural effusion (6,24), but the occurrence of pleural adhesion has not been shown to be influenced by the administration of corticosteroids(24). However, in one study, the administration of corticosteroids decreased the amount of pleural thickening in the initial two to six months.
Some authors suggested that in the absence of contraindications, corticosteroids should be routinely prescribed with anti TB chemotherapy in the management of TB pleural effusion(11). But some others say that this is rarely necessary and no long-term benefit has been shown(6,9). With chemotherapy, patients usually become afebrile with 2 weeks. However, fever may persist for as long as 6 to 8 weeks(13).The pleural effusions usually resolve by the 6th week, but it can persist for 3 to 4 months. The amount of residual pleural scarring is small in simple TB pleural effusion(6).
Treatment of empyema:
standard chemotherapy should be instituted for TB empyema, it is unlikely to
clear the pleural space infection, probably because the penetration of the anti
TB agent into pleural cavity is limited(4,6). For
this reason surgical drainage is often necessary(6). This may be
accomplished with a standard thoracostomy tube or extrapleural pneumonectomy(3,4,6).
Sometimes it may be necessary to remove a localized empyema by operation(8). Unfortunately, many of these patients are poor surgical candidates(4).
Successful treatment without tube drainage or surgery has been reported with repeated thoracoccentesis and 24 months of triple drug therapy. In contrast to hypersensitivity type of pleural effusion, a TB empyema is associated with extensive residual pleural scarring and calcification(6).Pleural fibrosis may have an important effect on lung function with resultant shrinkage of the chest wall and later breathlessness(6,8). Also this predisposes the patient to recurrent pneumonias(6). Corticosteroid has no role in treating this form of pleural effusion(6).
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