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Paediatric Respiratory Reviews 12 (2011) 2730

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Paediatric RespirINTRODUCTION

Pleural tuberculosis is the most common presentation ofextrapulmonary tuberculosis and the most common cause ofpleural effusion worldwide1,2. There are few data regarding thespecic prevalence in children, since the majority of publicationson pleural tuberculosis (TB) include adolescents with adults. Theincidence of pleural disease varies among countries1. In highincome countries the prevalence of TB is increasing especially insome ethnic groups3. In a study undertaken in Tanzania, 38% of allTB cases had pleural involvement3. A Spanish series encompassing175 cases of primary pulmonary tuberculosis in children over a 13years period showed 39 (22%) patients with pleural TB4. Incontrast, from 202 cases of intrathoracic paediatric TB in Canadaonly 7 (4%) presented with a pleural effusion5.

In this review, we outline the general aspects of pleuraltuberculosis, with particular attention to the diagnostic assess-ment. Early diagnosis is fundamental, although it may be

challenging in situations where the availability of some diagnostictools are limited.

Pathophysiology

Pleural TB begins with the rupture of a subpleural tuberculousfocus, which triggers an inammatory response mediated by T-cells (previously sensitized to the TB antigen). The exudativepleural uid is due to a delayed hypersensitivity reaction toMycobacterium tuberculosis. The small number of bacilli in thepleural uid produces a granulomatous reaction. This reactionimproves spontaneously but relapses in 60% of cases6,7.

Themain cause of the inammatory process in the pleural spaceis a Type IV hypersensitivity reaction. The TB bacillus invades thepleural space after the rupture of a pulmonary caseous focus (Ghonfocus) in the subpleural region, by contiguity of the pulmonarylesion, by rupture of a mediastinal lymph node or via hemato-genous dissemination1,6,7.

The pleural effusion (PE) may occupy 30% to 60% of the affectedhemithorax. Rarely, a persistent loculated uid collection isdetected representing a tuberculous empyema, which correspondsto an uncommon chronic, active infection of the pleural space. Itariseswhen a bronchopleural stula spills the content of a cavity or

A R T I C L E I N F O

Keywords:

Pleural effusions

tuberculosis

child

diagnosis

X-rays

S U M M A R Y

Pleural tuberculosis effusion (PTE) in children is a diagnosis whichmust 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.

* 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.2010.11.001Mini-Symposium: Childhood TB in 2010

Pleural Tuberculosis in Children

Gilberto B. Fischer 1,3,*, Cristiano Feijo Andrade 2, J1 Professor of Paediatrics, Department of Paediatrics, Universidade Federal de Ciencias2 Thoracic Surgeon, Hospital da Crianca Santo Antonio, Hospital de Clnicas de Porto A3 Servico de Pneumologia, Hospital da Crianca Santo Antonio, Rua coronel Bordini 830

EDUCATIONAL AIMS THE READER WILL BECOME FAMILIAR

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 aetiologyo Bonfadini Lima 3

aude Porto Alegre, Rua coronel Bordini 830/509, CEP 90440-003

, Rua coronel Bordini 830/509, CEP 90440-003

, CEP 90440-003

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other parenchymal focus into the pleural space. Empyemanecessitans (an empyema in the pleural space reaching contiguousregions such as subcutaneous tissue or even bone tissue) is a veryrare condition1,6.

Diagnosis

The diagnosis of pleural tuberculosis in children is usuallymadefrom a history of contact with an adult with pulmonary TBcombined with suggestive clinical ndings (pleuritic chest pain,chest pressure, dyspnoea, and cough), a positive tuberculosis skintest (TST) and suggestive pleural uid analysis [exudate withlymphocyte predominance and high protein]4. The suspicion ofpleural tuberculosis arises in a child or adolescent with fever, chestpain, unilateral pleural effusion who appears non-toxaemic at theclinical examination. Close contact with an adult with diagnosedpulmonary tuberculosis or at least presenting clinical features ofTB (cough, weight loss, nocturnal sweats) reinforces the likelihoodof TB.

Imaging

G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 273028On the chest x-ray, pleural uid is seen and septation of thecollection in the pleural space may be apparent on the ultrasoundimages. Usually the pleural effusion is unilateral [Figure 1]. Pleuralthickening or pleural calcication may also be observed. There is awide 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 frompaediatric ndings. Furthermore, in the few published paediatricstudies regarding tuberculous pleural effusions there are a varietyof age groups, risk factors, and ethnicities reported4,7,8. However,hilar lymph node enlargement is consistently suggestive of atuberculous aetiology of the effusion.

Ultrasonography may help by demonstrating brin bands,mobile delicate septations, encysted pleural effusion, pleuralthickening, and occasionally pleural nodules6. Computerisedtomography (CT) scanning with contrast may improve thelikelihood of the diagnosis of parenchymal and mediastinalndings of TB9. CT scanning may also help in the detection ofextra pulmonary abnormalities such as bone involvement orcontiguous infections. However, the amount of radiation must beconsidered 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, inter-leukin-2) by activated pleural T-lymphocytes causes the tuber-culin skin test reactivity3. There is a wide variation of tuberculintest sensitivity among children with pleural TB. In countrieswhere TB prevalence is low and no obligatory vaccination withBCG is required, positive tuberculin skin test (TST) (reactiongreater than 10 mm) is supportive for a diagnosis of TB. Initially,the TST may be negative due to anergy or recent infection but ifrepeated 8 weeks later it will be positive6. A false-negative TSTmay be explained by connement of sensitized T-cells inside thepleural space, anergy (immunosuppression or malnourishment),recent infection and suppression by circulating mononuclearcells3,6. In countries with a high TB prevalence and BCGvaccination, the interpretation of a positive TST test may bemore difcult. A reaction above 15 mm is highly suggestive of TBbut results fewer than 10 mm are inconclusive in immunocom-petent children. However, in an HIV infected child, a TST of 5 mmis considered positive. However the TST cannot distinguishbetween latent infection and active TB. Therefore, the TST cannotbe used in isolation. It provides evidence of infection, which isuseful in children. It should be interpreted along with micro-biological and other investigations.

Pleural uid analysis

Pleural uid analysis in a tuberculous pleural effusion is usefulto exclude alternative aetiologies including a complicated para-pneumonic bacterial pleural effusion and other infective or rarelymalignant aetiologies. Characteristically it is an exudate with alymphocyte predominance and a high protein concentration{typically above 30 g/dl}. Other biochemical aspects (Lactatedehydrogenase level [LDH], glucose and pH) of pleural uid arevariable and inconclusive for the diagnosis of TB3,10.

Adenosine deaminase (ADA)

ADA is an enzyme involved in purine metabolism which istypically found in high concentrations in the pleural uid in casesof pleural TB3. Pleural activity of total ADA is dependent on twoprincipal isoenzymes, ADA1, and ADA2. ADA1 is found in all cellsand ADA2 reects monocyte/macrophage activation. The isoen-zyme ADA2 is typically elevated in pleural TB, with values above 40IU/l having high sensitivity and specicity (89 to 100%)2,3,6,11,12.The isoenzyme ADA1 may be elevated in the presence of empyemaand parapneumonic effusions as well as in lymphoma, malignantneoplasms and collagen vascular disease11. In cases of suspectedfalse negative or positive ADA levels, the ADA1/ADA (total) ratio is avaluable parameter11. Patients presenting with elevated levels ofADA with a high index of suspicion of pleural TB may avoid theneed for pleural biopsy1,2,10. In one study done exclusively inchildren with pleural TB, ADA levels were above 40 U/l in 90% ofcases4.

A prospective study done in Brazil, including adult andadolescent patients with pleural effusion compared the sensitivityand specicity of three different diagnostic tests 12. The authorsmeasured total ADA activity, Immunoglobulin A [IgA]-Elisa for twocombined specic Mycobacterium tuberculosis antigens and poly-merase chain reaction (PCR) for detection of M. tuberculosis DNA.When compared with the gold standard of histopathologicalexamination, the ADA activity showed 93% sensitivity and 100%specicity for diagnosing pleural TB12. Most published studies ofADA in pleural TB are from high TB prevalence countries andinclude all age groups. Further studies focused on pleural TB inchildren are needed.

effusion, pleural granulomata, and cutaneous sensitivity topuried 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 willprovide a more accurate diagnosis. Thoracocentesis providesimportant information regarding pleural uid characteristics suchas aspect, smell, viscosity and colour. A tuberculous pleuraleffusion is typically clear and straw coloured; however, it can beturbid or serosanguinous but rarely very bloody6. Furthermore, thebiochemical analysis often suggests the diagnosis of pleuraltuberculosis. Biopsy of the parietal pleura with or withoutechographic assistance18 is an invasive but sensitive diagnostictest for tuberculous pleural effusions. The ndings of granulomaswith caseous necrotic tissue in the pleural biopsy makes thediagnosis of tuberculosis highly probable. A pleural biopsy can bemade with the use of Cope, Abrams or Tru-cut needle withpositivity for Mycobacterium tuberculosis varying from 57% to80%, and at least 1 specimen for culture19. Histologic examinationof tissue from the pleural biopsy may demonstrate granulomatousinammation, caseous necrosis, or acid-fast bacilli.

G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 2730 29Inammatory mediators

Elevated levels of interferon-g (iIFN-g) are highly associatedwith pleural TB3,6,7. Its diagnostic yield is comparable to ADA in TBpleurisy, showing high sensitivity and specicity (around 95%) withcut-off values between 0, 3 to 5 IU/ml6,7,12. It seems that IFN-g doesnot 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 beenstudied for research purposes in pleural TB; although no relevanceto clinical practice has been found6. Several systematic reviewsshow that both ADA and free (unstimulated) IFN-gamma are usefulbiomarkers of pleural TB, although data are mostly from adultstudies14. Interferon-gamma release assays (IGRAs) have beenattempted in pleural uid specimens, but do not appear to workwell (high indeterminate rates) and do not perform better thanfree, 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 andcultures are also often negative. Histological examination of apleural biopsy has high sensitivity (around 80%) for the diagnosisof pleural TB6,7.

Other sources for bacteriological tests such as gastric aspirate orsputum analysis are rarely useful since pleural TB may occurwithout pulmonary lesions. However, in a series of cases describedby Cruz and et al8, gastric aspirate or sputum culture were positivein one-third of children who had normal x-rays, suggesting thatsuch cultures should be performed even when patients haveisolated pleural disease.

Polymerase chain reaction - PCR

PCR studies in pleural uid have been done with differentextraction methods leading to variable results. Diagnostic sensi-tivity ndings varied from 20% to 80% probably due to differentassays and experience3. The high costs of performing pcr testingmust be taken into account especially in low-income countries. Ameta-analysis of PCR for pleural TB shows high specicity buthighly variable sensitivity. The case selection, limitations of thecollection techniques and the possibility of laboratory contamina-tion must also be considered. If one presumes good techniquewhen acquiring the pleural uid in cases of suspected pleural TB,there should not be false positive results. Conversely, a negativePCR does not rule out pleural TB17

The use of rapid culture method for TB diagnosis (Bactec1) hasbeen used with better results when compared to conventionalculture methods (sensitivity of 90% and specicity of 100%) insome centers3,6,7. Pleural uid or tissue culture for TB are the goldstandard for the diagnosis but are not practical for clinicaldecisions since their results are delayed.

Cellularity

The pleural uid cell count range is usually 500 to 2,500 withlymphocyte predominance of 80% or higher in the majority ofcases. However, in some cases an initial polymorphonuclearpredominance may be observed which changes to lymphocyticreaction over time7.

Invasive diagnosis (biopsy)

The diagnosis of a tuberculous pleural effusion can be difcultbecause the classic ndings (lymphocytic exudative pleuralIn patients with tuberculous pleural effusions, a closed pleuralbiopsy will demonstrate granulomas, with or without caseousnecrosis, in 50% to 97% of patients and culture yields mycobacteriain 39% to 80%20; when both methods of diagnosis are used, thediagnostic yield increases to 60% to 95%6. Even when granulomasare not visualized, the biopsy specimen should be examined foracid-fast bacilli and culture (in 10%, only organismsmay be seen inthe biopsy)7. Other causes of granulomatous pleuritis, such asfungal disease, sarcoidosis, rheumatoid arthritis, or nocardialinfection, need to be excluded6. Obtaining pleural tissue through aclosed-needle biopsy or medical thoracoscopy is still considered areference 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. Inadults, thoracoscopy should be indicated when less invasivetechniques do not provide adequate material or are not sufcientfor the diagnosis. Normally it is indicated after two inconclusivepleural biopsies and there is still suspicion of other diseases such aslymphoma21. Thoracoscopy may show yellow-white tubercles onthe parietal pleura, reddening of pleura and numerous adhesions[Figure 2]. In a study that compared various diagnostic modalitiesfor TB pleural effusions, thoracoscopy was the most accurate, butmost expensive tool for establishing the diagnosis with anaccuracy of 100% on histology and 76% positivity on culture22.Inyounger children, surgical diagnostic procedures such as needle[()TD$FIG]

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

stulae or disseminated disease3. Pleural thickening usuallyresolves in months with no sequelae reected in in lung function

[()TD$FIG] G.B. Fischer et al. / Paediatric Respiratory Reviews 12 (2011) 273030pleural biopsy need sedation or general anesthesia. For this reasonsometimes it ismore appropriate to perform thoracoscopy or videoassisted thoracoscopy, which has low morbidity, allows targetedbiopsy of suspicious lesions, permits clearing of the pleural cavity,

TST: interpretation depending

on local epidemiology, BCG

vaccination

X-ray with unilateral pleural effusion

( consolidation)

Non-toxaemic child

History of contact with TB

Thoracocentesis [exudate, lymphocte

predominance, raised protein]

ADA, Interferon-gamma

Culture for TB

PCR

Interferon-gamma,

ADA >40 and / or

Granuloma at biopsy

Yes No

TB Treatment Look for other aetiology

Figure 3. Suggested algorithm approoach to isolated pleural TB in children.Modied from Porcel26.and provides proper position for the chest tube or pigtail drain.During thoracoscopy, after evacuation of the pleural cavity withthe lung presenting appropriate expansion, it is unnecessary toleave the chest tube in since the inammatory process is self-limiting. Routine complete drainage of the pleural uid at the timeof diagnosis does not appear to improve middle or long-termoutcomes23. The response of tuberculous pleural effusions totherapy is generally good, with total uid reabsorption occurringwithin 2 to 4 months24. The prognosis is excellent, althoughresidual pleural thickening may occur 4. If the patient is dyspnoeicfrom a large pleural effusion leading to mediastinal shift, atherapeutic thoracocentesis should be performed. Drainage andinstillation of brinolytics, in addition to anti-TB medication, inpatients with symptomatic loculated TB effusions may hasten theresolution of pleural effusion and reduce the incidence of residualpleural thickening25 (Figure 3).

Treatment

Standard treatment for tuberculosis is adequate for childrenwith pleural TB and the addition of corticosteroids does not aid inthe recovery 1,2,3,4

Complications and sequelae

Pleural TB generally responds to appropriate therapy. Isolatedpleural disease has a good prognosis. Complications may occur inimunossupressed patients who may present with empyema,

2009;15:35865.17. Pai M, Flores LL, Hubbard A, Riley LW, Colford Jr JM. Nucleic acid amplication

tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 2004;4:6.

18. Chiu CY, Wu JH, Wong KS. Clinical spectrum of tuberculous pleural effusion inchildren. Pediatr Int 2007;49:35962.

19. Kirsch CM, Kroe DM, Azzi RL, Jensen WA, Kagawa FT, Wehner JH. The OptimalNumber of Pleural Biopsy Specimens for a Diagnosis of Tuberculous Pleurisy.Chest 1997;112:7026.

20. Maltezou HC, Spyridis P, Kafetzis DA. Extra-pulmonary tuberculosis in children.Arch Dis Child 2000;83:3426.

21. Seiscento M, Conde MB, Dalcolmo MMP. Tuberculose pleural. J Bras Pneumol2006;32:S17481.

22. Diacon AH, Van de Wal BW, Wyser C, et al. Diagnostic tools in tuberculouspleurisy: a direct comparative study. Eur Respir J 2003;22:58991.

23. Lai YF, Chao TY, Wang YH, Lin AS. Pigtail drainage in the treatment of tubercu-lous pleural effusions: a randomised study. Thorax 2003;58:14951.

24. Cohen M, Sahn SA. Resolution of Pleural Effusions*. Chest 2001;119:154762.25. Chung CL, Chen CH, Yeh CY, Sheu JR, Chang SC. Early effective drainage in the

treatment of loculated tuberculous pleurisy. Eur Respir J 2008;31:12617.

26. Porcel JM. Tuberculosis pleural effusion. Lung 2009;187:26370.testing1,2,3,4.

References

1. Lazarus AA, McKay S, Gilbert R. Pleural tuberculosis. Dis Mon 2007;53:1621.2. Wong PC. Management of tuberculous pleuritis: can we do better? Respirology

2005;10:1448.3. Chakrabarti B, Davies PD. Pleural tuberculosis. Monaldi Arch Chest Dis

2006;65:2633.4. Merino JM, Carpintero I, Alvarez T, Rodrigo J, Sanchez J, Coello JM. Tuberculous

pleural effusion in children. Chest 1999;115:2630.5. Pineda PR, Leung A, Muller NL, Allen EA, Black WA, FitzGerald JM. Intrathoracic

paediatric tuberculosis: a report of 202 cases. Tuber Lung Dis 1993;74:2616.6. Gopi A, Madhavan SM, Sharma SK, Sahn SA. Diagnosis and Treatment of

Tuberculous Pleural Effusion in 2006*. Chest 2007;131:8809.7. Porcel JM. Tuberculous pleural effusion. Lung 2009;187:26370.8. Cruz AT, Ong LT, Starke JR. Childhood pleural tuberculosis: a review of 45 cases.

Pediatr Infect Dis J 2009;28:9814.9. Moon WK, KimWS, Kim IO, et al. Complicated pleural tuberculosis in children:

CT evaluation. Pediatr Radiol 1999;29:1537.10. Light RW. Clinical practice. Pleural effusion. N Engl J Med 2002;346:19717.11. Perez-Rodriguez E, Walton IJP, Hernandez JJS, et al. ADA1 ADAp ratio in pleural

tuberculosis: an excellent diagnostic parameter in pleural uid. Respiratorymedicine 1999;93:81621.

12. Trajman A, Kaisermann C, Luiz RR, et al. Pleural uid ADA, IgA-ELISA and PCRsensitivities for the diagnosis of pleural tuberculosis. Scand J Clin Lab Invest2007;67:87784.

13. Villena V, Lopez-Encuentra A, Echave-Sustaeta J, Martin-Escribano P, Ortuno-de-Solo B, Estenoz-Alfaro J. Interferon-gamma in 388 immunocompromisedand immunocompetent patients for diagnosing pleural tuberculosis. Eur Respir J1996;9:26359.

14. Jiang J, Shi HZ, Liang QL. Diagnostic value of interferon-g in tuberculouspleurisy: a meta-analysis. Chest 2007;131:113341.

15. Joshi R, Pai M. Can pleural tuberculosis be diagnosed using interferon-gammarelease assays? Respiration 2008;76:12830.

16. Hooper CE, Lee YC, Maskell NA. Interferon-gamma release assays for thediagnosis of TB pleural effusions: hype or real hope? Curr Opin Pulm Med

PRACTICE POINTS

Pleural tuberculosis is the most common presentation ofextrapulmonary tuberculosis

Tuberculosis aetiology must be considered in isolatedpleural effusions in a child with contact with a case oftuberculosis

Fever, chest pain, unilateral pleural effusion are the mainfeatures of pleural tuberculosis

Pleural biopsy, pleural uid analysis, tuberculin skin test,adenosine deaminase, interferon-g and bacteriologic testsare useful for diagnostic conrmation.

Pleural Tuberculosis in ChildrenIntroductionPathophysiology

Educational aimsOutline placeholderDiagnosisImagingTuberculin skin test (TST)Pleural fluid analysisAdenosine deaminase (ADA)Inflammatory mediatorsMicrobiological testsPolymerase chain reaction - PCRCellularityInvasive diagnosis (biopsy)TreatmentComplications and sequelae

References

Practice points