Paediatric Respiratory Reviews 12 (2011) 2730

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Paediatric Respiratory Reviews

Mini-Symposium: Childhood TB in 2010

Pleural Tuberculosis in Children

Gilberto B. Fischer 1,3,*, Cristiano Feijo Andrade 2, Joao Bonfadini Lima 3
1

Professor of Paediatrics, Department of Paediatrics, Universidade Federal de Ciencias da Saude Porto Alegre, Rua coronel Bordini 830/509, CEP 90440-003
Thoracic Surgeon, Hospital da Crianca Santo Antonio, Hospital de Clnicas de Porto Alegre, Rua coronel Bordini 830/509, CEP 90440-003
3
Servico de Pneumologia, Hospital da Crianca Santo Antonio, Rua coronel Bordini 830/509, CEP 90440-003
2

EDUCATIONAL AIMS





THE READER WILL BECOME FAMILIAR WITH:

Epidemiologic data on Pleural Tuberculosis (PT) in children

The main clinical features of PT in children
The main radiologic ndings of PT in children
The main investigations for the conrmation of PT aetiology in children

A R T I C L E I N F O

S U M M A R Y

Keywords:
Pleural effusions
tuberculosis
child
diagnosis
X-rays

Pleural tuberculosis effusion (PTE) in children is a diagnosis which must be considered in isolated pleural
effusions in non-toxemic children. It is more common in children over 5 years of age. A history of close
contact with an adult with pulmonary tuberculosis reinforces the suspicion for its diagnosis. Pleural
effusion without any parenchymal lesion is the characteristic nding on the chest x-ray. However, in 20%
to 40% of patients, intrathoracic disease may also occur. Adenosine deaminase, interferon-gamma,
analysis of pleural uid and pleural biopsy are the main tools for diagnostic conrmation. Tuberculin
skin test may provide supporting evidence of tuberculous infection. PTE has a good prognosis in children
and no long term sequelae are expected.
2010 Elsevier Ltd. All rights reserved.

INTRODUCTION
Pleural tuberculosis is the most common presentation of
extrapulmonary tuberculosis and the most common cause of
pleural effusion worldwide1,2. There are few data regarding the
specic prevalence in children, since the majority of publications
on pleural tuberculosis (TB) include adolescents with adults. The
incidence of pleural disease varies among countries1. In high
income countries the prevalence of TB is increasing especially in
some ethnic groups3. In a study undertaken in Tanzania, 38% of all
TB cases had pleural involvement3. A Spanish series encompassing
175 cases of primary pulmonary tuberculosis in children over a 13
years period showed 39 (22%) patients with pleural TB4. In
contrast, from 202 cases of intrathoracic paediatric TB in Canada
only 7 (4%) presented with a pleural effusion5.
In this review, we outline the general aspects of pleural
tuberculosis, with particular attention to the diagnostic assessment. Early diagnosis is fundamental, although it may be

* Corresponding author. Servico de Pneumologia Pediatrica Av Independencia

155 Porto Alegre, Brazil CEP 90035-074 Fax: +555132148646.
E-mail address: gbuenof@terra.com.br (G.B. Fischer).
1526-0542/$ see front matter 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.prrv.2010.11.001

challenging in situations where the availability of some diagnostic

tools are limited.
Pathophysiology
Pleural TB begins with the rupture of a subpleural tuberculous
focus, which triggers an inammatory response mediated by Tcells (previously sensitized to the TB antigen). The exudative
pleural uid is due to a delayed hypersensitivity reaction to
Mycobacterium tuberculosis. The small number of bacilli in the
pleural uid produces a granulomatous reaction. This reaction
improves spontaneously but relapses in 60% of cases6,7.
The main cause of the inammatory process in the pleural space
is a Type IV hypersensitivity reaction. The TB bacillus invades the
pleural space after the rupture of a pulmonary caseous focus (Ghon
focus) in the subpleural region, by contiguity of the pulmonary
lesion, by rupture of a mediastinal lymph node or via hematogenous dissemination1,6,7.
The pleural effusion (PE) may occupy 30% to 60% of the affected
hemithorax. Rarely, a persistent loculated uid collection is
detected representing a tuberculous empyema, which corresponds
to an uncommon chronic, active infection of the pleural space. It
arises when a bronchopleural stula spills the content of a cavity or

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G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 2730

other parenchymal focus into the pleural space. Empyema

necessitans (an empyema in the pleural space reaching contiguous
regions such as subcutaneous tissue or even bone tissue) is a very
rare condition1,6.
Diagnosis
The diagnosis of pleural tuberculosis in children is usually made
from a history of contact with an adult with pulmonary TB
combined with suggestive clinical ndings (pleuritic chest pain,
chest pressure, dyspnoea, and cough), a positive tuberculosis skin
test (TST) and suggestive pleural uid analysis [exudate with
lymphocyte predominance and high protein]4. The suspicion of
pleural tuberculosis arises in a child or adolescent with fever, chest
pain, unilateral pleural effusion who appears non-toxaemic at the
clinical examination. Close contact with an adult with diagnosed
pulmonary tuberculosis or at least presenting clinical features of
TB (cough, weight loss, nocturnal sweats) reinforces the likelihood
of TB.
Imaging
On the chest x-ray, pleural uid is seen and septation of the
collection in the pleural space may be apparent on the ultrasound
images. Usually the pleural effusion is unilateral [Figure 1]. Pleural
thickening or pleural calcication may also be observed. There is a
wide range of associated parenchymal ndings (occurring in 20%67% of cases) such as cavitations, nodularity and consolidation3,6,8.
Most descriptions in the literature do not separate adult from
paediatric ndings. Furthermore, in the few published paediatric
studies regarding tuberculous pleural effusions there are a variety
of age groups, risk factors, and ethnicities reported4,7,8. However,
hilar lymph node enlargement is consistently suggestive of a
tuberculous aetiology of the effusion.
Ultrasonography may help by demonstrating brin bands,
mobile delicate septations, encysted pleural effusion, pleural
thickening, and occasionally pleural nodules6. Computerised
tomography (CT) scanning with contrast may improve the
likelihood of the diagnosis of parenchymal and mediastinal
ndings of TB9. CT scanning may also help in the detection of
extra pulmonary abnormalities such as bone involvement or
contiguous infections. However, the amount of radiation must be
considered in children and a CT scan is usually unnecessary.

[()TD$FIG]

Figure 1. X-ray showing TB pleural effusion in the left side female, 14 y old.

Tuberculin skin test (TST)

The production of cytokines (interferon [IFN]-gamma, interleukin-2) by activated pleural T-lymphocytes causes the tuberculin skin test reactivity3. There is a wide variation of tuberculin
test sensitivity among children with pleural TB. In countries
where TB prevalence is low and no obligatory vaccination with
BCG is required, positive tuberculin skin test (TST) (reaction
greater than 10 mm) is supportive for a diagnosis of TB. Initially,
the TST may be negative due to anergy or recent infection but if
repeated 8 weeks later it will be positive6. A false-negative TST
may be explained by connement of sensitized T-cells inside the
pleural space, anergy (immunosuppression or malnourishment),
recent infection and suppression by circulating mononuclear
cells3,6. In countries with a high TB prevalence and BCG
vaccination, the interpretation of a positive TST test may be
more difcult. A reaction above 15 mm is highly suggestive of TB
but results fewer than 10 mm are inconclusive in immunocompetent children. However, in an HIV infected child, a TST of 5 mm
is considered positive. However the TST cannot distinguish
between latent infection and active TB. Therefore, the TST cannot
be used in isolation. It provides evidence of infection, which is
useful in children. It should be interpreted along with microbiological and other investigations.
Pleural uid analysis
Pleural uid analysis in a tuberculous pleural effusion is useful
to exclude alternative aetiologies including a complicated parapneumonic bacterial pleural effusion and other infective or rarely
malignant aetiologies. Characteristically it is an exudate with a
lymphocyte predominance and a high protein concentration
{typically above 30 g/dl}. Other biochemical aspects (Lactate
dehydrogenase level [LDH], glucose and pH) of pleural uid are
variable and inconclusive for the diagnosis of TB3,10.
Adenosine deaminase (ADA)
ADA is an enzyme involved in purine metabolism which is
typically found in high concentrations in the pleural uid in cases
of pleural TB3. Pleural activity of total ADA is dependent on two
principal isoenzymes, ADA1, and ADA2. ADA1 is found in all cells
and ADA2 reects monocyte/macrophage activation. The isoenzyme ADA2 is typically elevated in pleural TB, with values above 40
IU/l having high sensitivity and specicity (89 to 100%)2,3,6,11,12.
The isoenzyme ADA1 may be elevated in the presence of empyema
and parapneumonic effusions as well as in lymphoma, malignant
neoplasms and collagen vascular disease11. In cases of suspected
false negative or positive ADA levels, the ADA1/ADA (total) ratio is a
valuable parameter11. Patients presenting with elevated levels of
ADA with a high index of suspicion of pleural TB may avoid the
need for pleural biopsy1,2,10. In one study done exclusively in
children with pleural TB, ADA levels were above 40 U/l in 90% of
cases4.
A prospective study done in Brazil, including adult and
adolescent patients with pleural effusion compared the sensitivity
and specicity of three different diagnostic tests 12. The authors
measured total ADA activity, Immunoglobulin A [IgA]-Elisa for two
combined specic Mycobacterium tuberculosis antigens and polymerase chain reaction (PCR) for detection of M. tuberculosis DNA.
When compared with the gold standard of histopathological
examination, the ADA activity showed 93% sensitivity and 100%
specicity for diagnosing pleural TB12. Most published studies of
ADA in pleural TB are from high TB prevalence countries and
include all age groups. Further studies focused on pleural TB in
children are needed.

G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 2730

Inammatory mediators
Elevated levels of interferon-g (iIFN-g) are highly associated
with pleural TB3,6,7. Its diagnostic yield is comparable to ADA in TB
pleurisy, showing high sensitivity and specicity (around 95%) with
cut-off values between 0, 3 to 5 IU/ml6,7,12. It seems that IFN-g does
not generate false positive results in HIV patients13. Unfortunately,
as this test is expensive it is not recommended routinely7,8.
Cytokines, tumor necrosis factora and lysosime have all been
studied for research purposes in pleural TB; although no relevance
to clinical practice has been found6. Several systematic reviews
show that both ADA and free (unstimulated) IFN-gamma are useful
biomarkers of pleural TB, although data are mostly from adult
studies14. Interferon-gamma release assays (IGRAs) have been
attempted in pleural uid specimens, but do not appear to work
well (high indeterminate rates) and do not perform better than
free, unstimulated IFN-gamma measurement in pleural uid15,16
Microbiological tests
Usually, pleural TB in children has a low number of bacilli.
Pleural uid microscopy rarely identies acid fast bacilli and
cultures are also often negative. Histological examination of a
pleural biopsy has high sensitivity (around 80%) for the diagnosis
of pleural TB6,7.
Other sources for bacteriological tests such as gastric aspirate or
sputum analysis are rarely useful since pleural TB may occur
without pulmonary lesions. However, in a series of cases described
by Cruz and et al8, gastric aspirate or sputum culture were positive
in one-third of children who had normal x-rays, suggesting that
such cultures should be performed even when patients have
isolated pleural disease.
Polymerase chain reaction - PCR
PCR studies in pleural uid have been done with different
extraction methods leading to variable results. Diagnostic sensitivity ndings varied from 20% to 80% probably due to different
assays and experience3. The high costs of performing pcr testing
must be taken into account especially in low-income countries. A
meta-analysis of PCR for pleural TB shows high specicity but
highly variable sensitivity. The case selection, limitations of the
collection techniques and the possibility of laboratory contamination must also be considered. If one presumes good technique
when acquiring the pleural uid in cases of suspected pleural TB,
there should not be false positive results. Conversely, a negative
PCR does not rule out pleural TB17
The use of rapid culture method for TB diagnosis (Bactec1) has
been used with better results when compared to conventional
culture methods (sensitivity of 90% and specicity of 100%) in
some centers3,6,7. Pleural uid or tissue culture for TB are the gold
standard for the diagnosis but are not practical for clinical
decisions since their results are delayed.

29

effusion, pleural granulomata, and cutaneous sensitivity to

puried protein derivative - PPD) have low specicity and sputum,
pleural uid, and pleural biopsy cultures have a low rate of success.
Surgical procedures help physicians to obtain samples that will
provide a more accurate diagnosis. Thoracocentesis provides
important information regarding pleural uid characteristics such
as aspect, smell, viscosity and colour. A tuberculous pleural
effusion is typically clear and straw coloured; however, it can be
turbid or serosanguinous but rarely very bloody6. Furthermore, the
biochemical analysis often suggests the diagnosis of pleural
tuberculosis. Biopsy of the parietal pleura with or without
echographic assistance18 is an invasive but sensitive diagnostic
test for tuberculous pleural effusions. The ndings of granulomas
with caseous necrotic tissue in the pleural biopsy makes the
diagnosis of tuberculosis highly probable. A pleural biopsy can be
made with the use of Cope, Abrams or Tru-cut needle with
positivity for Mycobacterium tuberculosis varying from 57% to
80%, and at least 1 specimen for culture19. Histologic examination
of tissue from the pleural biopsy may demonstrate granulomatous
inammation, caseous necrosis, or acid-fast bacilli.
In patients with tuberculous pleural effusions, a closed pleural
biopsy will demonstrate granulomas, with or without caseous
necrosis, in 50% to 97% of patients and culture yields mycobacteria
in 39% to 80%20; when both methods of diagnosis are used, the
diagnostic yield increases to 60% to 95%6. Even when granulomas
are not visualized, the biopsy specimen should be examined for
acid-fast bacilli and culture (in 10%, only organisms may be seen in
the biopsy)7. Other causes of granulomatous pleuritis, such as
fungal disease, sarcoidosis, rheumatoid arthritis, or nocardial
infection, need to be excluded6. Obtaining pleural tissue through a
closed-needle biopsy or medical thoracoscopy is still considered a
reference procedure in the evaluation of suspected pleural TB6.
Currently, with the advent of video-assisted thoracoscopic surgery,
there has been a renewed interest in the use of thoracoscopy. In
adults, thoracoscopy should be indicated when less invasive
techniques do not provide adequate material or are not sufcient
for the diagnosis. Normally it is indicated after two inconclusive
pleural biopsies and there is still suspicion of other diseases such as
lymphoma21. Thoracoscopy may show yellow-white tubercles on
the parietal pleura, reddening of pleura and numerous adhesions
[Figure 2]. In a study that compared various diagnostic modalities
for TB pleural effusions, thoracoscopy was the most accurate, but
most expensive tool for establishing the diagnosis with an
accuracy of 100% on histology and 76% positivity on culture22.In
younger children, surgical diagnostic procedures such as needle

[()TD$FIG]

Cellularity
The pleural uid cell count range is usually 500 to 2,500 with
lymphocyte predominance of 80% or higher in the majority of
cases. However, in some cases an initial polymorphonuclear
predominance may be observed which changes to lymphocytic
reaction over time7.
Invasive diagnosis (biopsy)
The diagnosis of a tuberculous pleural effusion can be difcult
because the classic ndings (lymphocytic exudative pleural

Figure 2. Thoracoscopy showing parietal pleural aspect in a four year-old girl with
an extensive tuberculous pleural effusion.

[()TD$FIG]

30

G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 2730

X-ray with unilateral pleural effusion

( consolidation)
Non-toxaemic child
History of contact with TB
TST: interpretation depending
on local epidemiology, BCG
vaccination
Thoracocentesis [exudate, lymphocte
predominance, raised protein]

ADA, Interferon-gamma
Culture for TB
PCR

stulae or disseminated disease3. Pleural thickening usually

resolves in months with no sequelae reected in in lung function
testing1,2,3,4.

PRACTICE POINTS
 Pleural tuberculosis is the most common presentation of
extrapulmonary tuberculosis
 Tuberculosis aetiology must be considered in isolated
pleural effusions in a child with contact with a case of
tuberculosis
 Fever, chest pain, unilateral pleural effusion are the main
features of pleural tuberculosis
 Pleural biopsy, pleural uid analysis, tuberculin skin test,
adenosine deaminase, interferon-g and bacteriologic tests
are useful for diagnostic conrmation.

Interferon-gamma,
ADA >40 and / or
Granuloma at biopsy

References
Yes

TB Treatment

No

Look for other aetiology

Figure 3. Suggested algorithm approoach to isolated pleural TB in children.

Modied from Porcel26.

pleural biopsy need sedation or general anesthesia. For this reason

sometimes it is more appropriate to perform thoracoscopy or video
assisted thoracoscopy, which has low morbidity, allows targeted
biopsy of suspicious lesions, permits clearing of the pleural cavity,
and provides proper position for the chest tube or pigtail drain.
During thoracoscopy, after evacuation of the pleural cavity with
the lung presenting appropriate expansion, it is unnecessary to
leave the chest tube in since the inammatory process is selflimiting. Routine complete drainage of the pleural uid at the time
of diagnosis does not appear to improve middle or long-term
outcomes23. The response of tuberculous pleural effusions to
therapy is generally good, with total uid reabsorption occurring
within 2 to 4 months24. The prognosis is excellent, although
residual pleural thickening may occur 4. If the patient is dyspnoeic
from a large pleural effusion leading to mediastinal shift, a
therapeutic thoracocentesis should be performed. Drainage and
instillation of brinolytics, in addition to anti-TB medication, in
patients with symptomatic loculated TB effusions may hasten the
resolution of pleural effusion and reduce the incidence of residual
pleural thickening25 (Figure 3).
Treatment
Standard treatment for tuberculosis is adequate for children
with pleural TB and the addition of corticosteroids does not aid in
the recovery 1,2,3,4
Complications and sequelae
Pleural TB generally responds to appropriate therapy. Isolated
pleural disease has a good prognosis. Complications may occur in
imunossupressed patients who may present with empyema,

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