Extrapulmonary tuberculosis, part 1: Pleural and lymph node disease
Extrapulmonary tuberculosis, part 1: Pleural and lymph node disease
In the past decade, there has been a significant increase in the prevalence of tuberculosis and its extrapulmonary manifestations worldwide.1 Factors that have contributed to this include the rising number of immunosuppressed persons, the development of drug- resistant strains of Mycobacterium tuberculosis, aging-population demographics, and an increase in the number of health care workers who are exposed to tuberculosis.2 The incidence of extrapulmonary manifestations is approximately 50% in patients who have both AIDS and tuberculosis, compared with 10% to 15% in HIV-negative patients with tuberculosis.3
Tuberculosis that involves the lymph nodes, bone (excluding the spine), peripheral joints, or skin is classified as a less severe form of disease. The severe forms include meningitis, abdominal involvement, miliary tuberculosis, pericarditis, bilateral or extensive pleural effusion, spinal involvement, and genitourinary involvement.
In some patients, it can be difficult to make the diagnosis of extrapulmonary tuberculosis. Although imaging studiesor a positive tuberculin skin test may support the diagnosis, negative results do not exclude extrapulmonary tuberculosis.4 However, recognition of the common and uncommon radiologic findings can be helpful.
In a series of articles, we will focus on the more common forms of extrapulmonary tuberculosis. In this article, we will review the presentation and diagnosis of pleural and lymph node (peripheral and mediastinal) involvement. In coming issues of The Journal of Respiratory Diseases, we will discuss CNS, abdominal, and skeletal manifestations of tuberculosis.
Lymph node involvement and pleural tuberculosis are the 2 most common extrapulmonary manifestations of tuberculosis. Most cases are caused by M tuberculosis; a fewcases caused by other mycobacteria, including Mycobacterium bovis, have been reported.5
Tuberculous pleural effusion is usually seen in children and young adults. It characteristically occurs 3 to 7 months after initial infection with M tuberculosis. An upward shift in the age spectrum and a more frequent association with reactivation disease have been reported in many series in the past decade.6,7
Underlying pulmonary parenchymal disease is also being documented, thereby confounding the classification of pleural disease as extrapulmonary tuberculosis. In general, patients who have tuberculous pleural effusion are younger than patients who have parenchymal tuberculosis.8
Neutrophils appear to play a key role in the initiation of inflammatory reactions in tuberculous effusion. In addition, pleural mesothelial cells produce a neutrophil chemotactic cytokine, interleukin (IL)-8, and a mononuclear cell chemotactic cytokine, monocyte chemotactic peptide-1 (MCP-1). MCP-1 is produced by inflammatory macrophages and endothelial cells. This cytokine may be at least partly responsible forthe recruitment of macrophages.
Transforming growth factor-13 (TGF-13) is an immunosuppressive cytokine and a potent modulator in tissue repair. It suppresses the release of tumor necrosis factor (TNF)-a and TNF-g by inflammatory cells. Levels of TGF-13 are significantly elevated in tuberculous pleural effusion compared with nontuberculous pleural effusion. This may play an important role in regression of granulomatous inflammation and promotion of pleural fibrosis by stimulating mesothelial cells and fibroblasts.
The traditional explanation forthe development of a tuberculous pleural effusion is that a small subpleural focusof M tuberculosis ruptures into the patient's pleural space, initiating an interaction between the bacilli and CD4+ T lymphocytes. The clinical syndrome reflects an in situdelayed hypersensitivity reaction.9,10
A significant decrease in the removal of protein from the pleural cavity has been documented, contrary to an anticipated augmentation in the formation of protein resulting from inflammation. The intense inflammatory reaction obstructs the lymphatic pores in the parietal pleura, resulting in accumulation of protein in the pleural cavity.
The pleural fluid may become loculated as a result of adhesions. The formation of these adhesions depends on pH, cellular components, and fibrinogen content of the fluid; it usually occurs during antituberculosis treatment.
Most patients with pleural involvement complain of pleuritic chest pain followed by nonproductive cough and dyspnea. Although tuberculosis is generally a chronic disease, tuberculous pleural effusion most often manifests as an acute illness. Infrequently, the onset may be less acute, with mild chest pain, low-grade fever, cough, weight loss, and anorexia.
Tuberculous pleural effusion is almost always unilateral and is usually small to moderate in size, although massive effusion can occur. The loculation of effusion prolongs the recovery. In India, tuberculosis is the most common cause of loculated effusion.11
The diagnosis of tuberculous pleural effusion depends on the demonstration of acid-fast bacilli (AFB) in pleural fluid or pleural biopsy specimens, or the presence of caseous granulomas in the pleura. Other supportive findings include tuberculin skin test results and the erythrocyte sedimentation rate.
Radiologic investigations: The chest radiograph usually demonstrates a unilateral pleural effusion (Figure 1). Ultrasonography of the pleural cavity may be helpful when suspected tuberculous pleural effusion is not detected on radiography; it demonstrates septations and pleural thickening.
Ultrasonography and CT scanning are also useful in the diagnosis of an encysted effusion. Most often, loculated effusions occur on the right side along the posterior parietal pleural surface.
Subpulmonic encystment needs to be distinguished from subpulmonic collection of free fluid, since they present with an identical radiologic picture. A lateral decubitus radiograph usually provides the correct diagnosis.
Enzymes and cytokines: The pleural fluid adenosine deaminase (ADA) has long been used as a marker of pleural tuberculosis. The sensitivity and specificity range from 93% to 100% and 76% to 100%, respectively. False-positive results can be caused by pyothorax, lung cancer, lymphoma, or pleural mesothelioma. False-negative results can occur in patients who have an inadequate immune response or early-stage disease.
A ratio of ADA to lysozyme is reported to be useful in differentiating tuberculosis from pyogenic empyema effusion. A threshold value above 3.3 is highly specific for tuberculous pleural effusion.12
Studies have suggested that elevated pleural fluid interferon (IFN)-g can be used as a marker for the diagnosis of tuberculosis. It is now well documented that a significantly higher ratio of IFN-g to IL-4 in the pleural fluid than in the peripheral blood suggests sequestering of TH1 cells in the pleural fluid and is consistent with the presence of pleural tuberculosis.
IL-8 has been shown to be significantly elevated in patients with empyema and parapneumonic effusion, compared with those who have tuberculous pleural effusion.13 Marked elevation of soluble IL-2 receptors in pleural fluid and serum is found in patients with tuberculous pleural effusion and helps distinguish tuberculosis from malignant pleural effusion.14
Pleural fluid examination: On thoracocentesis, pleural fluid is typically straw-colored. The characteristic observation is a high protein content with marked lymphocytosis, although lower protein content may be found in patients with AIDS. The presence of a large number of mesothelial cells (more than 1% of white blood cells) and eosinophils (more than 10%) is strong evidence against the diagnosis of tuberculosis.15
Pleural fluid pH is usually higher than 7.3, and pleural fluid glucose concentration is not significantly decreased. Pleural fluid culture yields M tuberculosis in 13% to 70% of cases. The yield is the same with conventional culture methods and with the rapid diagnostic system. The detection of mycobacterial DNA by polymerase chain reaction has a sensitivity of 61% to 90% and a specificity of 78% to 100%.12 Until the gene amplification tests have proved reliable and quality-control procedures have been established, the clinical validity of these tests remains controversial.
Pleural biopsy: The combination of culture and histopathologic examination of pleural biopsy specimens has been described as the most sensitive diagnostic test for pleural tuberculosis. The histologic finding of granulomatous inflammation is used as a diagnostic criterion for tuberculosis and is seen on pleural biopsy in 50% to 80% of cases.16 However, caution must be exercised in interpreting the presence of granuloma, because other diseases, especially sarcoidosis and fungal infection, can produce similar findings.
The demonstration of AFB on stained smears of pleural fluid, with histopathologic evidence of granulomas, is the gold standard for diagnosis. The combined yield of direct AFB stains of pleural fluid and biopsy tissue, coupled with mycobacterial culture, exceeds 90%.
The pleural biopsy has potential disadvantages, such as pneumothorax and needle breakage. Moreover, patchy involvement of pleura may result in an inconclusive finding on biopsy.
Ultrasonography-guided needle biopsy and video-assisted thoracoscopic pleural biopsy are being used to increase sensitivity. The higher sensitivity of these procedures is related to the delineation of focal pleural abnormalities.17
Since there is a greater burden of bacilli as a result of the impaired host response in patients with HIV infection, the yield of AFB in pleural tissue is significantly higher in these patients than it is in HIV-negative patients.18