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Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?

A. Trajman, M. Pai, K. Dheda, R. van Zyl Smit, A. A. Zwerling, R. Joshi, S. Kalantri, P. Daley, D. Menzies
European Respiratory Journal 2008 31: 1098-1106; DOI: 10.1183/09031936.00147507
A. Trajman
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M. Pai
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K. Dheda
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R. van Zyl Smit
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A. A. Zwerling
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R. Joshi
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S. Kalantri
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P. Daley
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D. Menzies
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Abstract

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested.

  • Biomarkers
  • diagnosis
  • pleuritis
  • sensitivity
  • specificity
  • tuberculosis

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis (TB) and is the most common cause of pleural effusion in many countries 1–3. Pleural TB occurs as a result of a TB antigen entering the pleural space, usually through the rupture of a subpleural focus, followed by a local, delayed hypersensitivity reaction mediated by CD4+ cells 4. This process may occur during primary or re-activation TB and may or may not involve viable bacilli entering the pleural space 5.

The presence of mycobacterial antigens in the pleural space elicits an intense immune response, initially by neutrophils and macrophages 6, 7, followed by interferon (IFN)-γ-producing T-helper cell (Th) type 1 lymphocytes 4, 8, resulting in a lymphocyte-predominant exudative effusion. This cellular trafficking is facilitated by homing surface markers and chemokine gradients 9, 10. This intense but poorly understood local immune response by sensitised lymphocytes to TB antigen is synonymous with the Koch phenomenon 11. A recent study indicates that cells of an alternative T-cell profile, CD4(+)/CD25(+)/FoxP3(+) regulatory T-cells, are expanded in TB pleural effusion and can suppress some effector responses, although the precise role of these cells remains unclear.

Conventional diagnostic tests for pleural TB include microscopic examination of the pleural fluid for acid-fast bacilli, mycobacterial culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue for granulomatous inflammation. These tests have recognised limitations for clinical use, although, in combination, they have been recognised as the best reference standard for evaluation of the accuracy of novel tests 12.

Microscopy of the pleural fluid for acid-fast bacilli is positive in <5% of TB pleuritis cases, due to the paucibacillary nature of the disease 12, 13. Mycobacterial culture of pleural fluid also has low sensitivity (24–58%) 13, 14 and is limited by the lengthy delay in obtaining results: up to 8 weeks if solid culture media are used. Biopsy of pleural tissue for combined histological examination and mycobacterial culture of pleural fluid and tissue is the most sensitive of the currently available diagnostic methods, but may still be falsely negative in 15–20% of these cases 12, 15. In addition, pleural biopsy is invasive, and yield as well as complication rates are dependent on the skill of the operator because it is technically difficult, particularly in children. Hence, biopsy adds considerable risk and cost to the workup. Mycobacterial culture of spontaneous sputum or gastric lavage has a variable yield, from 0% 16 to ∼30% 17, depending on the presence of associated lung parenchymal lesions 17. Since patients with pleural TB rarely produce sputum spontaneously, routine collection of induced sputum has been proposed for the diagnosis of pleural TB. In a prospective study of 113 patients with confirmed pleural TB, induced sputum had a sensitivity of 52%, compared with 12% sensitivity of pleural fluid culture 18. Due to these limitations of conventional tests, plus the delay of several weeks for mycobacterial culture results, newer rapid tests and biomarkers have been evaluated. The present review provides a narrative overview of the literature on the tests, summarised in table 1⇓ and illustrated in figure 1⇓, and reviews their performance characteristics for the diagnosis of pleural TB.

Fig. 1—
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Fig. 1—

Schematic representation of pathways and systems involved in biomarkers for pleural tuberculosis. IFN: interferon; ESAT: early secreted antigenic target; CFP: culture filtrate protein; BMI: body mass index; ADA: adenosine deaminase; TNF: tumour necrosis factor; IL: interleukin.

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Table 1—

Novel tests and biomarkers for the diagnosis of tuberculous pleural effusions

For clarity, all tests were grouped into the following categories, although some overlap exists: 1) nonspecific inflammatory and immune response markers; 2) specific markers of immune response; 3) nucleic acid amplification tests; and 4) scoring systems based on combinations of tests.

NONSPECIFIC INFLAMMATORY AND IMMUNE RESPONSE MARKERS

Adenosine deaminase

Adenosine deaminase (ADA), released by activated lymphocytes, macrophages and neutrophils, is a nonspecific marker of inflammation. The ADA2 isoenzyme released from monocytes and macrophages is the predominant contributor to total ADA activity 49. A high diagnostic accuracy of ADA activity measurement has been reported in several studies. In a meta-analysis, Greco et al. 19 found that among 31 studies published prior to 2000, including 4,738 patients, the pooled sensitivity was 92% (range 56–100%) and pooled specificity was 89% (55–100%) using composite reference standards including culture, histology, sputum culture and response to therapy. The specificity for discriminating TB from malignant effusions, an important differential diagnosis in elderly patients, remained high (95%) but was disappointingly low for parapneumonic effusions.

Greco et al. 19 concluded that in low and intermediate TB incidence settings, the negative predictive value was sufficient that a negative ADA activity result would preclude the need for pleural biopsy. However, in the same settings, the positive predictive value was poor. In contrast, in high prevalence settings, a positive ADA would provide a 99% post-test probability of TB. This crucial point, that the predictive value of a test is highly dependent on the prevalence of the disease, explains the differences in performance of this test in different studies. Thus, the clinical context must be taken into account when interpreting the ADA result.

Many studies in the review by Greco et al. 19 included <30 patients, resulting in wide confidence intervals (CIs) around sensitivity and specificity estimates and significant heterogeneity between estimates. In addition, few studies reported blinding or described in detail the inclusion criteria for the control group.

Using histopathology as the reference standard, pleural fluid ADA activity, PCR and immunoglobulin (Ig)A-ELISA tests were evaluated in a high TB incidence country 20 among 77 patients with pleural effusion, 60 of whom had TB pleuritis. ADA activity was the only test that had a significantly higher sensitivity than histopathological examination. The study included only 17 nontuberculous effusions, and, therefore, specificity could not be adequately estimated 21.

Determination of ADA isoenzyme activity in pleural fluid may increase the accuracy of the test. ADA1 is secreted by lymphocytes and monocytes, while ADA2 is secreted only by monocytes and is found in a higher concentration in TB pleuritis 22, 23. However, because the additional yield is small, a study would require a very large sample size to demonstrate that isoenzymes have significantly higher specificity than total ADA activity.

Neopterin

Neopterin is a marker of Th1 immune activation, as it is secreted by activated macrophages. Neopterin levels in pleural fluid have been found to be higher in patients with TB than patients with malignancy 24, 25 or other 26 conditions. Very high levels of neopterin have been observed in uremic pleural effusions 27, raising doubts about its specificity for TB. In one study that used histological evidence of caseating granuloma as the reference standard for TB, the sensitivity and specificity of neopterin were 44 and 85%, respectively 25. In a second study, which used ADA as the reference standard, the sensitivity was 85% and the specificity was 93% 26. However, ADA may not be a suitable reference standard because it is also an indicator of nonspecific inflammation, so a high degree of correlation may reflect the same underlying inflammatory response as neopterin.

Leptin

Leptin, a 16-kDa product of the obese (ob) gene, may be involved in cross-regulation between nutritional status and the immune response in TB. Serum leptin levels have been shown to be reduced in patients with active pulmonary TB 50 and cancer 51. One study evaluated total leptin pleural fluid levels and leptin pleural fluid/serum ratio in 17 patients with pleural TB, and parapneumonic (n = 7) and malignant (n = 21) effusions 28. The reference standard for TB in this study was the presence of granuloma in pleural tissue. ADA activity was also measured in pleural fluid. Pleural ADA activity sensitivity and specificity were both 100% and pleural leptin (<9.85 ng·mL−1) sensitivity and specificity were 82% (p = 0.01). Thus, there is no evidence that leptin performs better than pleural fluid ADA.

Lysozyme

Lysozyme is present in epithelial cells of granulomas, macrophages and activated granulocytes. In a study of patients with pleural effusion in a setting with high TB incidence, Valdés et al. 29 measured ADA activity in 405 specimens, lysozyme in 276 specimens and IFN-γ in 145 specimens. Using culture of pleural fluid or tissue and histopathological evidence of caseous granuloma in pleural tissue as the reference standard, the sensitivity of ADA, lysozyme and IFN-γ were 100, 85.7 and 94.2%, respectively, while specificities were 94.9, 61.6 and 91.8%, respectively. Thus, ADA and IFN-γ were more accurate than lysozyme levels. However, 51 patients were excluded from the analysis because a final definitive diagnosis could not be achieved, and the criteria for selection of specimens for lysozyme and IFN-γ testing were not reported. For these reasons, potential selection bias cannot be excluded.

Moriwaki et al. 30 found that lysozyme could discriminate malignant from tuberculous effusions with a sensitivity of 100% and a specificity of 83%, compared with culture and/or histopathology of pleural tissue. The pleural fluid/serum lysozyme ratio had a sensitivity of 100% and a specificity of 88%. The mean fibronectin concentration in pleural fluid with tuberculous effusion was significantly higher than that in malignant effusion, but there was a marked overlap between the groups. In this study, lysozyme and fibronectin were less accurate than pleural fluid ADA 30.

Cytokines

Of all the cytokines, IFN-γ has been the most studied. The evidence for use of IFN-γ in pleural fluid for diagnosis of TB has been reviewed by Greco et al. 19 and Jiang et al. 31. In the latter review, based on 22 studies including 782 TB patients and 1,319 non-TB patients, the summary estimate of sensitivity was 89% (95% CI 87–91%) and of specificity was 97% (96–98%) 31. IFN-γ was more sensitive and specific for the diagnosis of pleural TB than interleukin (IL)-12p40, IL-18, immunosuppressive acidic protein or soluble IL-2 receptor, in a study that directly compared these tests in the same samples 33. In another study, the accuracy of IFN-γ was superior to that of ADA 19.

The concentration of other pro-inflammatory cytokines, such as tumour necrosis factor-α and IL-1β, has been shown to be higher in tuberculous than in malignant effusions, but no cut-off value for positivity has been established 34. In another study, IL-8 and IL-6, and soluble IL-6 receptor were detected in carcinomatous but not in tuberculous pleural effusions 52.

Complement activation

Porcel et al. 53 measured SC5b-9 and C3a-desArg, two products of complement activation, in the pleural fluid of 83 patients using commercial ELISA tests. The sensitivity was 84% for SC5b-9 and 81% for C3a-desArg. Hara et al. 35 showed SC5b-9 had a higher sensitivity (100%) and ADA activity had a higher specificity than conventional tests (culture and/or histopathological examination). Discrimination of TB pleuritis from malignant effusions was better than discrimination from autoimmune or parapneumonic effusions. In fact, the SC5b-9 level seemed more useful for the diagnosis of rheumatoid pleural effusions 36 and for differentiation of empyema from uncomplicated parapneumonic effusions 37.

Cell subsets

Tuberculous effusions are usually rich in mononuclear cells 12. In one study, although pleural fluid ADA activity correlated with the number of CD4+ T-cells in the pleural space 38, the number of pleural CD4+ cells was not an accurate diagnostic test for TB.

In conclusion, among the nonspecific inflammatory biomarkers that have been evaluated, ADA and IFN-γ are the most accurate for pleural TB diagnosis, with consistently high sensitivity in many studies. Specificity of ADA is a concern because of the nonspecific nature of inflammatory response. Most studies used in-house methods for ADA activity estimation, which may demonstrate considerable variability in performance. Commercial kits have been used in a few studies, but these kits should be validated in different settings. ADA activity measurement is simple and inexpensive to perform and does not require special equipment, making it an attractive option for settings with high TB incidence and limited resources. In contrast, measurement of IFN-γ is expensive, estimated to be as much as the cost of treatment for six TB patients 32.

SPECIFIC MARKERS OF IMMUNE RESPONSE

T-cell response to specific antigens

Recently, in vitro, T-cell-based IFN-γ release assays (IGRAs) have been developed and licensed for diagnosis of latent TB infection. Normally, these tests use peripheral blood mononuclear cells (PBMCs), but they can be used with pleural fluid mononuclear cells. These assays detect IFN-γ secreted by mononuclear cells in response to in vitro stimulation with the Mycobacterium tuberculosis-specific antigens early secreted antigenic target-6 and culture filtrate protein-10. The genes that encode these antigens are not present in any of the M. bovis bacille Calmette–Guerin (BCG) strains or certain common nontuberculous (environmental) mycobacteria 54. Thus, in theory, the test should not cross-react with antigens present due to BCG vaccination 54, 55. In a recent study 39, the T-SPOT.TB test (Oxford Immunotec Ltd, Oxford, UK) was performed on PBMCs and mononuclear cells from pleural fluid from 20 patients clinically suspected to have TB pleuritis and 21 subjects with other diagnoses. The sensitivity of T-SPOT.TB was 90% using the blood assay and 95% for pleural fluid, but the specificity was only 67% for blood and 76% for pleural fluid. This poor specificity may reflect positive reactions due to coincidental latent TB infection, coexisting or transient infection.

An alternative commercially available T-cell assay using an ELISA platform is the QuantiFERON®-TB Gold in-tube test (Cellestis Ltd, Carnegie, Australia), which is more amenable to high throughput and flexibility with analysis. However, unpublished preliminary observations indicate that high background IFN-γ levels in the negative control tube precludes the use of ex vivo unprocessed pleural fluid in the assay. Pre-specified numbers of mononuclear cells in culture medium may overcome this drawback.

IGRAs, designed to detect latent TB infection, will only be useful for the diagnosis of pleural TB disease if it can be shown that persons with latent TB infection and pleural effusions due to nontuberculous causes, such as cancer, have positive IGRA using serum, but negative IGRA using pleural fluid. This finding would suggest that TB-sensitised lymphocytes remain in peripheral blood but are not present among the lymphocytes found in the pleural fluid. This hypothesis as yet remains unproven. Until this issue is settled, these assays may not offer any additional value for the diagnosis of pleural effusion, beyond the measurement of free IFN-γ in the pleural fluid.

B-cell response (antibody detection)

Although detection of serum antibodies against TB antigens is known to have poor and highly variable sensitivity and specificity 56, 57, attempts have been made to detect antibodies in pleural fluid specimens using techniques such as ELISA. Among pleural fluid antibody tests, detection of IgA against MPT-64 and MT-10.3 (Rv3019c), two recombinant protein antigens, had the best sensitivity 20, 40. Anti-A60 IgM and IgG antibodies in pleural fluid had suboptimal sensitivity for TB 41. Using antibodies against five different antigens, Chierakul et al. 42 found the performance of serology of pleural fluid to be disappointing, with sensitivity and specificity <60%. Anti-P32 levels were reported to be higher among five patients with pleural TB, but the sensitivity and specificity were not reported 43. Sensitivity to anti-lipoarabinomannan (LAM) and to anti-TB glycolipid antibodies was very low in other studies, although specificity was high 44–47.

One study reported a simple and cost-effective diagnostic tool (an in-house TB screen test) for pulmonary and extrapulmonary TB, using a liposome agglutination assay to detect serological responses to purified mycobacterial glycolipid antigens 58. The assay was able to detect very low anti-glycolipid antibody concentrations in the serum of individuals with TB. The status for latent TB in the control group was not reported. To date, the test has not been applied to pleural fluid specimens, although four subjects with pleural TB were serum tested 58.

In conclusion, serologic tests using antibodies against mycobacterial protein and glycolipids show some potential for the diagnosis of pleural TB because of their high specificity, but are limited by very poor sensitivity.

DETECTION OF M. TUBERCULOSIS NUCLEIC ACID SEQUENCES BY AMPLIFICATION TESTS

Several commercial and in-house assays exist for the amplification and detection of M. tuberculosis nucleic acids from specimens such as sputum. These tests have also been used with specimens such as pleural fluids. In a meta-analysis of 40 studies of nucleic acid amplification tests (NAATs) for pleural TB, Pai et al. 48 reported that commercial NAATs have a potential role in confirming TB pleuritis because of high specificity (98 (95% CI 96–98)%). However, these tests had low and variable sensitivity (62 (43–77)%) and, therefore, were not useful in excluding the disease. The accuracy of in-house NAATs was poorly defined because of heterogeneity across studies, presumably reflecting the heterogeneity of in-house test protocols. Similar results have been reported with NAATs for TB meningitis 59 and TB lymphadenitis 60.

The reasons for the low sensitivity of NAATs in pleural fluid specimens are unclear. The presence of inhibitory substances in pleural fluid is an unsatisfactory explanation, as most commercial assays have an internal positive control to account for inhibition. The small amount of mycobacteria in pleural effusion may play some role, but the low sensitivity is more likely to be related to a technical aspect of nucleic acid extraction. Thus, caution is needed when interpreting negative NAAT results in pleural fluids, and performance will depend largely on pre-test probability.

In conclusion, the evidence is consistent that NAATs have modest sensitivity but excellent specificity for pulmonary and extrapulmonary TB. At present, no commercial kit has been approved by the US Food and Drug Administration for the diagnosis of extrapulmonary TB, and NAATs cannot be used in isolation to rule in or rule out pleural TB.

SCORING SYSTEMS BASED ON COMBINATIONS OF MARKERS

Due to the limitations of individual tests, scoring systems have been developed, based on the results of multiple tests (table 2⇓). A scoring system that makes use of simple clinical and pleural fluid data was created by Porcel and Vives 61 to discriminate between TB and malignant pleural effusions. Two models were developed, one with and one without ADA activity measurement. In the first model, four variables predicted a tuberculous aetiology: ADA ≥40 U·L−1 (five points); age <35 yrs (two points); temperature ≥37.8°C (two points); and pleural fluid red blood cell count <5×109·L−1 (one point). In the second model, TB was predicted by: age <35 yrs (two points); temperature ≥37.8°C (two points); pleural fluid red blood cell count <5×109·L−1 plus no history of malignancy (three points); pleural protein ≥50 g·L−1 (one point); and pleural fluid/serum lactate dehydrogenase ratio ≥2.2 (one point). Summated scores of at least five in model one and at least six in model two yielded measures of sensitivity (95 and 97%, respectively) and specificity (94 and 91%, respectively) for discriminating TB from malignant effusions.

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Table 2—

Combination of tests and biomarkers for the diagnosis of tuberculous pleural effusions

Villegas et al. 62 also proposed a combination of clinical and biological markers. In their study, ADA activity, IFN-γ levels and PCR were tested in the same samples for the diagnosis of microbiologically and/or histologically confirmed pleural TB. The sensitivities of ADA activity, IFN-γ levels and PCR were 88, 86 and 74%, respectively, and the specificities were 86, 97 and 90%, respectively. The combination of PCR, IFN-γ and ADA activity allowed an increase of sensitivity and specificity compared with individual methods in isolation. However, in other studies using different tests in the same samples, in which ADA activity had a higher accuracy, no other test significantly added sensitivity to the ADA 20, 65.

In a logistic regression model, a combination of duration of disease, protein levels, total leukocyte count, percentage of lymphocytes and ADA activity measurement was >95% sensitive and specific for the diagnosis of TB in a high prevalence setting 63. The first four variables added specificity to ADA activity, without loss of sensitivity. The lymphocyte/neutrophil ratio has also added to ADA specificity in another study of 472 pleural effusions 64.

More models, which take into account clinical features and simple, inexpensive and rapid diagnostic tests, can be developed with the use of modelling tools. These models are highly relevant to clinicians practising in poor resource settings. Even when ADA is unavailable, use of demographic and clinical information in combination with a cell differential count, in high incidence settings, can yield a diagnosis of TB with a high predictive value.

EMERGING TECHNOLOGIES THAT NEED TO BE EVALUATED FOR PLEURAL TB

In the past few years, several new TB diagnostics have been developed. These include tests such as loop-mediated isothermal amplification, detection of LAM (a TB antigen) using ELISA, phage-based assays and rapid culture systems 66, 67. To date, none of these have been adequately evaluated for TB pleuritis.

In addition to laboratory tests, biological processes found in nature are being used to inspire the development of new technologies. Artificial intelligence represents an attempt to simulate the human brain in resolving complex questions by breaking them down into small problems. Neural network systems have been used to extract relevant information from complex databases, categorise them into groups with similar characteristics and organise them into distinct patterns 68. The neural network system can help in identifying patients’ variables that may not make biomedical sense but could be relevant for the diagnosis of diseases. It can also detect errors in databases. This tool has been useful in predicting pulmonary TB in patients with negative sputum smears 69, 70. The tool can also easily generate scoring models based on clinical and laboratory data. Research is needed to evaluate the usefulness of neural network systems for the diagnosis of pleural TB.

FUTURE DIRECTIONS

Table 3⇓ presents some suggested research directions. Diagnostic studies on pleural TB are particularly needed in specific populations, including individuals with HIV infection, children and other high-risk populations where traditional diagnostic tests have worse yield. In addition, commercially available tests for diagnosis of pulmonary TB should be validated for diagnosis of pleural TB. Better tests are needed, and/or available tests, such as NAAT or serologic tests that have good specificity, need to be modified to improve sensitivity.

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Table 3—

Recommendations for future research

Multidrug-resistant and extensively drug-resistant TB are spreading worldwide and have become a special issue for TB control. There are no reports on the drug-resistance profile of strains isolated from pleural specimens, but given the trend of ever-increasing resistance, development of new techniques, such as NAATs, to identify drug-resistant strains causing pleural TB will be important.

Efforts are also needed to improve the quality and reporting of TB diagnostic studies, according to the Standards for Reporting of Diagnostic Accuracy recommendations 71. The main limitation of many published studies is the absence of a well-defined reference standard (culture and histopathological evidence of TB), leading to test performance results that may be biased. In addition to the lack of a definitive gold standard, diagnostic studies are plagued by methodological and design flaws that compromise validity, such as lack of a consecutive or random patient-sampling method, use of a case–control design (where severe cases are often compared with healthy controls) and lack of blinding 72–74. Statistical analysis of results should receive special attention in future studies 21, 75. Sensitivities and specificities are proportions, and their confidence intervals must be calculated and reported 75. When using statistical tests for comparison of sensitivities, only patients with the disease should be compared, while for specificity, only patients without the disease should be compared 21.

CONCLUSION

Diagnosis of pleural TB remains a challenge, as summarised in table 1⇑. Among nonconventional tests, ADA and IFN-γ have the best sensitivity and specificity, but they are biomarkers of the inflammatory process in the pleural space and do not confirm the aetiologic agent. NAATs and serology are promising but need further development to improve sensitivity. Limited evidence is available for other novel tests and biomarkers.

Combinations of tests seem to perform better than any single test, especially combinations that include adenosine deaminase, but only a few studies have evaluated scoring systems (table 2⇑). Further work is necessary to identify the best (and simplest) combination that will be most useful in clinical practice.

Support statement

For a full list of all grants and funding received, please see the Acknowledgements section.

Statement of interest

None declared.

Acknowledgments

A. Trajman received funding from an International Clinical, Operational and Health Services Research Training Award for AIDS and TB, Fogarty International Center, National Institutes of Health, no. 5U2 R TW006883-03. M. Pai is supported by a Canadian Institutes of Health Research New Investigator Award, and D. Menzies by a Fonds de la Recherche en Santé du Québec Chercheur National salary award. K. Dheda is supported by a South African National Research Foundation Research Chair award and a Medical Research Council career development award. R. Joshi is a recipient of a training fellowship from the Fogarty AIDS International Training Program, grant no. 1-D43-TW00003-17, USA.

  • Received November 6, 2007.
  • Accepted January 24, 2008.
  • © ERS Journals Ltd

References

  1. ↵
    Liam CK, Lim KH, Wong CM. Causes of pleural exudates in a region with a high incidence of tuberculosis. Respirology 2000;5:33–38.
    OpenUrlCrossRefPubMed
  2. Selig L, Cunha AJLA, Teixeira EG, Belo MTCT, Branco MMC, Trajman A. [Anti-HIV testing for tuberculosis patients in Rio de Janeiro State]. Pulmão RJ 2001;10:8–13.
    OpenUrl
  3. ↵
    Valdés L, Pose A, San José E, Martinez Vázquez JM. Tuberculous pleural effusions. Eur J Intern Med 2003;14:77–88.
    OpenUrlCrossRefPubMed
  4. ↵
    Barnes PF, Mistry SD, Cooper CL, Pirmez C, Rea TH, Modlin RL. Compartmentalization of a CD4+ T lymphocyte subpopulation in tuberculous pleuritis. J Immunol 1989;142:1114–1119.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Kim HJ, Lee HJ, Kwon SY, et al. The prevalence of pulmonary parenchymal tuberculosis in patients with tuberculous pleuritis. Chest 2006;129:1253–1258.
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    Antony VB, Repine JE, Harada RN, Good JT Jr, Sahn SA. Inflammatory responses in experimental tuberculosis pleurisy. Acta Cytol 1983;27:355–361.
    OpenUrlPubMedWeb of Science
  7. ↵
    Antony VB, Sahn SA, Antony AC, Repine JE. Bacillus Calmette-Guérin-stimulated neutrophils release chemotaxins for monocytes in rabbit pleural spaces and in vitro. J Clin Invest 1985;76:1514–1521.
    OpenUrlCrossRefPubMedWeb of Science
  8. ↵
    Sharma SK, Mitra DK, Balamurugan A, Pandey RM, Mehra NK. Cytokine polarization in miliary and pleural tuberculosis. J Clin Immunol 2002;22:345–352.
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    Gopi A, Madhavan SM, Sharma SK, Sahn SA. Diagnosis and treatment of tuberculous pleural effusion in 2006. Chest 2007;131:880–889.
    OpenUrlCrossRefPubMedWeb of Science
  10. ↵
    Mitra DK, Sharma SK, Dinda AK, Bindra MS, Madan B, Ghosh B. Polarized helper T cells in tubercular pleural effusion: phenotypic identity and selective recruitment. Eur J Immunol 2005;35:2367–2375.
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    Dheda K, Booth H, Huggett JF, Johnson MA, Zumla A, Rook GA. Lung remodeling in pulmonary tuberculosis. J Infect Dis 2005;192:1201–1209.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Light RW. Useful tests on the pleural fluid in the management of patients with pleural effusions. Curr Opin Pulm Med 1999;5:245–249.
    OpenUrlCrossRefPubMed
  13. ↵
    Bueno EC, Clemente GM, Castro CB, et al. Cytologic and bacteriologic analysis of fluid and pleural biopsy specimens with Cope's needle. Study of 414 patients. Arch Intern Med 1990;150:1190–1194.
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    Seibert AF, Haynes J Jr, Middleton R, Bass JB Jr. Tuberculous pleural effusion. Twenty-year experience. Chest 1991;99:883–886.
    OpenUrlCrossRefPubMedWeb of Science
  15. ↵
    Palomino JC, Leão SC, Ritacco V. eds. Tuberculosis 2007. From Basic Science to Patient Care. 1st Edn. www.tuberculosistextbook.com/tuberculosis2007.pdf Date last accessed: February 21, 2008. Date last updated: June 2007
  16. ↵
    Arrington CW, Hawkins JA, Richert JH, Hopeman AR. Management of undiagnosed pleural effusions in positive tuberculin reactors. Am Rev Respir Dis 1966;93:587–593.
    OpenUrlPubMedWeb of Science
  17. ↵
    Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973;63:88–92.
    OpenUrlCrossRefPubMedWeb of Science
  18. ↵
    Conde MB, Loivos AC, Rezende VM, et al. Yield of sputum induction in the diagnosis of pleural tuberculosis. Am J Respir Crit Care Med 2003;167:723–725.
    OpenUrlCrossRefPubMedWeb of Science
  19. ↵
    Greco S, Girardi E, Masciangelo R, Capoccetta GB, Saltini C. Adenosine deaminase and interferon-γ measurements for the diagnosis of tuberculous pleurisy: a meta-analysis. Int J Tuberc Lung Dis 2003;7:777–786.
    OpenUrlPubMedWeb of Science
  20. ↵
    Trajman A, Kaisermann C, Luiz RR, et al. Pleural fluid ADA, IgA-ELISA and PCR sensitivities for the diagnosis of pleural tuberculosis. Scand J Clin Lab Invest 2007;67:877–884.
    OpenUrlCrossRefPubMedWeb of Science
  21. ↵
    Trajman A, Luiz RR. McNemar Chi(2) test revisited: comparing sensitivity and specificity of diagnostic examinations. Scand J Lab Clin Invest 2008;68:77–80.
    OpenUrlCrossRef
  22. ↵
    Pérez-Rodríguez E, Pérez Walton IJ, Sanchez Hernández JJ, et al. ADA1/ADAp ratio in pleural tuberculosis: an excellent diagnostic parameter in pleural fluid. Respir Med 1999;93:816–821.
    OpenUrlCrossRefPubMedWeb of Science
  23. ↵
    Gorguner M, Cerci M, Gorguner I. Determination of adenosine deaminase activity and its isoenzymes for diagnosis of pleural effusions. Respirology 2000;5:321–324.
    OpenUrlCrossRefPubMed
  24. ↵
    Baganha MF, Mota-Pinto A, Pêgo MA, Marques MA, Rosa MA, Cordeiro AJ. Neopterin in tuberculous and neoplastic pleural fluids. Lung 1992;170:155–161.
    OpenUrlPubMedWeb of Science
  25. ↵
    Cok G, Parildar Z, Basol G, et al. Pleural fluid neopterin levels in tuberculous pleurisy. Clin Biochem 2007;40:876–880.
    OpenUrlCrossRefPubMedWeb of Science
  26. ↵
    Tozkoparan E, Deniz O, Cakir E, et al. The diagnostic values of serum, pleural fluid and urine neopterin measurements in tuberculous pleurisy. Int J Tuberc Lung Dis 2005;9:1040–1045.
    OpenUrlPubMedWeb of Science
  27. ↵
    Chiang CS, Chiang CD, Lin JW, Huang PL, Chu JJ. Neopterin, soluble interleukin-2 receptor and adenosine deaminase levels in pleural effusions. Respiration 1994;61:150–154.
    OpenUrlPubMedWeb of Science
  28. ↵
    Celik G, Kaya A, Poyraz B, et al. Diagnostic value of leptin in tuberculous pleural effusions. Int J Clin Pract 2006;60:1437–1442.
    OpenUrlCrossRefPubMedWeb of Science
  29. ↵
    Valdés L, San José E, Alvarez D, et al. Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon-γ. Chest 1993;103:458–465.
    OpenUrlCrossRefPubMedWeb of Science
  30. ↵
    Moriwaki Y, Kohjiro N, Itoh M, et al. Discrimination of tuberculous from carcinomatous pleural effusion by biochemical markers: adenosine deaminase, lysozyme, fibronectin and carcinoembryonic antigen. Jpn J Med 1989;28:478–484.
    OpenUrlPubMed
  31. ↵
    Jiang J, Shi HZ, Liang QL, Qin SM, Qin XJ. Diagnostic value of interferon-γ in tuberculous pleurisy: a metaanalysis. Chest 2007;131:1133–1141.
    OpenUrlCrossRefPubMedWeb of Science
  32. ↵
    Sharma SK, Banga A. Pleural fluid interferon-γ and adenosine deaminase levels in tuberculosis pleural effusion: a cost-effectiveness analysis. J Clin Lab Anal 2005;19:40–46.
    OpenUrlCrossRefPubMedWeb of Science
  33. ↵
    Hiraki A, Aoe K, Eda R, et al. Comparison of six biological markers for the diagnosis of tuberculous pleuritis. Chest 2004;125:987–989.
    OpenUrlCrossRefPubMedWeb of Science
  34. ↵
    Hua CC, Chang LC, Chen YC, Chang SC. Proinflammatory cytokines and fibrinolytic enzymes in tuberculous and malignant pleural effusions. Chest 1999;116:1292–1296.
    OpenUrlCrossRefPubMedWeb of Science
  35. ↵
    Hara N, Abe M, Inuzuka S, Kawarada Y, Shigematsu N. Pleural SC5b-9 in differential diagnosis of tuberculous, malignant, and other effusions. Chest 1992;102:1060–1064.
    OpenUrlCrossRefPubMedWeb of Science
  36. ↵
    Salomaa ER, Viander M, Saaresranta T, Terho EO. Complement components and their activation products in pleural fluid. Chest 1998;114:723–730.
    OpenUrlCrossRefPubMedWeb of Science
  37. ↵
    Vives M, Porcel JM, Gázquez I, Pérez B, Rubio M. Pleural SC5b-9: a test for identifying complicated parapneumonic effusions. Respiration 2000;67:433–438.
    OpenUrlCrossRefPubMedWeb of Science
  38. ↵
    Gaga M, Papamichalis G, Bakakos P, et al. Tuberculous effusion: ADA activity correlates with CD4+ cell numbers in the fluid and the pleura. Respiration 2005;72:160–165.
    OpenUrlCrossRefPubMedWeb of Science
  39. ↵
    Losi M, Bossink A, Codecasa L, et al. Use of a T-cell interferon-γ release assay for the diagnosis of tuberculous pleurisy. Eur Respir J 2007;30:1173–1179.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    Kaisermann MC, Sardella IG, Trajman A, et al. IgA antibody responses to Mycobacterium tuberculosis recombinant MPT-64 and MT-10.3 (Rv3019c) antigens in pleural fluid of patients with tuberculous pleurisy. Int J Tuberc Lung Dis 2005;9:461–466.
    OpenUrlPubMedWeb of Science
  41. ↵
    Kunter E, Cerrahoglu K, Ilvan A, et al. The value of pleural fluid anti-A60 IgM in BCG-vaccinated tuberculous pleurisy patients. Clin Microbiol Infect 2003;9:212–220.
    OpenUrlCrossRefPubMedWeb of Science
  42. ↵
    Chierakul N, Damrongchokpipat P, Chaiprasert A, Arjratanakul W. Antibody detection for the diagnosis of tuberculous pleuritis. Int J Tuberc Lung Dis 2001;5:968–972.
    OpenUrlPubMedWeb of Science
  43. ↵
    Van Vooren JP, Farber CM, De Bruyn J, Yernault JC. Antimycobacterial antibodies in pleural effusions. Chest 1990;97:88–90.
    OpenUrlCrossRefPubMedWeb of Science
  44. ↵
    Demkow U, Filewska M, Białas B, et al. [Antimycobacterial antibody level in pleural, pericardial and cerebrospinal fluid of patients with tuberculosis.]. Pneumonol Alergol Pol 2004;72:105–110.
    OpenUrlPubMed
  45. Yokoyama T, Rikimaru T, Kinoshita T, Kamimura T, Oshita Y, Aizawa H. Clinical utility of lipoarabinomannan antibody in pleural fluid for the diagnosis of tuberculous pleurisy. J Infect Chemother 2005;11:81–83.
    OpenUrlCrossRefPubMed
  46. Morimoto T, Takanashi S, Hasegawa Y, et al. Level of antibodies against mycobacterial glycolipid in the effusion for diagnosis of tuberculous pleural effusion. Respir Med 2006;100:1775–1780.
    OpenUrlCrossRefPubMedWeb of Science
  47. ↵
    Anie Y, Sumi S, Varghese P, Madhavi LG, Sathish M, Radhakrishnan VV. Diagnostic approaches in patients with tuberculous pleural effusion. Diagn Microbiol Infect Dis 2007;59:389–394.
    OpenUrlCrossRefPubMedWeb of Science
  48. ↵
    Pai M, Flores LL, Hubbard A, Riley LW, Colford JM Jr. Nucleic acid amplification tests in the diagnosis of tuberculous pleuritis: a systematic review and meta-analysis. BMC Infect Dis 2004;4:6
    OpenUrlCrossRefPubMed
  49. ↵
    Ungerer JP, Oosthuizen HM, Retief JH, Bissbort SH. Significance of adenosine deaminase activity and its isoenzymes in tuberculous effusions. Chest 1994;106:33–37.
    OpenUrlCrossRefPubMedWeb of Science
  50. ↵
    van Crevel R, Karyadi E, Netea MG, et al. Decreased plasma leptin concentrations in tuberculosis patients are associated with wasting and inflammation. J Clin Endocrinol Metab 2002;87:758–763.
    OpenUrlCrossRefPubMedWeb of Science
  51. ↵
    Lagiou P, Signorello LB, Trichopoulos D, Tzonou A, Trichopoulou A, Mantzoros CS. Leptin in relation to prostate cancer and benign prostatic hyperplasia. Int J Cancer 1998;76:25–28.
    OpenUrlCrossRefPubMedWeb of Science
  52. ↵
    Hoheisel G, Izbicki G, Roth M, et al. Proinflammatory cytokine levels in patients with lung cancer and carcinomatous pleurisy. Respiration 1998;65:183–186.
    OpenUrlCrossRefPubMedWeb of Science
  53. ↵
    Porcel JM, Vives M, Gázquez I, Vicente de Vera MC, Pérez B, Rubio M. Usefulness of pleural complement activation products in differentiating tuberculosis and malignant effusions. Int J Tuberc Lung Dis 2000;4:76–82.
    OpenUrlPubMedWeb of Science
  54. ↵
    Menzies D, Pai M, Comstock G. Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007;146:340–354.
    OpenUrlCrossRefPubMedWeb of Science
  55. ↵
    Pai M, Riley LW, Colford JM Jr. Interferon-γ assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761–776.
    OpenUrlCrossRefPubMedWeb of Science
  56. ↵
    Steingart KR, Henry M, Laal S, et al. A systematic review of commercial serological antibody detection tests for the diagnosis of extrapulmonary tuberculosis. Thorax 2007;62:911–918.
    OpenUrlAbstract/FREE Full Text
  57. ↵
    Steingart KR, Henry M, Laal S, et al. Commercial serological antibody detection tests for the diagnosis of pulmonary tuberculosis: a systematic review. PLoS Med 2007;4:e202
    OpenUrlCrossRefPubMed
  58. ↵
    Tiwari RP, Tiwari D, Garg SK, Chandra R, Bisen PS. Glycolipids of Mycobacterium tuberculosis strain H37Rv are potential serological markers for diagnosis of active tuberculosis. Clin Diagn Lab Immunol 2005;12:465–473.
    OpenUrlCrossRefPubMed
  59. ↵
    Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM Jr. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 2003;3:633–643.
    OpenUrlCrossRefPubMedWeb of Science
  60. ↵
    Daley P, Thomas S, Pai M. Nucleic acid amplification tests for the diagnosis of tuberculous lymphadenitis: a systematic review. Int J Tuberc Lung Dis 2007;11:1166–1176.
    OpenUrlPubMedWeb of Science
  61. ↵
    Porcel JM, Vives M. Differentiating tuberculous from malignant pleural effusions: a scoring model. Med Sci Monit 2003;9:CR175–CR180.
    OpenUrlPubMed
  62. ↵
    Villegas MV, Labrada LA, Saravia NG. Evaluation of polymerase chain reaction, adenosine deaminase and interferon-γ in pleural fluid for the differential diagnosis of pleural tuberculosis. Chest 2000;118:1355–1364.
    OpenUrlCrossRefPubMedWeb of Science
  63. ↵
    Neves DD, Dias RM, Cunha AJ. Predictive model for the diagnosis of tuberculous pleural effusion. Braz J Infect Dis 2007;11:83–88.
    OpenUrlPubMedWeb of Science
  64. ↵
    Burgess LJ, Maritz FJ, Le Roux I, Taljaard JJ. Combined use of pleural adenosine deaminase with lymphocyte/neutrophil ratio. Increased specificity for the diagnosis of tuberculous pleuritis. Chest 1996;109:414–419.
    OpenUrlCrossRefPubMedWeb of Science
  65. ↵
    Trajman A, Kaisermann MC, Kritski AL, Sperhacke RD, Rossetti ML. Diagnosing pleural tuberculosis. Chest 2004;125:2366
    OpenUrlCrossRefPubMed
  66. ↵
    Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part I. Latent tuberculosis. Expert Rev Mol Diagn 2006;6:413–422.
    OpenUrlCrossRefPubMedWeb of Science
  67. ↵
    Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance. Expert Rev Mol Diagn 2006;6:423–432.
    OpenUrlCrossRefPubMedWeb of Science
  68. ↵
    Haykin S. ed. Neural Networks: a Comprehensive Foundation: International Edition. 2nd Edn. Harlow, Pearson Education, 1998
  69. ↵
    Souza Filho JBO, Antunes PHS, Seixas JM, Maidantchik CLL. [Neural networks for the diagnosis of paucibacillary pulmonary tuberculosis.] In: Proceedings of the VIII Brazilian Conference on Neural Networks. Florianópolis, Brazilian Society for Neural Networks, 2007; pp. 1–5
  70. ↵
    Maidantchik C, Seixas JM, Kritski A, et al. NEURALTB Web System. Support to the smear negative pulmonary tuberculosis diagnosis. In: Cardoso J, Cordeiro J, Filipe J, eds. ICEIS 2007 – Proceedings of the Ninth International Conference on Enterprise Information Systems, Volume AIDSS. Funchal, Institute for Systems and Technologies of Information, Control and Communication, 2007; pp. 198–203
  71. ↵
    Bossuyt PM, Reitsma JB, Bruns DE, et al. Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. Standards for Reporting of Diagnostic Accuracy. Clin Chem 2003;49:1–6.
    OpenUrlAbstract/FREE Full Text
  72. ↵
    Pai M, O'Brien R. Tuberculosis diagnostics trials: do they lack methodological rigor?. Expert Rev Mol Diagn 2006;6:509–514.
    OpenUrlCrossRefPubMedWeb of Science
  73. Small PM, Perkins MD. More rigour needed in trials of new diagnostic agents for tuberculosis. Lancet 2000;356:1048–1049.
    OpenUrlCrossRefPubMedWeb of Science
  74. ↵
    Dinnes J, Deeks J, Kunst H, et al. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection. Health Technol Assess 2007;11:1–196.
    OpenUrlPubMedWeb of Science
  75. ↵
    Gardner MJ, Altman DG. Calculating confidence intervals for proportions and their differences. In: Gardner MJ, Altman DG, eds. Statistics with Confidence. 1st Edn. London, BMJ Books, 1989; pp. 28–33
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Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?
A. Trajman, M. Pai, K. Dheda, R. van Zyl Smit, A. A. Zwerling, R. Joshi, S. Kalantri, P. Daley, D. Menzies
European Respiratory Journal May 2008, 31 (5) 1098-1106; DOI: 10.1183/09031936.00147507

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Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?
A. Trajman, M. Pai, K. Dheda, R. van Zyl Smit, A. A. Zwerling, R. Joshi, S. Kalantri, P. Daley, D. Menzies
European Respiratory Journal May 2008, 31 (5) 1098-1106; DOI: 10.1183/09031936.00147507
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  • Article
    • Abstract
    • NONSPECIFIC INFLAMMATORY AND IMMUNE RESPONSE MARKERS
    • SPECIFIC MARKERS OF IMMUNE RESPONSE
    • DETECTION OF M. TUBERCULOSIS NUCLEIC ACID SEQUENCES BY AMPLIFICATION TESTS
    • SCORING SYSTEMS BASED ON COMBINATIONS OF MARKERS
    • EMERGING TECHNOLOGIES THAT NEED TO BE EVALUATED FOR PLEURAL TB
    • FUTURE DIRECTIONS
    • CONCLUSION
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    • Statement of interest
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