Currently, tuberculosis remains the most morbid and deadly preventable infectious disease worldwide. Tuberculous pleural effusion is a common form of extrapulmonary TB, second only to lymph node TB. Tuberculous pleural effusion occurs in approximately 5% of TB patients.
I. Clinical features
Most tuberculous pleural effusions have an acute onset, with symptoms appearing within 1 week in about 1/3 of patients and within 1 month in 2/3 of patients. The most common symptoms are pleuritic pain (75%) and dry cough (70%). Tuberculous pleural effusions tend to occur in young adults with a mean age of 28 years compared to 54 years for substantial pulmonary TB. Epstein et al. found an increased median age (5 years) for the development of tuberculous pleural effusions in patients with secondary pulmonary TB. Therefore, pleural tuberculosis should be considered in any adult or older patient with unilateral pleural effusion.
The typical TB pleural effusion is a small to moderate unilateral pleural effusion, usually no more than 2/3 of the unilateral pleural cavity, and HIV-positive patients with TB pleural effusion have a higher rate of positive pleural fluid smears and cultures for Mycobacterium tuberculosis and pleural biopsies, as well as a higher rate of focal dissemination. Patients with tuberculosis are also more likely to have fever, dyspnea, night sweats, malaise, diarrhea, marked shortness of breath, hepatosplenomegaly and lymph node tuberculosis, and usually have a negative tuberculin test, low hematocrit and high beta2-microglobulin; pleural fluid tests often show low albumin and high globulin.
Chronic tuberculous pustulosis is a manifestation of chronic active infection in the pleural cavity and is less common than tuberculous pleural effusion. Tuberculous abscess pleura is often caused by the following routes.
(1) progression of a primary tuberculous pleural effusion combined with a large amount of pleural fluid
(2) direct spread of lesions from the thoracic lymph nodes or subtransverse septum to the pleural cavity
(3) Bloodstream dissemination.
(4) Post-pneumonectomy. The abnormality can be found in the routine chest X-ray of chronic tuberculous pustular chest.
II. Diagnosis
The diagnosis of tuberculous pleural effusion is confirmed by finding Mycobacterium tuberculosis in sputum, pleural fluid, or pleural biopsy. The diagnosis is also supported by the finding of tuberculous granuloma in the pleura and an increase in pleural fluid ADA.
1. Sputum examination
The traditional view is that sputum examination for pleural TB without pulmonary lesions should be negative and non-infectious. However, a study [4] showed that the single positive rate of induced sputum culture was already very high (52%) and the positive rate of sputum smear was 12%. Even in patients with normal lung parenchyma on chest radiograph, the positive rate of induced sputum culture can still be up to 55%.
2. Tuberculin test
For areas with low incidence of TB (or no vaccine), a positive tuberculin test result is often a strong evidence for the diagnosis of TB pleural effusion. However, 1/3 of patients still have a negative tuberculin test. This is mainly because of.
(1) Immunosuppressed state or severe malnutrition.
(2) Recent infection.
(3) suppression of peripheral blood-specific T lymphocytes by circulating monocytes.
(4) sequestration of purified protein derivatives of T lymphocytes in the pleural space. However, once immune function returns to normal or the tuberculin test is repeated 6 to 8 weeks after a recent infection, the results are almost always positive.
3. Imaging
Chest radiographs of patients with tuberculous pleural effusion usually show a small to moderate amount of unilateral pleural effusion. Ultrasonography reveals fibrin bands of various lengths, mobile microsegments, encapsulated pleural effusion, pleural hypertrophy, and occasional pleural nodules, all of which are helpful in the diagnosis of TB pleural effusion, and CT-enhanced scans can show the associated substantial injuries and lymph node lesions, thus improving the correct diagnosis. CT scans of the chest in patients with TB pleural effusion reveal 86% of combined parenchymal lung injury and 37% of active TB. In addition, CT can also detect complications of tuberculous pleural effusion, such as pleural hypertrophy, calcification, limited exudate, abscess chest, self-inflating abscess chest and bronchopleural fistula.
4.Thoracentesis
General examination of pleural fluid
Typical tuberculous pleural effusion is straw yellow and clear; sometimes it may be cloudy or plasma but never obviously bloody. TB pleural fluid is usually exudative in nature, with a pH usually ranging from 7.30 to 7.40, although 20% of TB pleural fluid is < 7.30. 80% to 85% of TB pleural fluid has a glucose concentration > 3.33 mmol/L, and about 15% of TB pleural fluid has a glucose concentration < 1.67 mmol/L. In the early stages of disease, the pleural fluid cell count shows predominantly In the early stage of the disease, the pleural fluid cell count showed predominantly neutrophils, but successive chest penetration lymphocytes gradually became the predominant cells. Early literature showed few mesothelial cells >5% in TB pleural effusions. However, a large number of mesothelial cells can be seen in tuberculous pleural effusions in patients with HIV infection. In addition, eosinophilia is rarely seen in tuberculous pleural effusions unless there is a combined pneumothorax or combined thoracic hemorrhage after thoracentesis.
Pleural fluid smear and culture
Direct detection of pleural fluid by Zeihl Neelsen staining requires a density of 10,000/ml of mycobacteria; therefore, the detection rate of acid-resistant mycobacteria by this method is <10%. However, in patients with co-infection with hiv, the detection rate can be >20%. Pleural fluid cultures require at least 10 to 100 viable organisms, so the positivity rate can be 12 to 70%, with the majority of cases showing <30% positive pleural fluid cultures in tuberculous pleural effusions. The use of bedside pleural fluid inoculation and the application of liquid media or bactec systems can improve the sensitivity of mycobacterial cultures. In addition, the detection time using the radioactive mycobacterial culture system is much faster than the conventional method (from 33 days to 18 days.)
Adenosine deaminase (adenosine deaminase , ADA)
Piras et al. first reported a significant increase in ADA levels in patients with tuberculous pleural effusion in 1978. Various subsequent studies have found that ADA levels in pleural fluid > 70 IU/L are highly suggestive of tuberculosis, and conversely, if < 40 IU/L, tuberculosis can be largely excluded. The ADA test is widely used because of its low cost, low invasiveness, convenience, and high sensitivity and specificity of 95% and 90%, respectively. However, the ADA of pleural fluid can also be increased in patients with lymphocyte-rich pleural fluid such as rheumatoid arthritis, bronchoalveolar carcinoma, mesothelioma, mycoplasma and chlamydial pneumonia, psittacosis, pulmonary schistosomiasis, infectious mononucleosis, prurigo, Mediterranean fever, histoplasmosis, coccidioidomycosis, and most pustules. HIV/AIDS and organ transplantation The ADA activity in postoperative patients is comparable to that of immunocompetent individuals.ADA has two isozymes, ADA1 and ADA2, both of which selectively use deoxyadenosine as a substrate.ADA1 is found in all cells and its activity is highest in lymphocytes and monocytes.ADA2 is mainly found in monocytes/macrophages. A study [7] found that the increased ADA activity in tuberculous pleural effusions was mainly caused by ADA2, with a median contribution ratio of 88%. Therefore, pleural fluid with high ADA activity and ADA1/total ADA < 0.45 is highly suggestive of possible tuberculosis, and isoenzyme assays can further improve the diagnostic value of ADA in pleural fluid.
Recently, we also performed a systematic evaluation of the English literature to summarize the sensitivity, specificity, and other indices of ADA for the diagnosis of tuberculous pleural effusion in each study using a random-effects model, to plot summary subject workup characteristics curves and to explore its diagnostic properties. The results showed that 61 independent studies were included in this meta-analysis according to the selection criteria, and the overall sensitivity of ADA for the diagnosis of TB pleural effusion: 0.92 (95% CI 0.91 C 0.93), specificity: 0.90 (95% CI 0.89 C 0.91), positive likelihood ratio: 8.82 (95% CI 7.05 C 11.04), negative likelihood ratio : 0.10 (95% CI 0.07 C 0.14), and diagnostic advantage ratio: 105.15 (95% CI 68.38 C 167.89). Therefore, the sensitivity and specificity of ADA for the diagnosis of tuberculous pleural effusion are high, and the measurement of ADA in PE helps to diagnose tuberculous pleural effusion. Analysis of ADA measurement results should be combined with clinical findings as well as routine test results.
Interferon-gamma (IFN-γ)
Although the efficiency of the IFN-γ assay for the diagnosis of tuberculous pleural effusion has been widely studied, the diagnostic value of IFN-γ remains controversial. An earlier published meta-analysis showed that the diagnostic efficiency of IFN-γ assay in PE for TB pleural effusion was quite high, but the paper did not evaluate the positive likelihood ratio, the negative likelihood ratio, or the diagnostic advantage ratio. The meta-analysis included 13 relevant early studies, and additional clinical studies of IFN-γ concentration assays have been reported since then. Recently, we again performed a new meta-analysis aimed at elucidating the overall diagnostic efficiency of IFN-γ for tuberculous pleural effusion. Twenty-two independent studies in English were eventually included in this meta-analysis according to the inclusion criteria [9]. A random effects model was applied to calculate the overall sensitivity: 0.89 [95% confidence interval (CI) 0.87 C 0.92], specificity: 0.97 (95% CI 0.96 C 0.98), positive likelihood ratio: 24.6 (95% CI 18.0 C 33.5), negative likelihood ratio: 0.11 (95% CI 0.07 C 0.16), diagnostic dominance ratio: 301.2 (95% CI 159.2 C 569.9). The results of this meta-analysis showed that the sensitivity and specificity of IFN-γ assay for the diagnosis of tuberculous pleurisy are high, and the determination of IFN-γ concentration in PE is helpful for the diagnosis of tuberculous pleurisy, which can be combined with clinical manifestations and routine test results for comprehensive analysis.
Polymerase chain reaction (PCR)
PCR is positive in 100% of culture-positive pleural fluid from tuberculous pleural effusions, while it is negative in only 30-60% of culture-negative pleural fluid. The sensitivity of the Mycobacterium bifidum genome is higher when the sample is ploidized and then systematically amplified with DNA fragments than when target amplification is performed on a single sample only. The advantages of PCR include: rapid diagnosis, greatly improved specificity and sensitivity, and no need for the subject to have complete immune function. the disadvantages of PCR include: expensive, high risk of contamination, and its operation is not yet available as a routine diagnostic method for clinical use.
5.Pleural biopsy
Since its first application in 1955, mural pleural biopsy has become the most sensitive method for diagnosing tuberculous pleural effusion. Histological examination of pleural tissue can reveal granulomatous inflammation, caseous necrosis, or antacid mycobacteria. Granulomas are found on pleural biopsy in 50% to 97% of patients with tuberculous pleural effusion, and Mycobacterium avium can be cultured in 39% to 80%. Even in cases where no granulomas are found, the biopsy tissue should be examined for AFB. Other granulomatous pleuritis such as fungal disease, nodular disease, rheumatoid arthritis, and Nocardia need to be excluded.
6.Thoracoscopy
Thoracoscopy is widely used in the diagnosis of pleural tuberculosis and malignancy, and can detect yellowish-white nodules, erythema, and extensive adhesions on the mural pleura, as well as biopsy of suspected lesions, especially in the area of the cribriform angle. A study comparing various diagnostic tools for tuberculous pleural effusion concluded that thoracoscopy is the most accurate and expensive diagnostic method, with 100% histologic accuracy and 76% culture positivity rate.
III. Treatment
1.Anti-tuberculosis drugs
The natural course of untreated tuberculous pleural effusion is usually 4 to 16 weeks, with 43% to 65% of cases progressing to active tuberculosis or other extrapulmonary tuberculosis after several years. It is important to properly diagnose and treat TB pleural effusions. According to the guidelines for treatment with short-course therapy, a standard regimen should be used for patients with severe disease with extensive or bilateral pleural effusions and positive sputum coating (acute treatment with 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by maintenance with isoniazid and rifampin for 4 months). In case of pure tuberculous pleural effusion, isoniazid, rifampin, pyrazinamide should be used for 2 months, followed by isoniazid and rifampin for 4 months of maintenance. However, some limited tuberculous pleural effusions may have delayed complete resorption of their pleural fluid even after completing 6 months of anti-TB therapy.
The emergence of multidrug resistance tuberculosis (MDR-TB) poses a serious threat to TB treatment. Appropriate use of second-line drugs, supervised treatment, prompt review of imaging and bacteriology with attention to clinical manifestations, and optimal timing of surgical treatment are all key to the treatment of MDR-TB. New treatment options, such as DOTS-Plus (Directly Observed Therapy Supplement to Short Course Supervised Chemotherapy), have shown promising results for MDR-TB in the developmental stage and have a bright future.
Patients with TB pleural effusion in combination with HIV/AIDS are treated essentially the same as patients with non-HIV/AIDS TB pleural effusion. Clinicians should be aware of interactions between highly active antiviral drugs and antituberculosis drugs, drug side effects, antagonistic effects or immune reconstitution inflammatory syndrome, the latter often manifesting as worsening symptoms, such as an increase in the amount of pre-existing pleural fluid, or the appearance of pleural fluid during the course of treatment.
2.Glucocorticoids
The anti-inflammatory effect of glucocorticoids can accelerate the absorption of pleural fluid and prevent pleural adhesions in the anti-TB process. Three randomized trials have studied the effects of oral glucocorticoids in tuberculous pleural effusions. Clinical symptoms such as fever, chest pain and dyspnea were relieved at an early stage when taken at a dose of 0.75-1 mg/kg/d for 4 to 12 weeks. Although there was a tendency to reduce the amount of residual pleural water at the end of the course of treatment, follow-up did not reveal an advantage in preventing pleural thickening or adhesions. Lung function was also essentially the same in the experimental group compared to the control group at the end of the course of treatment. All three studies did not consistently follow patients to death, and no deaths occurred in the studies.The Cochrane evaluation concluded that there was insufficient evidence that hormone application was effective in the treatment of tuberculous pleural effusions. In addition, it has been suggested that hormone application may also increase the likelihood of opportunistic infections in HIV-positive patients. The opposite view is that the application of hormones to inhibit lymphocyte activation and viral replication may slow the progression of HIV disease. Because it does not prolong survival and may increase the risk of Kaposi’s sarcoma, hormone therapy for tuberculous pleural effusion with HIV infection is not recommended at this time.
3. Pleural fluid aspiration or drainage
Wyser et al. recommended early and complete drainage of pleural fluid in addition to anti-tuberculosis treatment, but this option has caused much controversy. A recent study in Taiwan evaluated the effect of pleural fluid drainage in 61 patients with tuberculous pleural effusion receiving standard antituberculosis chemotherapy, and although the time to relief of dyspnea was shortened from 8 to 4 days, there was no difference in the incidence of pleural hypertrophy, fever, or relief of other symptoms. Repeated aspiration or drainage of moderate or massive pleural fluid in addition to antituberculous therapy is currently recommended only in cases of severe symptoms.