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TUBERCULOSIS PLEURAL EFFUSIONS AND A CASE OF EMPYEMA

NECESSITATIS (NECESSITANS)
David Griffith, MD

CASE HISTORY
A 15 year old pregnant female presented to the emergency department of a local hospital with
respiratory distress at 32 weeks gestation. She had failed to gain weight appropriately during her
pregnancy and throughout her third trimester of pregnancy had cough, shortness of breath and night
sweats. She had an abnormal chest radiograph suggesting miliary tuberculosis and bilateral pleural
effusions left side greater than the right. The patient was sent by air ambulance to a tertiary referral
center where she was treated with broad spectrum antibiotic therapy in addition to multi-drug
antituberculosis therapy including coverage for possible drug resistant TB with isoniazid, rifampin
pyrazinamide, ethambutol, moxifloxacin and amikacin. Due to respiratory distress, labor was induced
and a healthy baby was delivered vaginally. Initial evaluation of the child showed no evidence of
tuberculosis.
The patient was noted on admission to have an anterior chest wall abscess. Thick, purulent fluid was
obtained which was very difficult to aspirate. The abscess fluid was AFB smear positive and
subsequently grew M TB sensitive to all first line antituberculous medications. Ultrasound and CT
examination following delivery suggested that the pleural fluid was too thick to be aspirated or
evacuated. Following delivery, the patient was able to produce sputum that was smear and
subsequently culture positive for M TB. The patient responded well to the antituberculosis therapy in
general, including, resolution of fever, decrease in cough, normalization of albumin and improvement in
the bilateral pulmonary densities and effusions. The chest mass decreased in size following the initial
aspiration and then enlarged to a 2 X 2 cm tender area of fluctuance without erythema in her right
lower anterior chest. A CT scan of the chest revealed bilateral pleural effusions with extenstion of the
pleural fluid on the right between her ribs into the soft tissues of her anterior chest wall (emypema
necessitatis). After approximately 4 weeks of antituberculosis therapy she underwent a right video
assisted thoracoscopy (VATS) with complete decortication of the anterior chest wall and pleural
abscess. The surgeon noted a clear tract through the chest wall into the right pleural space. The
patient had an uneventful postoperative recovery with no drainage from the surgical incision.
CASE DISCUSSION
PATHOPHYSIOLOGY
Mycobacterium tuberculosis affects the pleura at different stages of pulmonary and systemic disease as
the pleura can be involved in either primary or post-primary (reactivation) TB disease. In primary
disease, pleural TB occurs as a result of mycobacterial antigen entering the pleural space, perhaps due
to the rupture of a subpleural caseous focus, causing a delayed hypersensitivity (DTH) immunogenic
reaction mediated primarily by CD4 cells but also involving other inflammatory cells and a complex
array of inflammatory mediators including interferon gamma and tumor necrosis factor alpha. The
initial cellular reaction in the first 2-5 days is macrophage predominate but from then onward,
lymphocytic cells generally predominate and PPD reactivity is usually found. Paradoxically, PPD
reactivity may be delayed in some patients, possibly as a consequence of the sequestration of DTH
mediating cells, such as CD4 cells, in the pleural space. This form of TB pleural effusion is
pauci-bacillary and tubercle bacilli are typically difficult to isolate in this setting. In contrast,
tuberculous emypema is a chronic active infection of the pleural space that contains a large number of
tubercle bacilli, also likely introduced into the pleural space via rupture of a sublpleural caseous focus.
Other factors predisposing to this type of effusion may be progression of a primary TB pleural effusion
or direct extension of infection into the pleural space from a tubercle on the surface of the lung or from
thoracic lymph nodes. Hematogenous spread of the organism to the pleural space is also possible,
especially in immune compromised patients. The accumulation of fluid is multi-factorial, but the
primary mechanism is likely intense inflammation that impedes lymphatic drainage of the pleural
space.
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EPIDEMIOLOGY
The frequency of tuberculous pleural effusions varies by location. In the United States they are
relatively rare, occurring in perhaps 3-5% of all tuberculosis cases, and are reportedly the 10th most
common cause of pleural effusion in the U.S. (see below). In contrast, in areas of the developing world
where TB is more endemic than in the U.S., TB is the most common cause of pleural effusion,
especially exudative pleural effusion. In the industrialized world, pleural effusion with TB is more likely
due to reactivation of TB disease whereas in the developing world it is more likely a manifestation of
progressive primary disease. In that context, HIV coinfection and multidrug resistant TB are altering
the epidemiology of TB pleuritis. In one series, the incidence of TB pleural effusions in HIV/TB
coinfected patients was as high as 90%.
CLINICAL PRESENTATION
For some patients with TB pleural effusions associated with primary tuberculosis, the appearance of
pleural fluid may occur without symptoms and the pleural effusion is recognized only when a chest
radiograph is done as part of a routine evaluation. This combination of minimal symptomotology and
lack of sensitive culture techniques (see below) would suggest that tuberculous effusions, especially
those associated with primary disease are under-diagnosed. More commonly, however, the illness is
manifested by onset of fever, cough, pleuritic chest pain and dyspnea. 90% of patients have
symptoms for less than one month. TB pleural effusions affect one hemithorax in 90-95% of cases.
Massive effusions are unusual. Untreated pleural effusion as a manifestation of primary TB is usually a
self-limited inflammatory process. In 90% of cases, there is complete resolution, even without
treatment, spontaneously occurring within weeks to months. However, even this relatively benign and
self-limited process is an important harbinger of the progression to active pleuro-pulmonary or extrapulmonary disease which occurs in 40-60% of patients with untreated pleural effusions within 5 years.
Residual pleural thickening is also common and may occur in 50% of cases. Patients with TB empyema
are invariably symptomatic with fever, sweats, cough, dyspnea and pleuritic chest pain. This type of
effusion will not spontaneously resolve and may progress to more serious complications such as
empyema necessitatis.
DIAGNOSIS
Tuberculin skin testing or interferon gamma release assay (IGRA). A positive PPD or IGRA, alone, is
not adequate for diagnosing TB pleural effusion but can be important supportive evidence in the
appropriate context. Conversely, a negative PPD or IGRA does not rule out the diagnosis. As noted
previously, sequestration of DTH cells in the pleural space may delay the onset of the positive PPD, but
the majority of patients with TB pleural effusion (excluding patients with advanced immune
suppression) will at some point in the course of the illness have a positive PPD or IGRA.
Thoracentesis to obtain pleural fluid for cellular, biochemical and microbiological analysis is an
absolutely essential element for diagnosing tuberculous pleural effusions. There is no substitute for
obtaining pleural fluid for analysis. TB effusions are exudative, sometimes with protein concentrations
> 5 g/dL. The differential cell count is almost invariably lymphocyte predominant (>50%
lymphocytes), although for some effusions, especially TB emypema, in the first few weeks there may
be a polymorphonuclear (PMN) cellular predominance that evolves into the classic lymphocyte
predominant effusion. Cellular findings in the fluid that do not suggest TB effusion include a
differential cell count with > 5% mesothelial cells or > 10% eosinophils (unless there is concomitant
pneumothorax or intrapleural bleeding which can be associated with a high pleural fluid eosinophil
count).
Pleural fluid should be sent for AFB staining and culture, even though microbiological analysis is not a
sensitive diagnositic tool. However, positive cultures remain the gold standard for diagnosis. AFB
smears are positive in only approximately 20-25 % of TB effusions, although that percentage would be
higher with TB emypema or in HIV coinfected patients. Cultures are positive in a many as 40% of TB
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CASE PRESENTATIONCONTINUED FROM PAGE 6

effusions, again higher with TB empyema and HIV coinfection. These figures vary with populations
studied and the type of TB effusion present, but they demonstrate the importance of ancillary testing
for confirming the diagnosis of TB effusion in a majority of patients.
Some patients, perhaps 20%, will also have evidence of parenchymal lung involvement associatedwith
TB effusion. The parenchymal involvement is usually on the same side of the chest as the effusion.
This percentage would likely be higher with the use of chest CT scanning. The yield from sputum
analysis is sometimes confirmatory with sputum smears positive in approximately 20% of patients.
Sputum AFB cultures may be positive in as many as 50% of patients with aggressive efforts to collect
sputum , such as sputum induction. As with pleural fluid specimens, the yield of sputum AFB analysis
varies with the population studied and the type of TB effusion.
Adenosine deaminase (ADA) is the enzyme that catalyzes the conversion of adenosine to inosine and
is found in high concentrations in TB pleural effusions. Values of ADA > 70 U/L are virtually diagnostic
of TB effusions and values < 40 U/L virtually exclude the diagnosis of TB effusion. The higher the ADA
value, the more likely TB is the diagnosis. The differential diagnosis of elevated ADA in a pleural
effusion includes empyema (bacterial) and rheumatoid pleuritis which can usually be eliminated as
possibilities after taking into account the other factors included in the pleural fluid analysis such as cell
type predominance in the pleural fluid. Overall, an ADA level > 40 U should raise suspicion of TB
pleural effusion. In one recent meta analysis the sensitivity and specificity of ADA for diagnosing TB
effusions were 92% respectively. ADA levels are widely available and relatively inexpensive . This test
is almost universally recommended for suspected TB pleural effusions, but clinically underutilized.
Some authors propose measurement of interferon gamma (IFG) in pleural effusions to differentiate TB
effusions from other etiologies. An IFG cutoff of 3.7 IU/ml in one study had a sensitivity of 98% and
specificity of 98% for diagnosing TB effusions. This test is not yet widely available or approved for use
in this setting.
Closed pleural biopsies, while potentially quite helpful when performed by experienced clinicians is a
procedure that is done with progressively less frequency due to declining numbers of clinicians who are
comfortable and experienced with this procedure. Currently, pleural biopsies are more likely done via
video assisted thoracoscopy (VATS) either by a pulmonary physician or thoracic surgeon. Pleural
biopsies have the advantage of demonstrating pathologic changes such as granulomatous inflammation
in the parietal pleura with AFB smears positive in 26% and cultures positive in 56 % in patient with TB
effusions. The differential diagnosis of granulomatous pleuritis includes fungal disease, sarcoidosis,
and rheumatoid disease. Pleural biopsies are generally reserved for patients who prove to be
diagnostic delimnas after other less invasive evaluation is inconclusive. Additionally, biopsies may be
necessary for patients in whom malignancy is a concern as malignant pleural effusions also present as
a lymyphocyte predominate exudates.
The nucleic acid amplification tests (NAAT) offer extremely high diagnostic specificity (> 95%) but
variable diagnositic sensitivity for non-respiratory specimens such as pleural fluid . Currently, neither
of the commercially available NAAT are FDA approved for use in the diagnosis of extra-pulmonary TB.
At some point, these test may prove to be a very valuable addition to the diagnostic evaluation of
pleural TB.
DIAGNOSIS SUMMARY
The diagnosis of TB pleural effusion includes clinical suspicion, radiographic confirmation of pleural
fluid, +/- radiographic evidence of parenchymal tuberculosis disease, thoracentesis with protein/LDH
measurement, cell count and differential, ADA level, AFB smear and culture. Sputum AFB smear and
culture (induced if necessary). Pleural biopsy would then be considered under some circumstances.

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TREATMENT
TB effusions associated with primary TB usually resolve spontaneously. For large effusions that cause
respiratory compromise, an attempt to externally drain the effusion by thoracentesis or by pigtail
catheter would be indicated. Indwelling tube thoracostomy is rarely necessary in this circumstance.
Appropriate antituberculosis therapy should also be instituted. The role of steroids is controversial in
this context with the exception of effusions associated with
immune reconstitution syndrome in which case, steroids may be
of substantial benefit, as with other manifestations of the IRIS
syndrome.
TB emypemas should also be approached initially in a
conservative fashion with institution of adequate multidrug
antituberculosis therapy and an attempt to drain the effusion by
thoracentesis or pigtail catheter. These effusions a) tend to
recur and b) tend to septate and loculate, so it may be difficult
to completely remove the fluid by external drainage.
Sometimes serial thoracenteses are necessary to minimize fluid
reaccumulation. Even complete removal of pleural fluid,
however, may not decrease the amount of residual pleural
thickening. Tube thoracostomy should only be considered under
specific circumstances such as bronchopleural fistula, which is
likely not to heal spontaneously. Chest tubes tend to be
associated with prolonged fluid drainage and may also be
(Above) Chest radiograph of a 50
associated with pleural-cutaneous fistulas when removed.
year old man with pleuropulmonary Pleural decortication is generally not considered until the patient
TB with loculated right pleural effu- has had at least 6 months of therapy and then only if there is
sion (TB emypema). Patient did not significant residual pleural fibrosis with pulmonary function
have significant improvement with
restriction. The majority of TB emypemas will improve
medication alone and had signifisufficiently (minimal residual pleural thickening/fibrosis) with
cant lung restriction at the end of
medication alone so that surgical intervention is not necessary.
therapy. He required thoracoscopic Surgery may be necessary with a thick residual pleural rind and
pleural decortication in the right
significant lung restriction or in the rare case of emypema
chest.
necessitatIs.
EMYPEMA NECESSITATIS
Empyema Necessitatis is a rare complication of tuberculous empyema whereby the infected pleural
fluid penetrates through the pleural space and chest cavity into the chest wall and then, without
intervention, may spontaneously drain through the skin of the chest wall, creating a pleural-cutaneous
fistula (and sometimes a bronch-pleuro-cutaneous fistula). Extension of the purulent fluid occurs along
the path of least resistance and along tissue planes. Increased pressure within the pleural loculation,
chonic inflammation, and necrosis with erosion and fluid extension all contribute to this process. TB is
reported to be the most common cause of empyema necessitates in the U.S. followed by
actinomycosis. Prior to the advent of effective antituberculosis drugs, empyema necessitatis was
associated with a high mortalitity. In the current era of effective anti-tuberculosis medication, the
occurrence and mortality of this process have dramatically declined. In fact, it has become so
unusual, that few current TB clinicians have experience with emypema necessitatis and few reference
texts or review manuscripts offer specific instruction or advice on handling this potentially dangerous
and disfiguring TB complication. The consensus appears to be that aggressive measures are necessary
including appropriate aggressive antituberculosis therapy, early surgical intervention, preferably by
VATS, with elimination of the abscess penetrating the chest wall and decortication of the adjacent
infected pleural space. Early recognition is the key to successful therapy. Consultation with clinicians,
including thoracic surgeons, experienced with empyema necessitatis is strongly advised.
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TEACHING POINTS and KEY CONCEPTS

1.

Pleural effusions are a relatively uncommon complication of tuberculosis but can occur with
primary tuberculosis, reactivation tuberculosis and as part of an immune reconstitution
response.

2.

Pleural effusions associated with primary tuberculosis are due to a delayed type
hypersensitivity response to tuberculosis antigens in the pleural space. These effusions are
generally self limited and resolve spontaneously.

3.

Tuberculous empyemas are due to persistence of M. tuberculosis organisms in the pleural

space that results in a purulent effusion that will not resolve spontaneously.

4.

The evaluation of pleural effusions in patients with suspected or diagnosed tuberculosis

requires a thoracentesis. Most primary care clinicians should be able to perform this
procedure. Ultrasound guidance is a useful adjunct for safely guiding the placement of the
thoracentesis needle/catheter.

5. Pleural fluid from the thoracentesis should be sent for

a.
b.
c.
d.

LDH and protein concentrations

Cell count and differential
AFB smear and culture
Adenosine deaminase (ADA) level

6.

The characteristic profile of a tuberculous pleural effusion is an exudate with a lymphocyte

predominance associated with an ADA level > 40 U/L. AFB cultures are positive in less than
50% of tuberculous effusions, but are highly specific when positive.

7.

Patients with pleural effusion or empyema who are suspected to have active TB should
have smears and cultures of sputum in addition to those done on the pleural fluid. Nucleic
acid amplification (NAA) should be considered if sputum is AFB smear negative as up to
80% of smear negative active TB will be positive by NAA. Sputum smears are negative in
50% of persons with active pulmonary TB. Even in the absence of obvious pulmonary
densities, sputum cultures will be positive 40-50% of patients with TB involving the pleural
space. Induced sputum should be attempted if the patient is not able to spontaneously
provide natural sputum. Having the patient try to obtain a specimen upon arising after a
warm shower may also be helpful if sputum induction is not available.

8.

In general, effusions associated with primary TB require intervention only if there is

respiratory compromise. TB empyemas should be drained by thoracentesis or pigtail
catheter if possible. Repeated procedures may be necessary for recurrent effusions. Tube
thoracostomy should be reserved for special circumstances such as TB empyema associated
with bronchopleural fistula.

9.

Surgical intervention (pleural decortication) for patients with TB empyemas is usually

reserved for patients who have been treated with adequate antituberculosis therapy at least
6 months and have large residual pleural fluid/fibrosis with significant lung restriction.

10.

Treatment of empyema necessitatis involves both adequate antituberculosis therapy and

surgical drainage of the chest wall abscess as well as the pleural space abscess with local
pleural decortication.

11.

For questions about management of TB pleural effusions, expert consultation should be

requested.

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(Above Left) 15 year old female with pleuropulmonary tuberculosis. Bilateral primarily nodular densities
in the lung parenchyma with loss of the right costophrenic angle due to a pleural effusion.

(Above Right) Chest radiograph of the same 15 year

old female after thoracoscopic drainage of the chest
wall abscess and tuberculous empyema in the right
pleural space with pleural decortication in the lower
right pleural space.

(Left)) Chest CT cut from the same 15 year old

female demonstrating extension of the pleural fluid
into the chest wall causing a bulge in the skin over
the abscess created in the chest wall.

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