Pleural Tuberculosis in Children - Paediatric Respiratory Reviews

Paediatric Respiratory Reviews 12 (2011) 27–30

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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, Joaõ Bonfadini Lima 3 1

Professor of Paediatrics, Department of Paediatrics, Universidade Federal de Cieˆncias da Sau´de Porto Alegre, Rua coronel Bordini 830/509, CEP 90440-003 Thoracic Surgeon, Hospital da Criança Santo Antoˆnio, Hospital de Clıńicas de Porto Alegre, Rua coronel Bordini 830/509, CEP 90440-003 3 Serviço de Pneumologia, Hospital da Criança Santo Antoˆnio, 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 findings of PT in children The main investigations for the confirmation 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 finding on the chest x-ray. However, in 20% to 40% of patients, intrathoracic disease may also occur. Adenosine deaminase, interferon-gamma, analysis of pleural fluid and pleural biopsy are the main tools for diagnostic confirmation. Tuberculin skin test may provide supporting evidence of tuberculous infection. PTE has a good prognosis in children and no long term sequelae are expected. ß 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 specific 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. Serviço de Pneumologia Pedia´trica Av Independeˆncia 155 Porto Alegre, Brazil CEP 90035-074 Fax: +555132148646. E-mail address: [email protected] (G.B. Fischer). 1526-0542/$ – see front matter ß 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 inflammatory response mediated by Tcells (previously sensitized to the TB antigen). The exudative pleural fluid is due to a delayed hypersensitivity reaction to Mycobacterium tuberculosis. The small number of bacilli in the pleural fluid produces a granulomatous reaction. This reaction improves spontaneously but relapses in 60% of cases6,7. The main cause of the inflammatory 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 fluid collection is detected representing a tuberculous empyema, which corresponds to an uncommon chronic, active infection of the pleural space. It arises when a bronchopleural fistula spills the content of a cavity or

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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 findings (pleuritic chest pain, chest pressure, dyspnoea, and cough), a positive tuberculosis skin test (TST) and suggestive pleural fluid 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 fluid 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 calcification may also be observed. There is a wide range of associated parenchymal findings (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 findings. 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 fibrin 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 findings 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 confinement 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 difficult. 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 fluid analysis Pleural fluid 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 fluid 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 fluid 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 reflects monocyte/macrophage activation. The isoenzyme ADA2 is typically elevated in pleural TB, with values above 40 IU/l having high sensitivity and specificity (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 specificity of three different diagnostic tests 12. The authors measured total ADA activity, Immunoglobulin A [IgA]-Elisa for two combined specific 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% specificity 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.


Inflammatory 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 specificity (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 factor–a 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 fluid specimens, but do not appear to work well (high indeterminate rates) and do not perform better than free, unstimulated IFN-gamma measurement in pleural fluid15,16 Microbiological tests Usually, pleural TB in children has a low number of bacilli. Pleural fluid microscopy rarely identifies 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 fluid have been done with different extraction methods leading to variable results. Diagnostic sensitivity findings 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 specificity 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 fluid 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 specificity of 100%) in some centers3,6,7. Pleural fluid or tissue culture for TB are the gold standard for the diagnosis but are not practical for clinical decisions since their results are delayed.

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effusion, pleural granulomata, and cutaneous sensitivity to purified protein derivative - PPD) have low specificity and sputum, pleural fluid, 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 fluid 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 findings 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 inflammation, 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 sufficient 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 fluid 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 difficult because the classic findings (lymphocytic exudative pleural

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

[()TD$FIG]

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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

fistulae or disseminated disease3. Pleural thickening usually resolves in months with no sequelae reflected 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 fluid analysis, tuberculin skin test, adenosine deaminase, interferon-g and bacteriologic tests are useful for diagnostic confirmation.

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. Modified 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 inflammatory process is selflimiting. Routine complete drainage of the pleural fluid 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 fluid 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 fibrinolytics, 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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