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Communications to the Editor |

Diagnosing Tubercular Pleural Effusions FREE TO VIEW

Uday A. Gupta, MBBS; Sunil K. Chhabra, MD
Author and Funding Information

Affiliations: Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India,  National Sanyo Hospital, Respiratory Disease Center, Yamaguchi, Japan

Correspondence to: Sunil K. Chhabra, MD, Head, Department of Cardiorespiratory Physiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi 110 007, India; e-mail: skchhabra@mailcity.com



Chest. 2005;127(3):1078-1079. doi:10.1378/chest.127.3.1078
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To the Editor:

We read with interest the article by Hikari et al (March 2004)1 comparing the markers of tuberculosis in pleural effusions. We wish to express our disagreement with their statement that interferon (IFN)-γ should be measured routinely in all suspected cases of pleural tuberculosis. They have based their conclusion on the basis of a perfect area under the curve of 1.000 on receiver operator characteristic analysis for IFN-γ as compared to 0.958 for adenosine deaminase (ADA). The authors have failed to adequately review the fairly large body of literature on biological markers of tubercular pleural effusion.

ADA has been reported with perfect values in the literature (100% sensitivity,24 and also 100% specificity, positive predictive value, and negative predictive value5) in studies with larger sample sizes (n = 221, 48 tuberculous2; n = 405, 91 tuberculous3; n = 350, 76 tuberculous4; and n = 138, and 61 tuberculous5) than the present study (n = 55, 20 tuberculous).1 Valdes et al,3 using simultaneous measurement in the same set of patients (n = 405), reported a higher sensitivity for ADA (100%) than IFN-γ (94.2%) and a higher specificity (95% for ADA and 91.8% for IFN-γ). Villegas et al6compared ADA and IFN-γ (along with polymerase chain reaction [PCR]) simultaneously in 140 patients with 42 confirmed TB cases and reported a higher sensitivity (88.1% for ADA vs 85.7% for IFN-γ) and better negative predictive value than IFN in the whole prevalence range. Valdes et al7 reported that 253 of a total of 254 tuberculous pleuritis patients had ADA levels > 40 IU/mL, and in the 82 patients in whom both ADA and IFN-γ were done, the sensitivity of IFN was 89% (73 of 82 patients) against at least 98.78% (81 of 82 patients) for ADA.

Studies comparing ADA and IFN-γ simultaneously in the same set of patients have reported both ADA better than IFN-γ27 and IFN-γ better than ADA1,89 as diagnostic markers. In fact, a meta-analysis by Greco et al10 regarding the diagnostic accuracy of ADA vs IFN-γ included 31 studies in favor of ADA (total, n = 4,738) and 13 studies in favor of IFN-γ (total, n = 1,189). Using summary receiver operating characteristic curve, they found only a marginal difference in overall sensitivity and specificity: 93% for ADA, and 96% for IFN-γ. Using Bayes theorem, the posttest probability of a negative test result was calculated. The minute difference in posttest probabilities (ADA vs IFN-γ, 0.4% vs 0.22%, 2.4% vs 1.2%, and 24% vs 17%) was maintained over a wide prevalence range of 5 to 85%. The authors concluded that “ADA and IFN-γ appear to be reasonably accurate at detecting TB pleurisy.” Virtually similar sensitivity and specificity coupled with lower cost should favor the use of ADA as a diagnostic tool compared to IFN-γ.

Lastly, the authors suggest that PCR should be compared with IFN, etc. Such a study comparing PCR, IFN, and ADA simultaneously in pleural effusion patients has already been published in CHEST.6

Hiraki, A, Aoe, K, Eda, R, et al (2004) Comparison of six biological markers for the diagnosis of tuberculous pleuritis.Chest125,987-989. [CrossRef] [PubMed]
 
Ocana, I, Martinez-Vazquez, JM, Segura, RM, et al Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion.Chest1983;84,51-53. [CrossRef] [PubMed]
 
Valdes, L, San Jose, E, Alvarez, D, et al Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon-γ.Chest1993;103,458-465. [CrossRef] [PubMed]
 
Valdes, L, San Jose, E, Alvarez, D, et al Adenosine deaminase (ADA) isoenzyme analysis in pleural effusions: diagnostic role, and relevance to the origin of increased ADA in tuberculous pleurisy.Eur Respir J1996;9,747-751. [CrossRef] [PubMed]
 
Fontan Bueso, J, Verea Hernando, H, Garcia-Buela, JP, et al Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusions.Chest1988;93,303-307. [CrossRef] [PubMed]
 
Villegas, MV, Saravia, NG Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-γ in pleural fluid for the differential diagnosis of pleural tuberculosis.Chest2000;118,1355-1364. [CrossRef] [PubMed]
 
Valdes, L, Alvarez, D, San Jose, E, et al Tuberculous pleurisy.Arch Intern Med1998;158,2017-2021. [CrossRef] [PubMed]
 
Naito, T, Ohtsuka, M, Ishikawa, H, et al Clinical significance of cytokine measurement in pleural effusion.Kekkaku1997;72,565-572. [PubMed]
 
Ogawa, K, Koga, H, Hirakata, Y, et al Differential diagnosis of tuberculous pleurisy by measurement of cytokine concentrations in pleural effusion.Tuberc Lung Dis1997;78,29-34. [CrossRef]
 
Greco, S, Girardi, E, Masciangelo, R, et al Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis.Int J Tuberc Lung Dis2003;7,777-786. [PubMed]
 
To the Editor:

We are confused by the comments by Drs. Gupta and Chhabra concerning our article.1Indeed, high concentrations of adenosine deaminase (ADA) in the pleural fluid of patients with tuberculosis pleuritis have been confirmed by many studies. However, the statement that the use of ADA has been reported with perfect values for sensitivity and specificity in the literature is overstated. Perez-Rodriguez and Castro2summarized the results of 11 studies and reported the sensitivity and specificity for ADA are 77 to 100% (average, 93.3%) and 81 to 97% (average, 91.3%), respectively. Chen et al3summarized the results of eight studies and reported the sensitivity and specificity for ADA as 79 to 100% (average, 88.6%) and 80.5 to 96% (average, 85.4%), respectively. A meta-analysis including 40 articles conducted by Goto et al4 showed that the sensitivity of ADA ranged from 47.1 to 100% and the specificity from 50.0 to 100%. However, these studies24 also showed that the false-positive rate is relatively high. In a meta-analysis5 regarding the diagnostic accuracy of determining ADA vs interferon (IFN)-γ showed that IFN-γ is superior to ADA, although the difference is small. Therefore, establishing a diagnosis of tuberculosis pleuritis based only on pleural fluid ADA without pleural biopsy findings is still controversial.6

We do not intend to deny the usefulness of pleural fluid ADA for diagnosing tuberculosis pleuritis. Furthermore, we do not insist that pleural fluid INF-γ can replace pleural fluid ADA, or that pleural fluid INF-γ should be measured instead of measuring pleural fluid ADA for diagnosing tuberculous pleuritis. We would like to emphasize the usefulness of the measurement of pleural fluid INF-γ in addition to pleural fluid ADA, especially in low-incidence populations in developed countries, including Japan, because the measurement of IFN-γ is a relatively high-cost test, but has no associated complications.

References
Hiraki, A, Aoe, K, Eda, R, et al Comparison of six biological markers for the diagnosis of tuberculous pleuritis.Chest2004;125,987-989. [CrossRef] [PubMed]
 
Perez-Rodriguez, E, Jimenez Castro, D The use of adenosine deaminase and adenosine deaminase isoenzymes in the diagnosis of tuberculous pleuritis.Curr Opin Pulm Med2000;6,259-266. [CrossRef] [PubMed]
 
Chen, ML, Yu, WC, Lam, CW, et al Diagnostic value of pleural fluid adenosine deaminase activity in tuberculous pleurisy.Clin Chim Acta2004;341,101-107. [CrossRef] [PubMed]
 
Goto, M, Noguchi, Y, Koyama, H, et al Diagnostic value of adenosine deaminase in tuberculous pleural effusion: a meta-analysis.Ann Clin Biochem2003;40,374-381. [CrossRef] [PubMed]
 
Greco, S, Girardi, E, Masciangelo, R, et al Adenosine deaminase and interferon γ measurements for the diagnosis of tuberculous pleurisy: a meta-analysis.Int J Tuberc Lung Dis2003;7,777-786. [PubMed]
 

Figures

Tables

References

Hiraki, A, Aoe, K, Eda, R, et al (2004) Comparison of six biological markers for the diagnosis of tuberculous pleuritis.Chest125,987-989. [CrossRef] [PubMed]
 
Ocana, I, Martinez-Vazquez, JM, Segura, RM, et al Adenosine deaminase in pleural fluids: test for diagnosis of tuberculous pleural effusion.Chest1983;84,51-53. [CrossRef] [PubMed]
 
Valdes, L, San Jose, E, Alvarez, D, et al Diagnosis of tuberculous pleurisy using the biologic parameters adenosine deaminase, lysozyme, and interferon-γ.Chest1993;103,458-465. [CrossRef] [PubMed]
 
Valdes, L, San Jose, E, Alvarez, D, et al Adenosine deaminase (ADA) isoenzyme analysis in pleural effusions: diagnostic role, and relevance to the origin of increased ADA in tuberculous pleurisy.Eur Respir J1996;9,747-751. [CrossRef] [PubMed]
 
Fontan Bueso, J, Verea Hernando, H, Garcia-Buela, JP, et al Diagnostic value of simultaneous determination of pleural adenosine deaminase and pleural lysozyme/serum lysozyme ratio in pleural effusions.Chest1988;93,303-307. [CrossRef] [PubMed]
 
Villegas, MV, Saravia, NG Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-γ in pleural fluid for the differential diagnosis of pleural tuberculosis.Chest2000;118,1355-1364. [CrossRef] [PubMed]
 
Valdes, L, Alvarez, D, San Jose, E, et al Tuberculous pleurisy.Arch Intern Med1998;158,2017-2021. [CrossRef] [PubMed]
 
Naito, T, Ohtsuka, M, Ishikawa, H, et al Clinical significance of cytokine measurement in pleural effusion.Kekkaku1997;72,565-572. [PubMed]
 
Ogawa, K, Koga, H, Hirakata, Y, et al Differential diagnosis of tuberculous pleurisy by measurement of cytokine concentrations in pleural effusion.Tuberc Lung Dis1997;78,29-34. [CrossRef]
 
Greco, S, Girardi, E, Masciangelo, R, et al Adenosine deaminase and interferon gamma measurements for the diagnosis of tuberculous pleurisy: a meta-analysis.Int J Tuberc Lung Dis2003;7,777-786. [PubMed]
 
Hiraki, A, Aoe, K, Eda, R, et al Comparison of six biological markers for the diagnosis of tuberculous pleuritis.Chest2004;125,987-989. [CrossRef] [PubMed]
 
Perez-Rodriguez, E, Jimenez Castro, D The use of adenosine deaminase and adenosine deaminase isoenzymes in the diagnosis of tuberculous pleuritis.Curr Opin Pulm Med2000;6,259-266. [CrossRef] [PubMed]
 
Chen, ML, Yu, WC, Lam, CW, et al Diagnostic value of pleural fluid adenosine deaminase activity in tuberculous pleurisy.Clin Chim Acta2004;341,101-107. [CrossRef] [PubMed]
 
Goto, M, Noguchi, Y, Koyama, H, et al Diagnostic value of adenosine deaminase in tuberculous pleural effusion: a meta-analysis.Ann Clin Biochem2003;40,374-381. [CrossRef] [PubMed]
 
Greco, S, Girardi, E, Masciangelo, R, et al Adenosine deaminase and interferon γ measurements for the diagnosis of tuberculous pleurisy: a meta-analysis.Int J Tuberc Lung Dis2003;7,777-786. [PubMed]
 
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