Frequency of Tuberculosis and Malignancy in Transudative- pleural effusions: A rare but real finding

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-


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][2][3][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 ultrasoundguided 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 TBdiagnosis. 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 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.   Figure 1). 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-Xpert. As tuberculosis is endemic in our region, all exudative lymphocytic pleural effusions are considered as tubercular, until proven otherwise. 28  The main limitation of this study is that it is a singlecenter 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.