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(Chest. 1999;115:26-30.)
© 1999 American College of Chest Physicians

Tuberculous Pleural Effusion in Children*

José M. Merino, MD; Isabel Carpintero, MD; Teresa Alvarez, MD; Jesús Rodrigo, MD; Jesús Sánchez, MD and José M. Coello, MD

* From the Pediatric (Drs. Merino, Carpintero, Alvarez, Rodrigo, and Sánchez) and Radiologic (Dr. Coello) Departments, General Yagüe Hospital, Burgos, Spain.


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To describe the age distribution, clinical, laboratory, radiographic, and bacteriologic findings of pediatric patients with tuberculous pleural effusion.

Design: A retrospective study.

Patients and methods: We have identified all cases of primary pulmonary tuberculosis in children < 18 years, reported to the health department. We have collected information from medical records regarding demographics, clinical findings, bacteriologic results, and evolution. Chest radiographs obtained at the time of initial evaluation were reviewed independently by two groups of radiologists who were blind to the clinical and epidemiologic data.

Results: Between January 1983 and December 1996, 175 children <18 years were diagnosed as having primary pulmonary tuberculosis. Among them, 39 patients (22.1%) showed pleural effusion on chest radiograph. The mean age of patients with tuberculous pleural effusion was significantly higher (13.52 ± 0.5 years vs 6.97 ± 0.42 years). The sensitivity of the tuberculin test is 97.4% for an induration >= 5 mm. Pleural fluid analysis shows a lymphocytic exudative effusion. Chest radiograph review showed unilateral pleural effusion in all cases. Pleural effusion was the sole radiographic manifestation in 41% of cases. Parenchymal disease is associated in 23 cases (59%). Bacteriologic confirmation of tuberculosis was achieved in 22 cases (56.4%). Cultures of pleural fluid and biopsy material both yielded Mycobacterium tuberculosis in 15 of 34 (44.1%) and 12 of 18 (66.6%), respectively, for samples under study. Pleural biopsy specimens showed granulomatous inflammation in 18 of 23 cases (78.3%). Antituberculous therapy for 6 to 9 months was effective in all cases. Transient side effects occurred in 1 of 39 patients (2.9%).

Conclusions: Pleural effusion accounts for 22.1% of cases of pediatric pulmonary tuberculosis. Parenchymal consolidation is the most common associated radiographic finding. Bacteriologic confirmation was achieved in 56.4% of cases. A short course of chemotherapy is effective.

Key Words: bacteriology • children • clinical outcome • pleural effusion • radiology • tuberculosis


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Pleural effusion due to Mycobacterium tuberculosis is categorized as extrapulmonary disease.1 ,2 Pleurisy with effusion develops as a complication of primary pulmonary tuberculosis (TB) in 2 to 38% of children with pulmonary disease.2 ,3 ,4 ,5 ,6 ,7 Effusion is not a common feature of primary pulmonary TB in young children and it is more likely to be observed in adolescents and adults.3 ,7

Establishing a diagnosis of tuberculous pleural effusion (TPE) can be difficult because the classic findings (lymphocytic exudative pleural 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.

We have retrospectively reviewed our experience from 1983 to 1996 in pediatric patients with TPE to determine the following: (1) the age distribution of pediatric patients with TPE; (2) the main clinical and laboratory findings; (3) the associated radiologic patterns; (4) the efficacy of mycobacterial cultures in the diagnosis of pleural TB; and (5) the outcome of patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We selected for retrospective review all cases of primary pulmonary TB in children < 18 years reported to the health department from January 1983 to December 1996. All patients were admitted to our hospital, a tertiary care center with a reference population of 294,763 people, 68,155 of them < 18 years. We defined a case of TB if (1) M tuberculosis was detected from a clinical specimen, or (2) a child had clinical evidence of current disease and any of the following: (a) a history of contact with an adult case of TB; (b) positive tuberculin skin test (>= 5 mm); (c) suggestive appearances on chest radiograph; and (d) favorable response to specific antituberculous therapy. Clinical, laboratory, bacteriologic, radiologic, and treatment data were reviewed.

TPE was diagnosed if the patient showed a chest radiograph interpreted by a radiologist as depicting a pleural effusion and at least one of the following criteria: (1) positive culture for M tuberculosis from sputum, gastric aspirate, pleural fluid, or pleural biopsy specimen; (2) acid-fast bacilli in sputum, gastric aspirate, pleural fluid, or biopsy tissue; (3) pleural tissue histopathology compatible with TB (caseating granulomas with Langhans giant cells, epithelioid cells, and lymphocytes); (4) compatible clinical picture with positive tuberculin test and one of the following: lymphocytic pleural fluid (> 50%), exudative fluid (protein > 3 g/dL or lactate dehydrogenase [LDH] > 200 U/L) or pleural fluid levels of adenosine deaminase activity (ADA) > 40 U/L; and (5) radiographic pleural effusion that resolved with appropriate antimycobacterial therapy.

Tuberculin skin testing was made by means of an intradermal injection of 2 tuberculin units of PPD. All skin tests were undertaken by nursing personnel who are familiar with the technique. Induration was measured in 48 to 72 h and recorded in millimeters. A positive test was considered if the palpable induration was >= 5 mm.

Chest radiographs obtained at the time of initial evaluation were reviewed independently by two groups of radiologists who were blind to the clinical and epidemiologic data. Chest radiograph interpretation was made on the basis of the following patterns: (1) parenchymal consolidation (unilobar, multilobar, segmental, masslike); (2) atelectasis (lobar, segmental); (3) lymphadenopathy (hilar, paratracheal, hilar prominence, tracheal compression); (4) pleural effusion (effusion, empyema); and (5) miliary TB.

Specimens of sputum, gastric washing, pleural fluid, and biopsy tissue were obtained from patients with pleural effusion and studied for acid-fast bacilli detection by Ziehl-Neelsen smear and microscopic evaluation. Mycobacterial cultures were performed using Lowenstein-Jensen medium.

The statistical analyses were performed using the Mann-Whitney and {chi}2 tests.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Between January 1983 and December 1996, 175 children < 18 years were diagnosed as having primary pulmonary TB. Chest radiograph review disclosed 39 cases of TPE, which represented 22.1% of all forms of pulmonary disease due to M tuberculosis.

Epidemiologic, demographic, and skin test data are shown in Table 1 . A history of contact with a tuberculous case was present in 45 of 175 patients (25.7%), usually immediate family members (75.5%). Table 2 shows the main clinical and laboratory findings.


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  		Table 1. Epidemiologic and Tuberculin Test Data

 

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  		Table 2. Clinical and Laboratory Findings*

 
Radiologic records were available for review in all patients. Associated chest radiograph findings in patients with pleural effusion are shown in Table 3 . Parenchymal consolidation is the most common associated radiographic finding (59%). No statistical differences in the prevalence of parenchymal disease between children aged 10 years or more and younger were found (p = 0.76). There is a good agreement between the two groups of radiologists in the evaluation of chest radiographs (kappa index of 0.62).


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  		Table 3. Chest Radiograph Findings in Patients With Pleural Effusion

 
Bacteriologic confirmation of TB was achieved in 22 cases (56.4%). A total of 91 clinical specimens (24 sputum, 12 gastric washing, 32 pleural fluid, 2 synovial fluid, 3 ascitic fluid, and 18 pleural biopsy samples) from 37 patients were examined by microscopy. All but 5 of 18 (27.7%) pleural biopsy specimens were negative on microscopy examination. Ziehl-Neelsen stain recovery rate was 5.49%. A total of 70 clinical specimens (4 sputum, 9 gastric washing, 34 pleural fluid, 3 ascitic fluid, 2 synovial fluid, and 18 pleural biopsy samples) from 35 patients were submitted for Lowenstein-Jensen culture. M tuberculosis was recovered from 34 of 70 (48.5%) clinical specimens. Pleural fluid and biopsy material cultures yielded M tuberculosis in 15 of 34 (44.1%) and 12 of 18 (66.6%), respectively, of samples studied. The median time for growth detection was 34 and 35 days for pleural biopsy and pleural fluid Lowenstein-Jensen cultures, respectively. No statistical differences in mean ADA levels (77.4 ± 15.8 U/L vs 63 ± 7.0 U/L, p = 0.61), mean tuberculin skin test induration (12.95 ± 0.8 mm vs 15.5 ± 0.9 mm, p = 0.06), and parenchymal involvement (p = 0.09) were found between the positive and negative bacteriology group. However, mean age is significantly higher in bacteriology-positive patients (14.2 ± 0.45 vs 12.1 ± 0.99, p = 0.04). Table 4 shows the cytologic and biochemical analysis of pleural fluid.


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  		Table 4. Pleural Fluid Analysis

 
Histologic findings from pleural biopsy specimens were available in 23 patients and 18 of these 23 (78.3%) showed granulomatous inflammation. Of them, nine (50%) were also culture positive. Four patients (22.2%) showed granulomatous inflammation in pleural biopsy histologic examination but negative Ziehl-Neelsen stains and mycobacterial cultures.

Treatment changed over the study period. From 1983 to 1992–1993, most of the patients received a combination of isoniazid, rifampicin, and ethambutol for 9 months (27 of 39 [69.4%] patients with TPE in our review). After that, patients were treated with a combination of isoniazid, rifampicin, and pyrazinamide for 6 months (8 of 39 [20.5%] patients with TPE in our study). A short course of prednisone therapy (1 month) was added in nine patients (23%) if a large-volume pleural effusion or a prolonged course of fever was present. There was a complete resolution of the effusion in 34 patients (87.1%). Minimal residual pleural thickening was seen in five patients (13%) 1 year after the diagnosis. One patient (2.5%) showed transient elevated results of liver function tests.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Published reports describe TPE as a complication of primary pulmonary TB in 2 to 38% of children with pulmonary disease.1 ,2 ,3 ,4 ,6 ,7 Effusion is the sole radiographic manifestation of primary pulmonary TB in 38 to 63% of cases.3 In our series, TPE accounts for 39 of 175 cases (22.1%) of primary pulmonary TB and in 16 patients (9.6% of children with primary pulmonary TB), pleural effusion is the sole radiographic manifestation of primary pulmonary TB.

TPE is very uncommon in young children and is more likely to be observed in adolescents and adults.3 ,4 ,5 ,7 Mean age of patients with TPE was higher (13.52 years) than children without pleural effusion (6.97 years) in our study. Only six patients (15.4%) with TPE are < 10 years of age. However, no statistical differences in the prevalence of parenchymal abnormalities between children aged 10 years or more and younger were found in our review (p = 0.76).

TPEs are usually unilateral.2 ,3 ,7 No cases of bilateral effusion were seen in our study. Pleural effusion accompanied by underlying parenchymal disease was seen in 59% of our patients1 ,3 ,7 (Table 3 ). Parenchymal consolidation and bulging fissures are the most common associated radiographic manifestations.

The diagnosis of childhood TB is based on clinical findings, chest radiography, tuberculin skin testing, and a history of close contact with an adult case of pulmonary TB.4 A history of contact with a tuberculous case was present in 25.7% of cases in our study. The clinical picture of childhood TB is not specific.4 Patients with pleural effusion frequently had chest pain and respiratory distress.2 No differences in other clinical signs are detected in our review (Table 2 ).

Tuberculin tests showed a high sensitivity in our patients. Thirty-eight patients (97.4%) showed an induration of >= 5 mm. Significant cutaneous reactivity to tuberculin among patients with TPE has been reported in the literature.1 However, no differences in mean tuberculin skin test induration between the two groups were observed (Table 1 ).

Analysis of effusion usually shows a lymphocytic exudative effusion.1 In our series, 23 of 32 patients (71%) showed lymphocytic (> 50%) fluid. A neutrophil predominance (63.6 ± 6.3%, mean ± SEM) was found in the other nine patients (29%).

Some reports have shown the importance of the determination of pleural ADA in the differential diagnosis of tuberculous and nontuberculous pleural effusions.8 ,9 ,10 ,11 ,12 Specificity and sensitivity of the ADA test in TB are very high.8 ,9 ,10 Mean ADA activity was 73.8 ± 11.9 (mean ± SEM) in our series and 2 of 20 patients (10%) showed ADA activity < 40 U/L (Table 4 ). The sensitivity of test for values of >= 40 U/L is 90%. No statistical differences in ADA levels between negative or positive bacteriology and negative or positive histologic pleural biopsy findings were found.

Bacteriologic confirmation of childhood TB ranged from 20 to 42%4 ,6 in reported series. In our series, bacteriologic confirmation was achieved in 22 patients (56.4%). Most of our cases (17/22) were diagnosed on the basis of a culture of M tuberculosis from pleural biopsy material or pleural fluid.

Ziehl-Neelsen stain recovery rate is very low in our review (5.49%), as in reported series.4 ,6 Gastric aspirate, pleural fluid, and biopsy material cultures yielded M tuberculosis in 2 of 9 (22.2%), 15 of 34 (44.1%), and 12 of 18 (66.6%), respectively, of samples submitted for culture. No clinical, laboratory, and radiographic differences between patients with and without positive pleural biopsy culture were seen.

Pleural biopsy histologic examination revealing granulomatous inflammation is frequently used as a diagnostic criterion for pleural TB.1 In our series, 18 of 23 (78.3%) pleural biopsy specimens showed granulomatous inflammation. Four patients showed positive pleural biopsy histologic findings but negative mycobacterial cultures and Ziehl-Neelsen stains. Pleural fluid LDH levels were significantly higher in patients with positive histologic findings (1,171 ± 166 U/L vs 514 ± 97 U/L, p = 0.003). The combination of culture and histologic examination of pleura has been described as the most sensitive diagnostic test for pleural TB. Our data support the use of pleural fluid and biopsy cultures and pleural histologic examination in the approach to the pediatric patient with suspected TPE.

Tuberculous pleurisy is associated with low bacterial populations, as shown by the high index of negative sputum smears and the lack of positive cultures of pleural fluid and biopsy material.13 A short course of chemotherapy with two bactericidal drugs is effective in the treatment of tuberculous pleurisy.13 ,14 ,15 In our series, antituberculous therapy for 6 to 9 months with rifampicin and isoniazid, along with initial supplement of ethambutol/pyrazinamide, was effective in all cases. Side effects of the drugs occurred in one case (transient toxic hepatitis), which represents 2.9% of all cases.


   Footnotes
 
Correspondence to: José M. Merino, MD, Pediatric Department, Hospital General Yagüe, Avda. del Cid, s/n, 09006 Burgos, Spain

Abbreviations: ADA = adenosine deaminase activity; LDH = lactate dehydrogenase; TB = tuberculosis; TPE =tuberculous pleural effusion

Received for publication February 6, 1998. Accepted for publication August 27, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Seibert, AF, Haynes, J, Jr, Middleton, R, et al (1991) Tuberculous pleural effusion: twenty-year experience. Chest 99,883-886[Abstract/Free Full Text]
  2. Waagner, DC (1993) The clinical presentation of tuberculous disease in children. Pediatr Ann 22,622-628[ISI][Medline]
  3. Page McAdams, H, Erasmus, J, Winter, JA (1995) Radiologic manifestations of pulmonary tuberculosis. Radiol Clin North Am 33,655-676[ISI][Medline]
  4. Shaaf, HS, Beyers, N, Gie, RP, et al (1995) Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations. Pediatr Infect Dis J 14,189-194[ISI][Medline]
  5. Tournier, G (1994) Tuberculose de l'enfant. Rev Pneumol Clin 50,288-294[Medline]
  6. Pineda, PR, Leung, A, Muller, NL, et al (1993) Intrathoracic paediatric tuberculosis: a report of 202 cases. Tuber Lung Dis 74,261-266[CrossRef][ISI][Medline]
  7. Agrons, GA, Markowitz, RI, Kramer, SS (1993) Pulmonary tuberculosis in children. Semin Roentgenol 2,158-172[CrossRef]
  8. Fontán, J, Verea, H, Pérez, J, et al (1988) Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusions. Chest 93,303-307[Abstract/Free Full Text]
  9. Ocaña, I, Martínez-Vazquez, JM, Segura, RM, et al (1983) Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion. Chest 84,51-53[Abstract/Free Full Text]
  10. Orriols, R, Coloma, R, Ferrer, J, et al (1994) Adenosine deaminase in tuberculous pleural effusion. Chest 106,1633-1634[Free Full Text]
  11. Bandrés, R, Abal, J, Blanco, J, et al (1994) Actividad de adenosindesaminasa en líquido pleural: estudio realizado en 64 casos. Arch Bronconeumol 30,8-10[Medline]
  12. Serra, J, Jané, X, Solé, C, et al (1991) Adenosina desaminasa como parámetro diagnóstico del derrame pleural tuberculoso. Med Clin 96,636-637
  13. Cañete, C, Galarza, I, Granados, A, et al (1994) Tuberculous pleural effusion: experience with 6 months of treatment with isoniazid and rifampicin. Thorax 49,1160-1201[Abstract]
  14. Dutt, AK, Moers, D, Stead, WW (1992) Tuberculous pleural effusion: 6-month therapy with isoniazid and rifampin. Am Rev Respir Dis 145,1429-1432[ISI][Medline]
  15. Malik, SK, Behera, D, Gilhotra, R (1987) Tuberculous pleural effusion and lymphadenitis treated with rifampin-containing regimen. Chest 92,904-905[Abstract/Free Full Text]



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