- Email: [email protected]
Tuberculous Pleural Effusions: A New Look at an Old Problem
Author’s Accepted Manuscript Tuberculous Pleural Effusions: A New Look at An Old Problem Umair Ahmad Gauhar
www.elsevier.com
PII: DOI: Reference:
S0002-9629(17)30310-5 http://dx.doi.org/10.1016/j.amjms.2017.06.013 AMJMS488
To appear in: The American Journal of the Medical Sciences Cite this article as: Umair Ahmad Gauhar, Tuberculous Pleural Effusions: A New Look at An Old Problem, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2017.06.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Tuberculous pleural effusions: A new look at an old problem Umair Ahmad Gauhar, MD Assistant Professor of Medicine Interventional Pulmonology Program Division of Pulmonary, Critical Care, and Sleep Medicine University of Louisville Health Sciences Center Louisville, KY Email: [email protected]
Tuberculous pleural effusion (TBPE) is the most common cause of pleural effusion and the second most common form of extrapulmonary tuberculosis (after lymphatic involvement) in tuberculosis endemic areas1. Per World Health Organization Global tuberculosis report (2014), about 9 million people developed active TB in 2013 leading to 1.5 million deaths2. The incidence varied from region to region with 56% of the cases found in the South-East Asia and Western Pacific Regions2. Fortunately, TB incidence fell at an average rate of about 1.5% per year between 2000 and 2013 and globally, TB mortality decreased by an estimated 45% between 1990 and 20132. Extrapulmonary involvement of lymph nodes or pleura can be the initial presentation in about 25% of the cases3. The incidence of TBPE is highly variable among different countries with rates as high as 40% in China and as low as 0% in certain series in the United States 1. In this issue of The American Journal of Medical Sciences, Jaehee Lee and colleagues report a retrospective study on the predictive factors and treatment outcomes of patients with tuberculous pleural effusion in the setting of malignancy and anti-cancer therapy4. The authors aim to distinguish between tuberculous and malignant pleural effusions (MPE) in a set of patients with malignancy in a TB endemic area and hence considered at high risk for developing tuberculosis. The control group included patient with MPE and TBPE without cancer. Treatment outcomes were also compared between the various groups. In the final analysis, a serum Creactive protein (S-CRP) level of > 3.0 g/dl and pleural fluid adenosine deaminase (ADA) of > 40 U/L were found to help identify patients with TBE in the setting of malignancy. Using S-CRP or ADA, a sensitivity of 100% was achieved while a model combining S-CRP and ADA was more specific (98%). The negative predictive value of both methods was high (100% and 87% respectively). Overall treatment outcomes, including treatment completion rates, duration of treatment and recurrence rates, were not different in TBE patients with or without cancer. Although, time to initiation of anti-TB treatment was statistically longer in TBE patients with 1
cancer (5 days vs. 2 days respectively), the difference may not be considered clinically relevant in a chronic condition such as TB. Patients with malignancies are often malnourished which, combined with immunosuppressive effects of anti-cancer therapy, puts them at risk for tuberculosis especially in TB endemic areas. Both TBPE and MPE are lymphocyte predominant and exudates based on Light’s criteria making the distinction between the two difficult. Pleural fluid cytology in malignancy has low sensitivity. In a retrospective analysis of 1,427 patients including 466 patients with MPE, the first cytological analysis had a sensitivity of 48.5%, while a second and third analysis allowed 28.6% and 10.3% additional diagnoses, respectively5. Patients with malignancies can develop new pleural effusions from progression of underlying malignancy, drug-induced toxicity, atelectasis, pulmonary embolism and infectious causes including TB. The accurate determination of the underlying etiology of pleural effusion in this setting can be challenging, but is very important for further clinical decision making. Pleural fluid ADA is a well-known diagnostic test for TBPE with a sensitivity and specificity of 92% and 90%, respectively, based on a meta-analysis of 63 studies6. However, in developed countries with a lower incidence of TB, the negative predictive value of pleural fluid ADA remains high, but the positive predictive value declines1. The authors of the current study have shown that the pleural ADA remains a useful test in diagnosing TBPE even in patients with malignancies. Acid-fact bacilli (AFB) smear and Mycobacterial tuberculosis culture remain the most definitive way of diagnosing TB. Condi et al. prospectively evaluated 84 patients with TBE and found induced sputum to be smear positive in 12% and culture positive in 52% of the cases7. The yield of sputum cultures was high even in the absence of parenchymal lesions on chest radiograph. Although pleural fluid cultures can have a low sensitivity (36.6%), the combination of sputum and pleural fluid cultures offers a combined diagnostic yield of 79%8-10. The current study reports a higher culture positivity of 90%4. Occasionally, pleural biopsies are needed for diagnosis and demonstrate epithelioid cell granulomas and/or caseating granulomas. Closed needle biopsies have a lower diagnostic yield than thoracoscopic biopsies8,11. Interferon gamma (IFN-) is usually increased in TBPE and has been used as a diagnostic test with high sensitivity and specificity (89% and 97% respectively)12. However, it suffers from poor standardization making it unsuitable for routine use. Higher levels are also seen in empyemas and hematological malignancies13. Several other biomarkers (Neopterin, Leptin, PF/S Lysozyme, Fibronectin, RS-IL-2, TNF-α, IL-1β, complement activation SC5b-9, IL-12 p40, IL-6, CD-4+, IP-10 and lipoarabinomannan) have been used in the diagnosis of TBE, but their yield remains lower than ADA and IFN- Many studies have evaluated the combination of clinical, cellular and chemical variables to differentiate TBPE and non-TBPE with overall high sensitivity and specificities14.
2
The diagnosis of TBPE can require a complex decisional tree which can add time and cost to the diagnostic work up. The burden of disease is highest in developing countries where health care resources are often limited. In this regard, the current study reinforces the importance of pleural fluid ADA as a rapid and inexpensive diagnostic test
References 1. 2.
3. 4.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
Zhai K, Lu Y, Shi HZ. Tuberculous pleural effusion. J Thorac Dis. 2016;8(7):E486-E494. World Health Organization. Global tuberculosis report 2014. Geneva. World Health Organization,2014. Available online http://www.who.int/tb/publications/global_report/en/. Accessed 18 June 2017. Pocel JM. Tuberculous pleural effusion. Lung 2009;187:263-270 Lee J, Lee YD, Lim JK et al. Predictive factors and treatment outcomes of tuberculous pleural effusion in cancer patients with pleural effusion. https://doi.org/10.1016/j.amjms.2017.04.006 Bielsa S, Panadés MJ, Egido R et al. Accuracy of pleural fluid cytology in malignant effusions. An Med Interna. 2008 Apr;25(4):173-177. Liang QL, Shi HZ, Wang K et al. Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 2008;102:744-754. 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. Valdés L, Alvarez D, San José E, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017-2021. Ruan SY, Chuang YC, Wang JY, et al. Revisiting tuberculous pleurisy: pleural fluid characteristics and diagnostic yield of mycobacterial culture in an endemic area. Thorax 2012:67:822-877. Von Groote-Bidlingmaier F, Koegelenberg CF, Bollinger CT, et al. The yield of different pleural fluid volumes for Mycobacterium tuberculosis culture. Thorax 2013;68:290-291 Wang Z, Xu LL, Wu YB, et al. Diagnostic value and safety of medical thoracoscopy in tuberculous pleural effusion. Respir Med 2015;109:1188-1192. Jiang J, Shi HZ, Liang QL, et al. Diagnostic value of interferon-gamma in tuberculous pleurisy: a meta-analysis. Chest. 2007; 131:1133-1141 Villena V, López-Encuenta A, Pozo F, et al. Interferon gamma levels in pleural fluid for diagnosis of tuberculosis. Am J Med 2003l115:365-370. Ferreiro L, San José E, Valdés L. Tuberculous Pleural Effusion. Arch Bronconeumol. 2014;50:435-443.
3
www.elsevier.com
PII: DOI: Reference:
S0002-9629(17)30310-5 http://dx.doi.org/10.1016/j.amjms.2017.06.013 AMJMS488
To appear in: The American Journal of the Medical Sciences Cite this article as: Umair Ahmad Gauhar, Tuberculous Pleural Effusions: A New Look at An Old Problem, The American Journal of the Medical Sciences, http://dx.doi.org/10.1016/j.amjms.2017.06.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Tuberculous pleural effusions: A new look at an old problem Umair Ahmad Gauhar, MD Assistant Professor of Medicine Interventional Pulmonology Program Division of Pulmonary, Critical Care, and Sleep Medicine University of Louisville Health Sciences Center Louisville, KY Email: [email protected]
Tuberculous pleural effusion (TBPE) is the most common cause of pleural effusion and the second most common form of extrapulmonary tuberculosis (after lymphatic involvement) in tuberculosis endemic areas1. Per World Health Organization Global tuberculosis report (2014), about 9 million people developed active TB in 2013 leading to 1.5 million deaths2. The incidence varied from region to region with 56% of the cases found in the South-East Asia and Western Pacific Regions2. Fortunately, TB incidence fell at an average rate of about 1.5% per year between 2000 and 2013 and globally, TB mortality decreased by an estimated 45% between 1990 and 20132. Extrapulmonary involvement of lymph nodes or pleura can be the initial presentation in about 25% of the cases3. The incidence of TBPE is highly variable among different countries with rates as high as 40% in China and as low as 0% in certain series in the United States 1. In this issue of The American Journal of Medical Sciences, Jaehee Lee and colleagues report a retrospective study on the predictive factors and treatment outcomes of patients with tuberculous pleural effusion in the setting of malignancy and anti-cancer therapy4. The authors aim to distinguish between tuberculous and malignant pleural effusions (MPE) in a set of patients with malignancy in a TB endemic area and hence considered at high risk for developing tuberculosis. The control group included patient with MPE and TBPE without cancer. Treatment outcomes were also compared between the various groups. In the final analysis, a serum Creactive protein (S-CRP) level of > 3.0 g/dl and pleural fluid adenosine deaminase (ADA) of > 40 U/L were found to help identify patients with TBE in the setting of malignancy. Using S-CRP or ADA, a sensitivity of 100% was achieved while a model combining S-CRP and ADA was more specific (98%). The negative predictive value of both methods was high (100% and 87% respectively). Overall treatment outcomes, including treatment completion rates, duration of treatment and recurrence rates, were not different in TBE patients with or without cancer. Although, time to initiation of anti-TB treatment was statistically longer in TBE patients with 1
cancer (5 days vs. 2 days respectively), the difference may not be considered clinically relevant in a chronic condition such as TB. Patients with malignancies are often malnourished which, combined with immunosuppressive effects of anti-cancer therapy, puts them at risk for tuberculosis especially in TB endemic areas. Both TBPE and MPE are lymphocyte predominant and exudates based on Light’s criteria making the distinction between the two difficult. Pleural fluid cytology in malignancy has low sensitivity. In a retrospective analysis of 1,427 patients including 466 patients with MPE, the first cytological analysis had a sensitivity of 48.5%, while a second and third analysis allowed 28.6% and 10.3% additional diagnoses, respectively5. Patients with malignancies can develop new pleural effusions from progression of underlying malignancy, drug-induced toxicity, atelectasis, pulmonary embolism and infectious causes including TB. The accurate determination of the underlying etiology of pleural effusion in this setting can be challenging, but is very important for further clinical decision making. Pleural fluid ADA is a well-known diagnostic test for TBPE with a sensitivity and specificity of 92% and 90%, respectively, based on a meta-analysis of 63 studies6. However, in developed countries with a lower incidence of TB, the negative predictive value of pleural fluid ADA remains high, but the positive predictive value declines1. The authors of the current study have shown that the pleural ADA remains a useful test in diagnosing TBPE even in patients with malignancies. Acid-fact bacilli (AFB) smear and Mycobacterial tuberculosis culture remain the most definitive way of diagnosing TB. Condi et al. prospectively evaluated 84 patients with TBE and found induced sputum to be smear positive in 12% and culture positive in 52% of the cases7. The yield of sputum cultures was high even in the absence of parenchymal lesions on chest radiograph. Although pleural fluid cultures can have a low sensitivity (36.6%), the combination of sputum and pleural fluid cultures offers a combined diagnostic yield of 79%8-10. The current study reports a higher culture positivity of 90%4. Occasionally, pleural biopsies are needed for diagnosis and demonstrate epithelioid cell granulomas and/or caseating granulomas. Closed needle biopsies have a lower diagnostic yield than thoracoscopic biopsies8,11. Interferon gamma (IFN-) is usually increased in TBPE and has been used as a diagnostic test with high sensitivity and specificity (89% and 97% respectively)12. However, it suffers from poor standardization making it unsuitable for routine use. Higher levels are also seen in empyemas and hematological malignancies13. Several other biomarkers (Neopterin, Leptin, PF/S Lysozyme, Fibronectin, RS-IL-2, TNF-α, IL-1β, complement activation SC5b-9, IL-12 p40, IL-6, CD-4+, IP-10 and lipoarabinomannan) have been used in the diagnosis of TBE, but their yield remains lower than ADA and IFN- Many studies have evaluated the combination of clinical, cellular and chemical variables to differentiate TBPE and non-TBPE with overall high sensitivity and specificities14.
2
The diagnosis of TBPE can require a complex decisional tree which can add time and cost to the diagnostic work up. The burden of disease is highest in developing countries where health care resources are often limited. In this regard, the current study reinforces the importance of pleural fluid ADA as a rapid and inexpensive diagnostic test
References 1. 2.
3. 4.
5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
Zhai K, Lu Y, Shi HZ. Tuberculous pleural effusion. J Thorac Dis. 2016;8(7):E486-E494. World Health Organization. Global tuberculosis report 2014. Geneva. World Health Organization,2014. Available online http://www.who.int/tb/publications/global_report/en/. Accessed 18 June 2017. Pocel JM. Tuberculous pleural effusion. Lung 2009;187:263-270 Lee J, Lee YD, Lim JK et al. Predictive factors and treatment outcomes of tuberculous pleural effusion in cancer patients with pleural effusion. https://doi.org/10.1016/j.amjms.2017.04.006 Bielsa S, Panadés MJ, Egido R et al. Accuracy of pleural fluid cytology in malignant effusions. An Med Interna. 2008 Apr;25(4):173-177. Liang QL, Shi HZ, Wang K et al. Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis. Respir Med 2008;102:744-754. 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. Valdés L, Alvarez D, San José E, et al. Tuberculous pleurisy: a study of 254 patients. Arch Intern Med 1998;158:2017-2021. Ruan SY, Chuang YC, Wang JY, et al. Revisiting tuberculous pleurisy: pleural fluid characteristics and diagnostic yield of mycobacterial culture in an endemic area. Thorax 2012:67:822-877. Von Groote-Bidlingmaier F, Koegelenberg CF, Bollinger CT, et al. The yield of different pleural fluid volumes for Mycobacterium tuberculosis culture. Thorax 2013;68:290-291 Wang Z, Xu LL, Wu YB, et al. Diagnostic value and safety of medical thoracoscopy in tuberculous pleural effusion. Respir Med 2015;109:1188-1192. Jiang J, Shi HZ, Liang QL, et al. Diagnostic value of interferon-gamma in tuberculous pleurisy: a meta-analysis. Chest. 2007; 131:1133-1141 Villena V, López-Encuenta A, Pozo F, et al. Interferon gamma levels in pleural fluid for diagnosis of tuberculosis. Am J Med 2003l115:365-370. Ferreiro L, San José E, Valdés L. Tuberculous Pleural Effusion. Arch Bronconeumol. 2014;50:435-443.
3