296 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 Original Article Frequency of Tuberculosis and Malignancy in Transudative- pleural effusions: A rare but real finding Abdul Rasheed Qureshi1, Muhammad Irfan2, Huma Bilal3, Muhammad Sajid4, Zeeshan Ashraf5 1,2 Assistant Professor, Gulab Devi Teaching Hospital, Lahore. 3 Women Medical Officer, Gulab Devi Teaching Hospital, Lahore. 4 Medical Officer, Gulab Devi Teaching Hospital, Lahore. 5 Lecturer, Department of Statistics, Gulab Devi Educational Complex, Lahore. Author’s Contribution 1 Conception of study 2,3,4 Experimentation/Study conduction 1,2,3,4,5 Analysis/Interpretation/Discussion 1 Manuscript Writing 1,5 Critical Review 2,3,4,5 Facilitation and Material analysis Corresponding Author Dr. Muhammad Irfan, Assistant Professor, Gulab Devi Teaching Hospital, Lahore Email: irfan16d2@gmail.com Article Processing Received: 30/11/2019 Accepted: 08/07/2020 Cite this Article: Qureshi, A.R., Irfan, M., Bilal, H., Sajid, M., Ashraf, Z. Frequency of Tuberculosis and Malignancy in Transudative-pleural effusions: A rare but real finding. Journal of Rawalpindi Medical College. 30 Dec. 2020; 24(4): 296-301. DOI: https://doi.org/10.37939/jrmc.v24i4.1159 Conflict of Interest: Nil Funding Source: Nil Access Online: Abstract Objectives: To determine the frequency of tuberculosis and malignancy in transudative pleural effusions. Material and Method: The study was conducted in Pulmonology-OPD, Gulab Devi Teaching Hospital Lahore from Oct. 2017 to Feb. 2019. One hundred and twenty-eight consecutive patients with transudative pleural effusions and 14-69 years age, willing for invasive investigations & ADA estimation were included, while those not willing for further investigations, participation in the study, and exudative effusions were excluded. The clinical features, pleural fluid analysis findings, ADA (Adenosine deaminase) estimation results, hematology, echocardiography, bronchoscopy, Lymph node biopsy, CT-thorax, ultrasound chest & abdomen results were recorded on a preformed proforma. Findings were summarized, tabulated, and analyzed statistically using SPSS- 16 software. Results: Out of 1370 cases of pleural effusion, 128 cases (9.34%) with pleural transudate were isolated. In all patients, pleural fluid protein/serum protein level was < 0.5. The age ranged 14-69 years with a mean of 39 years + 11.3. Fifty-two cases (40.62%) had right-sided, 38 cases (29.68%) left-sided while 38 cases (29.68%) had bilateral pleural effusions. Seventy-six aspirates (59.37%) were yellow, 20 (15.62%) reddish, 18 (14.06%) straw-colored and 14 fluids (10.93%) were watery in color. Out of 128 transudative effusions, malignant etiology was found in 23 cases (17.96%), tubercular in 17 cases (13.28%) and 19 cases (14.84%) of Para-pneumonic origin were detected. Conclusion: Tuberculosis and malignancy can be the possible etiology of transudative effusion. Keywords: Pleural transudate, Malignancy, Systemic disorders, TB. 297 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 Introduction A pleural effusion is always due to underlying disease and can be exudative or transudative, depending upon the pleural fluid protein and serum protein content. Classification into exudate or transudate is usually done according to the Light’s criteria. Transudative pleural effusions develop when the hydrostatic and oncotic pressures across the pleural membrane are disturbed & dynamic equilibrium between the fluid formation and absorption is lost. There is no change in the pleural membrane, the endothelium is usually intact and cells & protein content of effusion is low.1-4 About 5-25% of total pleural effusions are usually transudative in nature.5 According to conventional teaching, this effusion is considered mainly due to cardiac, hepatic, renal, and systemic disorders.6-7 But tuberculosis and malignancy can also be infrequent etiology.8 Malignant cells have been detected in a significant number of transudates, representing advanced malignant processes with high morbidity and mortality, precluding the possibility of treatment with a curative approach. Metastatic adenocarcinoma is the commonest histological finding, while the primary tumor is not identified in approximately 10% of patients of malignant pleural effusions.9-10 Similarly, cases with tubercular etiology have also been reported in transudates and pleural fluid estimation of ADA (Adenosine deaminase) level is found a good diagnostic tool for TB diagnosis.11-12 Because of this association of malignancy and TB (Tuberculosis) with transudative PE, pleural fluid cytology and Adenosine deaminase (ADA) estimation should be employed for all transudative pleural effusions.11,13 We designed this study to identify and compute the proportion of TB and malignancy associated with transudative pleural effusions. Materials and Methods Objectives: To determine the frequency of tubercular and malignant etiology in transudative pleural effusions & also to evaluate the need for performing cytology and ADA estimation in pleural transudates. Study Design: Prospective study. Patients and Methods: This study was conducted at the out-patient department of Respiratory Medicine, Gulab Devi Chest Hospital Lahore a 1500 bedded tertiary care hospital, from October 2017 to February 2019. Inclusion criteria: A total of 128 consecutive adult patients, with 14-69 years of age, no obvious evidence of TB or malignancy, no history of diuretic therapy, with transudative pleural effusion, willing for invasive investigations, and participation in the study, were included. Exclusion criteria: Patients below 14 years, exudates, incomplete data, on diuretic therapy, not willing for ADA estimation, invasive investigation or participation in the study and known cases, or having radiological suspicion of tubercular or malignant etiology were excluded. Method: The study was approved ethically by the IRB of the hospital vide No. Admin/GDEC/18.491 and conducted over a period of 17-months. Detailed clinical history including cigarette smoking and contact with a TB-patient were recorded. A thorough physical examination was performed. Chest x-ray-PA and Lateral views, ultrasound abdomen, pelvis, and chest were done which was followed by ultrasound- guided pleural aspiration, and the fluid sample was sent for biochemistry including ADA & LDH estimation, cytology, and bacteriology. CBC with ESR, Serum Protein, serum LDH, LFTs, RFTs, thyroid function tests, and viral markers for hepatitis was performed in pertinent cases. Sputum was evaluated by Gram stain, Z-N stain & cytology. Light’s Criteria was applied for differentiating transudate from exudate. A transudative pleural effusion was defined by meeting at least one of the following criteria: 1. Pleural fluid protein/serum protein level < 0.5., 2. Pleural fluid LDH level < 2/3 of the upper limits of the normal serum value. 3. Pleural fluid LDH/serum LDH value < 0.6. ECG, Echocardiography, CT-thorax, Bronchoscopy & biopsy along with BAL (Broncho-alveolar lavage) cytology were employed for precise diagnosis, in pertinent cases. Lymph node biopsy and histopathology were carried out in the required cases. Pleural fluid culture & sensitivity was utilized to isolate pyogenic etiology. Pleural fluid ADA level, 40 IU/L and above was considered as the cut-off for TB- diagnosis. Tubercular patients were put on anti-TB therapy via standard DOTS regimen and were followed for six months. The response to treatment was noted. Fluid immuno-staining and cytopathology diagnosed malignant etiology. All clinical findings were recorded in the pre-formed proforma. Data was summarized; organized, tabulated, and SPSS-16 software was used for statistical analysis to reach the conclusion. Descriptive 298 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 statistics including mean with + SD were calculated. Categorical data were presented as a percentage. Results Out of 1370 cases of pleural effusion, 128 cases (9.34%) with pleural transudate were isolated. In all patients, pleural fluid protein/serum protein level was < 0.5. The age ranged 14-69 years with a mean of 39 years + 11.3. Eighty-six patients (67.18%) were male while 42 patients (32.81%) were female. The male to female ratio was 2:1. Majority of the patients presented with respiratory complaints (Table 1). Cigarette smoking (73.43%), history of contact with a TB-patient (10.15%), and Diabetes Mellitus (30.46%) were major risk factors. Table 1: Clinical presentation in 128 patients Nos. Clinical features Observed cases Percentage (%) 1. Chest pain. 115 89.84 2. Cough 102 79.68 3. Fever 97 75.78 4. Shortness of breath 93 72.65 5. Weight loss 70 54.68 6. Loss of Appetite 62 48.43 Fifty-two cases (40.62%) had right-sided, 38 cases (29.68%) left-sided while 38 cases (29.68%) had bilateral pleural effusions. Seventy-six aspirates (59.37%) were yellow, 20 (15.62%) reddish, 18 (14.06%) straw-colored and 14 fluids (10.93%) were watery in color. Cytology and bacteriology of 128 pleural fluids are tabulated (Table 2). BAL analysis revealed malignant cells in 03 cases while 01 case was diagnosed as TB on Gene-Xpert. Out of 04, two lymph node biopsies showed lymphoma and two caseation granuloma. Table 2: Pleural Fluid Cytology and Bacteriology n=128 Pleural Fluid Cytology in 128 patients Nos. Microscopic Appearance Observed cases Percentage 1. Lymphocytic 102 79.68 % 2. Neutrophillic 26 20.31 % 3. Malignant cytology 18 14.06 % Pleural Fluid Bacteriology in 19 patients 1. Streptococcus Pneumonie 06 31.57 % 2. Staphylococcus Aureus 05 26.31 % 3. Gram –ve Rods 03 15.78 % 4. Pseudomonas 03 15.78 % 5. No-growth 02 10.52 % *n= total pyogenic transudates. Out of 128 transudates, 105 patients (82.03%) were diagnosed with non-malignant while 23 cases (17.96 %) with malignant pathologies (Table 3 & Figure 1). Table 3: Frequency of non-malignant pathologies with ADA values n=105 No Diagnosis Observed Cases Percentage of (n)* ADA Range IU/L Mean ADA value IU/L 1. TB PE 17 16.19 % 34-85.6 55.86 2. Para-pneumonic 19 18.09 % 07-11 09.2 3. Cardiogenic cause 35 33.33 % 07-16 8.66 4. CLD 13 12.38 % 07-18 12.95 5. CRF 10 9.52 % 9.8-12 11.34 6. Hypo-proteinemia 03 2.85 % 14-19 16.5 7. Non Specific 04 3.80 % 12-15.5 13.7 8. SLE 03 2.85 % 17-18 17.4 9. Rheumatoid Arthritis 01 0.95 % 14.0 14.0 * Percentage is calculated for 105 non-malignant transudates. 299 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 Figure 1: Break-up of malignant etiology in 23 transudates Discussion While investigating an undiagnosed pleural effusion, biochemistry is utilized for deciding exudative or transudative nature & transudate fluids are investigated by keeping a focus on systemic causes without including tuberculosis and malignancy in the list of differential diagnosis because of their documented exudative nature.14-15 This study last for a 17-month period during which 1370 pleural effusions were investigated and 128 cases (9.34%) of pleural transudates were isolated, which included 35 cases (27.34%) cardiac, 23 cases (17.96%) malignant, and 19 cases (14.84%) of Para-pneumonic origin while 17 cases (13.28%) with tubercular etiology were also obtained. The study population had a mean age of 39 years + 11.3 and two of third patients were men. This age along with (73.43%) cigarette smoking and (30.46%) diabetes mellitus favor cardiac and renal etiology. We had 35/128 cases with cardiogenic and 10/128 cases with renal etiologies in our study. As smoking is more common in men, we had 67.18% of patients with the male gender. Smoking is started early in childhood in males than in females, they consume more pack-year and are more vulnerable to the risk of smoking as compared to females. We had 73.43% of patients with smoking, which is itself an established risk factor for cardiac and malignant disorders.16-17 Ferreiro L et al reported the prevalence of malignant transudative pleural effusion as 10% (18), Ashchi M et al reported as 4.6% among 171 malignant pleural transudates.19 Yuri Moltyaner et al displayed 8% malignancy20 while our series exhibited a prevalence of 17.96% malignancy, in 128 transudates. The possible explanation for malignant transudate formation is that initially fluid is accumulated due to lymphatic-obstruction; low protein level-ultra-filtrate is formed without pleural seeding with malignant foci. Confounding co-morbidities like heart failure may also be responsible for transudate formation. Similarly, any tumor or lymph node causing bronchial obstruction and atelectasis can result in transudate formation.21 Commonly the tumor of lung, breast, and lymphoma invading mediastinal lymph nodes cause lymphatic obstruction, resulting in transudate formation.22-23 Bayhan Gl and colleagues concluded their study by commenting that pleural TB can present in the form of transudates.24 Doerr CH and co-workers reported 27% of patients with benign tumors, tuberculosis, and heart failure, for transudative effusions.25 Agrawal V reported 14.28% tubercular transudates.26 A Spanish study of 3077 cases during 19 years, revealed 9.0% etiology due to tuberculosis.27 We found 13.28% tubercular etiology in 128 transudates (19 months period) which is fairly comparable with these studies. In this study, 13/17 cases (76.47%) diagnosed as tuberculosis had a history of contact with a TB patient in their family, which created a high index of suspicion about tubercular etiology. Tuberculosis was diagnosed by pleural fluid ADA level in all cases except three with border-line values, two were diagnosed by lymph node biopsy and one case was detected by BAL Gene- 300 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 Xpert. As tuberculosis is endemic in our region, all exudative lymphocytic pleural effusions are considered as tubercular, until proven otherwise.28 But transudative effusions are dealt with differently. On finding a transudative pleural effusion, the diagnostic plan is oriented toward systemic causes while TB & malignancy are over-looked, that is why transudates with TB and malignant pathologies remain undetected. It is very much pertinent to make this note that tuberculosis is a curable disease if diagnosed timely, if it is missed, it can be a risk for the patient and the community as well. As pleural fluid ADA estimation is a useful biomarker for TB diagnosis in endemic areas, it should be frankly utilized for the workup of all TB-suspect transudates.29 Similarly, malignant pleural effusions are almost always categorized as exudates. The presence of malignant cells in transudative effusion indicates a mitotic lesion with high-grade morbidity & mortality with a brief expected life span (only 4–9 months), that is why a timely diagnosis of such patients is valuable for the patient as well as for the treating physician. It can only be achieved by having a high index of suspicion. \Although, British Thoracic Society does not recommend thoracentesis for bilateral pleural effusions, suspected to be transudate, if sampled, BTS suggests cytology for all.30 Porcel J.M. and associates analyzed 840 malignant effusions and found that cytology was 59% accurate in detecting malignancy.31- 32 In our study, 18/23 cases (78.26%) of malignancy were diagnosed by pleural fluid cytology, 03 cases (13.04%) by BAL cytology, and 02/23 cases were diagnosed by lymph node biopsy. Moltyaner Y et al. suggested that every transudate should be investigated by cytology to maximize the diagnostic yield.20 The traditional teaching suggests performing cytology on a transudative pleural effusion in search of a malignant cause, might not be cost-effective. In the current era of cost-effective medicine, it is mandatory to ensure that we should not sacrifice the quality of care for cost. Therefore, pleural fluid cytology seems to be essential in all transudative effusions to avoid the chances of missing malignant pathologies. Additionally, ADA estimation can be very much helpful in differentiating between malignant and tubercular transudates. 19/128 cases (14.84%) of transudate with pyogenic etiology is an eye-opening figure. Bacteriologic work- up (Table-II) reflecting the internal story, thus necessitates the need for culture and sensitivity examination for all pleural transudate. It is, therefore, suggested that in the absence of any obvious systemic etiology, all transudative pleural effusions must be subjected to fluid cytology, bacteriology & ADA estimation. The main limitation of this study is that it is a single- center study performed on limited sample size (n=128). By further elongation of the study or a study with larger sample size and preferably, a multi-center study can further explore the subject and strengthen the study. Our results can find very useful applications in populations with a high prevalence of tuberculosis and increasing malignant disorders due to heavy smoking, industrialization, environmental and occupational pollution, for diagnostic as well as disease control objectives. In the light of this discussion, we have no hesitation in commenting that a transudative pleural effusion is just a false re-assurance against malignancy and tuberculosis. Therefore, all pleural transudates must be investigated from the perspective of tuberculosis and malignancy in addition to infective & systemic disorders. Conclusion • Tuberculosis and malignancy can be the possible etiology of transudative pleural effusions. • Pleural fluid cytology and ADA estimation & pyogenic culture and sensitivity should be included in the diagnostic algorithm of transudative pleural effusions. • The history of contact with a TB patient must be dug out to create a high index of suspicion about tuberculosis. References 1. Thomas JM, Musani AI. Malignant pleural effusions: a review. Clinics in Chest Medicine. 2013 Sep 1;34(3):459-71. DOI:https://doi.org/10.1016/j.ccm.2013.05.004 2. Grabczak EM, Krenke R, Zielinska-Krawczyk M, Light RW. Pleural manometry in patients with pleural diseases–the usefulness in clinical practice. Respiratory medicine. 2018 Dec 1;145:230-6. 3. Guinde J, Georges S, Bourinet V, Laroumagne S, Dutau H, Astoul P. Recent developments in pleurodesis for malignant pleural disease. The Clinical Respiratory Journal. 2018 Oct;12(10):2463-8. https://doi.org/10.1111/crj.12958 4. Cornes MP, Chadburn AJ, Thomas C, Darby C, Webster R, Ford C, Gama R. The impact of between analytical platform variability on the classification of pleural effusions into exudate or transudate using Light's criteria. Journal of Clinical Pathology. 2017 Jul 1;70(7):607-9. 5. Kugasia IA, Kumar A, Khatri A, Saeed F, Islam H, Epelbaum O. Primary effusion lymphoma of the pleural space: report of a rare complication of cardiac transplant with review of the 301 Journal of Rawalpindi Medical College (JRMC); 2020; 24(4): 296-301 literature. Transplant Infectious Disease. 2019 Feb;21(1):e13005. https://doi.org/10.1111/tid.13005 6. Farrag M, El Masry A, Shoukri AM, ElSayed M. Prevalence, causes, and clinical implications of pleural effusion in pulmonary ICU and correlation with patient outcomes. Egyptian Journal of Bronchology. 2018 Apr 1;12(2):247. DOI: 10.4103/ejb.ejb_117_17 7. Karki A, Riley L, Mehta HJ, Ataya A. Abdominal etiologies of pleural effusion. Disease-a-month: DM. 2019 Apr;65(4):95. DOI: 10.1016/j.disamonth.2018.09.001 8. Riley L, Karki A, Mehta HJ, Ataya A. Obstetric and gynecologic causes of pleural effusions. Disease-a-Month. 2019 Apr1;65(4):109-14. https://doi.org/10.1016/j.disamonth.2018.09.003 9. Dixit R, Agarwal KC, Gokhroo A, Patil CB, Meena M, Shah NS, Arora P. Diagnosis and management options in malignant pleural effusions. Lung India: official organ of Indian Chest Society. 2017 Mar;34(2):160. DOI: 10.4103/0970- 2113.201305 10. Heffner JE, Klein JS. Recent advances in the diagnosis and management of malignant pleural effusions. InMayo Clinic Proceedings 2008 Feb 1 (Vol. 83, No. 2, pp. 235-250). Elsevier. https://doi.org/10.4065/83.2.235 11. Jolobe OM. Atypical tuberculous pleural effusions. European journal of internal medicine. 2011 Oct 1;22(5):456-9. https://doi.org/10.1016/j.ejim.2011.03.011 12. Ryu JS, Ryu ST, Kim YS, Cho JH, Lee HL. What is the clinical significance of transudative malignant pleural effusion?. The Korean journal of internal medicine. 2003 Dec;18(4):230. DOI: 10.3904/kjim.2003.18.4.230 13. Zhai K, Lu Y, Shi HZ. Tuberculous pleural effusion. Journal of thoracic disease. 2016 Jul;8(7):E486. DOI: 10.21037/jtd.2016.05.87 14. Rao KS, Kumar HA, Rudresh BM, Srinivas T, Bhat KH. A Comparative study and evaluation of serum adenosine deaminase activity in the diagnosis of pulmonary tuberculosis. 15. Mishra OP, Yusaf S, Ali Z, Nath G, Das BK. Adenosine deaminase activity and lysosyme levels in children with tuberculosis. J Tropical Pediatr 2013;46:175–178. 16. Alaarag AH, Mohammad OI, Farag NM. Diagnostic utility of serum adenosine deaminase level in the diagnosis of pulmonary tuberculosis. Egyptian Journal of Bronchology. 2016 May 1;10(2):133. DOI: 10.4103/1687-8426.184369 17. Farhana A, Islam MS, Rehena Z, Yasmin F, Nurullah A, Talukder SI, Ferdousi S, Rahman MQ, Ahmed AN. Adenosine deaminase and other conventional diagnostic parameters in diagnosis of tuberculous pleural effusion. Dinajpur Med Col J. 2013;6(2):105-2. 18. Ferreiro L, Gude F, Toubes ME, Lama A, Suárez-Antelo J, San-José E, González-Barcala FJ, Golpe A, Álvarez-Dobaño JM, Rábade C, Rodríguez-Núñez N. Predictive models of malignant transudative pleural effusions. Journal of thoracic disease. 2017 Jan;9(1):106. doi: 10.21037/jtd.2017.01.12 19. Ashchi MA, Golish JO, Eng PH, O'Donovan PE. Transudative malignant pleural effusions: prevalence and mechanisms. Southern medical journal. 1998 Jan;91(1):23-6. DOI: 10.1097/00007611-199801000-00004 20. Panacek E, Marshall J, Fischkoff S, Barchuk W, Teoh L. Neutralization of tnf by a monoclonal antibody improves survival and reduces organ dysfunction in human sepsis: results of the monacrcs trial. Chest. 2000 Oct 1;118(4):88S-. 21. Sahn SA. Malignancy metastatic to the pleura. Clinics in chest medicine. 1998 Jun 1;19(2):351-61. https://doi.org/10.1016/S0272-5231(05)70082-4 22. Bedient T.J., Musani A.I. Malignant pleural effusions. Pak. J. Chest Med. 2015;18(1) 23. Nam HS. Malignant pleural effusion: medical approaches for diagnosis and management. Tuberculosis and respiratory diseases. 2014 May 1;76(5):211-7. 24. Bayhan GI, Sayir F, Tanir G, Tuncer O. Pediatric pleural tuberculosis. International journal of mycobacteriology. 2018 Jul 1;7(3):261. DOI: 10.4103/ijmy.ijmy_91_18 25. Doerr CH, Allen MS, Nichols III FC, Ryu JH. Etiology of chylothorax in 203 patients. InMayo Clinic Proceedings 2005 Jul 1 (Vol. 80, No. 7, pp. 867-870). Elsevier. https://doi.org/10.4065/80.7.867 26. Agrawal V, Doelken P, Sahn SA. Pleural fluid analysis in chylous pleural effusion. Chest. 2008 Jun 1;133(6):1436-41. https://doi.org/10.1378/chest.07-2232 27. Porcel JM, Esquerda A, Vives M, Bielsa S. Etiology of pleural effusions: analysis of more than 3,000 consecutive thoracenteses. Archivos de Bronconeumología (English Edition). 2014 May 1;50(5):161-5. https://doi.org/10.1016/j.arbr.2014.03.012 28. Fatima R, Harris RJ, Enarson DA, Hinderaker SG, Qadeer E, Ali K, Bassilli A. Estimating tuberculosis burden and case detection in Pakistan. The International journal of tuberculosis and lung disease. 2014 Jan 1;18(1):55-60. DOI: https://doi.org/10.5588/ijtld.13.0198 29. Qureshi AR, Mahmood H, Irfan M, Waqar A. Diagnostic Efficacy of Pleural Fluid Adenosine Deaminase Level in diagnosing TB Pleural Effusion is Excellent in a High Prevalence Area. Annals of PIMS-Shaheed Zulfiqar Ali Bhutto Medical University. 2018 Apr 2;14(1):52-7. 30. Hooper C, Lee YG, Maskell N. Investigation of a unilateral pleural effusion in adults: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010 Aug 1;65(Suppl 2):ii4-17. http://dx.doi.org/10.1136/thx.2010.136978 31. Arnold DT, De Fonseka D, Perry S, Morley A, Harvey JE, Medford A, Brett M, Maskell NA. Investigating unilateral pleural effusions: the role of cytology. European Respiratory Journal. 2018 Nov 1;52(5). 32. Lepus CM, Vivero M. Updates in effusion cytology. Surgical pathology clinics. 2018 Sep 1;11(3):523-44. DOI:https://doi.org/10.1016/j.path.2018.05.003