Pleural Tuberculosis and its Treatment Outcomes

Purpose: To evaluate the incidence, treatment and clinical outcomes of tuberculosis pleuritis at a hospital in the state of Penang, Malaysia. Methods: A retrospective study was conducted in Hospital of Penang, Malaysia. Patient records were reviewed retrospectively to identify patients with confirmed diagnosis of tuberculous pleuritis from January 2006 to December 2008. Chest x-ray (CXR) and pleural biopsy were carried out on all patients. Directly observed therapy (DOT) was given to all patients. Data were analyzed using SPSS version 16. Results: Of 1548 tuberculosis cases, 80 (5.2 %) patients had tuberculous pleuritis. The mean age of the patients was 35.4 ± 12.87 years, with a male to female ratio of 3.4:1. Ethnically, a plurality (n = 30, 37.7 %) of cases among tuberculosis pleuritis patients were Chinese, followed by Malay (31.2 %). Out of the 80 patients with tuberculous pleuritis, 10 (12.5 %) also had diabetes mellitus, and 8 (10.0 %) HIV/AIDS. Fever, cough, chest pain and shortness of breathing were the most frequently reported symptoms. Treatment success rate was 1.558 times higher among TB group than pleuritis TB group (Odds ratio, 95 % CI, 1.06 – 2.59, p = 0.025). Conclusion: The incidence of TB pleuritis was genderand race-related, with DM and HIV the most commonly reported risk factors. Treatment success rate was higher among pulmonary TB group than in those with TB pleuritis (extra pulmonary TB).


INTRODUCTION
Tuberculosis (TB) is a leading source of morbidity and mortality throughout the world.It is estimated that in 2011, there was a total of 8.7 million new cases and 1.4 million deaths from TB [1].Although the African region has the highest estimated incidence (356 per 100,000 populations per year), the majority of patients with TB live in the most populous countries of the Asian subcontinent, which accounts for nearly half of the new cases that arise yearly [2].The frequency of pleural involvement in TB has been variously reported to range from 4 % in United States to 23 % in Spain) [3,4].TB pleural effusion is the second most common form of extrapulmonary tuberculosis (EPTB), only less frequent than lymph node TB.TB pleural effusion is increasingly recognized, even in developed nations [5], as the incidence of EPTB has more than doubled following HIV pandemic.The incidence of TB pleural effusions in human immunodeficiency virus / acquired immuno-deficiency syndrome (HIV/AIDS) has been variously reported to range from 15 to 90 % with effusion being more common in patients with higher CD4+ counts [6][7][8].
In some parts of the world, tuberculosis remains the most frequent cause of pleural effusion in the absence of an obvious pulmonary lesion.Diagnosis of tuberculosis in pleural effusion can be made by pleural fluid culture.Pleural biopsy can also be used to diagnose TB.When microscopic examination of biopsy specimen is combined with culture, diagnosis can be made in 90 % of patients, especially with the use of multiple biopsies [9].Malaysia, a multicultural and multiethnic country, has a population slightly above 26 million and an area of 33,000 km 2 .Tuberculosis is among the top five communicable diseases in the country with an incidence rate of 62.56 per 100,000 and mortality rate of 5.37 per 100,000 [10].The State of Penang is the eighth most populous state in Malaysia and among the top five states with the highest tuberculosis burden [10].Pulmonary tuberculosis has been the disease of interest for researchers but little work has been done on extra-pulmonary tuberculosis, especially, tuberculous pleura.The current study was designed to expand the current knowledge by gathering baseline data on the incidence, diagnosis, complications, management and treatment outcomes of tuberculous pleural effusion in a teaching hospital.

Methods
A retrospective study was conducted among patients visiting the respiratory clinic, Penang Hospital.Penang is one of thirteen states and is geographically situated in northern Malaysia.It is a multicultural state comprising of Malay (42.5 %), Chinese (46.5 %), Indian (10.6 %) and minorities (0.4 %), with an estimated population of 1.5 million [11].
A total of 1548 cases were registered for tuberculosis treatment from 1 st January 2006 to December 2008 at the respiratory diseases clinic of Penang Hospital.This clinic is a tertiary level referral centre for respiratory diseases in the state of Penang, Malaysia.Any person with a respiratory problem in the state of Penang can attend this centre with a physician's referral.
A retrospective evaluation of the medical records of patients with confirmed diagnosis of tuberculosis pleura was carried out.From each medical case file, the patient's history, physical parameters, chest radiographs and laboratory investigation was reviewed in order to obtain maximum information about the type and severity of TB.In addition, demographic factors, life style (smoking habit and alcohol use) and clinical characteristics were recorded.Among clinical characteristics, co-morbid medical complications (such as diabetes mellitus, HIV, asthma and chronic obstructive pulmonary disease COPD), medications for therapy and therapeutic outcomes were recorded, based on Chi-square and Odds ratio.The study protocol was approved by Clinical Research Center (CRC), Penang Hospital and Ministry of Health, Malaysia (ref no.KKM/NIHSEC/08/0804P87-177).

Statistical analysis
Data with quantitative variables were expressed by mean ± standard deviation (SD) and range while qualitative variables were estimated by frequency and percentage.Chi square (X 2 ) and Odds ratio were applied to compare outcomes, and differences were considered significant at p < 0.05.The data were analyzed using SPSS ® software, version 16.
Table 3 shows chest x-ray and laboratory results.The disease was mostly a primary infection rather than a reactivation of co-existing pulmonary tuberculosis (past history and/or family history of the disease was absent in 93.8% of cases, and evidence of parenchyma lung lesions were absent in 78 % of cases).Right pleural effusion was slightly more common than left pleural effusion (48.6 % compared to 27.5 %).Up to 3.8 % of cases had bilateral pleural effusion.ESR was elevated in a majority of cases (> 40 mm/h in 56.2 %).Pleural biopsies for culture and sensitivity were positive in 49 (61.3 %) of the cases.

Management and outcomes
All patients received directly observed therapy (DOTS) from six to nine months.Two months ethambutol, isoniazid, rifampicin and pyrazinamide with four months biweekly isoniazid and rifampicin (2EHRZ+4H2R2) were the therapeutic combination used for the majority 27 (33.8%) of the patients.Based on the clinical outcomes, the duration of intensive phase was increased to three months in 33.2 % patients while the treatment success rate for TB group being higher than pleuritis TB group (odd ratio = 1.558, 95% CI, 1.06 -2.59, p = 0.025).Six (7.5 %) patients defaulted the treatment and seven (8.7 %) patients were recorded as deceased during the course of therapy, as shown in Table 4.

DISCUSSION
There has been a rise in the prevalence of TB throughout the world with a propensity for extrapulmonary involvement.Similarly, HIV/AIDS cases continue to grow in numbers. in older age groups, suggesting that it may be Published data from some developed countries indicate that pleural tuberculosis is more frequent due to reactivation of the disease [3,7,8,13].However the situation in developing countries is not clear.In the current study, we found that the disease is mainly a primary one rather than a reactivation of previous parenchymal lung tuberculosis.In addition, we found that pleural tuberculosis tends to affect younger age groups (< 45 years) and this more pronounded in males.These findings may be explained partly by the reduction in incidence of tuberculosis in developed world [5].The unilateral tuberculous effusion reported in the present study confirms previous findings of right-sided predominance [3,14].
One recent study from Spain [15] that described pleural tuberculosis in children showed that history of contact with a tuberculous case was positive in 25.7 % of patients, but in the present study, we found only 3.8 % of our patients had such history, indicating that contact with tuberculous cases seems to be less evident in adults.
Pleural tuberculosis is still a difficult disease to diagnose; pleural biopsy remains the gold standard for the diagnosis of pleural tuberculosis [5,6].In a study of 42 patients with tuberculous effusions, closed needle biopsy achieved a diagnostic sensitivity of 79 % when histology and culture was declared a reliable tool for diagnosis [16].Seibert et al reported a yield of 66.7 % from closed pleural biopsy cultures and 84.6 % from histology [7].Pleural tissue simultaneously sent for mycobacterial culture in addition to histology may increase diagnostic yield further.The diagnostic yield has been reported to rise to 90% when closed pleural biopsies are cultured [17].
The diagnosis of tuberculous pleural effusion is an indication for treatment with anti-tuberculous chemotherapy.Standard short course chemotherapy with isoniazid, rifampicin, pyrazinamide and ethambutol followed by 4 months of isoniazid and rifampicin is sufficient in the majority of cases [18].Following the initiation of the standard 4-drug regimen mentioned above, subsequent treatment should be guided according to the results of drug sensitivity testing when they become available to the clinician.The incidence of residual pleural thickening and functional squeal can be reduced by effective anti-tubercular chemotherapy [19].Although studies by Dutt et al supported the effectiveness of a 6-month regimen of isoniazid and rifampicin in both pulmonary and pleural disease, this is generally not advised due to the problems associated with drug resistance [8].Paradoxical enlargement of the effusion has been reported after the commencement of anti-tuberculous chemotherapy similar to that seen in intra-cranial tuberculomas and this can require drainage, in some cases, for symptom relief [20].
A number of studies suggest increased incidence of pleural involvement in AIDS cases diagnosed with active tuberculosis.In a study comparing 963 HIV positive adults with pulmonary TB with 1000 HIV negative age-matched controls, there was a significantly higher incidence of pleural effusions (16 vs. 6.8 %) [21].In the western world, a study in South Carolina, USA appeared to show increased rates of pleural TB in AIDS cases (11 %) compared to non-AIDS cases (6 %) [22].
There is also evidence to suggest that HIV coinfection alters the clinical presentation of TB pleurisy.The duration of the presenting illness tends to be longer in a substantial number of such cases compared with that seen in HIV negative individuals.A study from Tanzania found that HIV positive patients tend to present with more constitutional symptoms such as dyspnoea, fevers, night sweats, Treatment of tuberculous pleurisy in HIV positive co-infection is generally successful with a good outcome in most cases.In a series of 22 patients, there were 2 deaths reported and only 1 after antituberculous chemotherapy was commenced [21].The current study's main focus is on pleurisy TB (EPTB) but comparison was made with PTB, to get a clear picture based on treatment outcomes.It was found that treatment completion rate was 48 (60.0 %), default and failure rate were 6 (7.4%) and 5 (6.2%) respectively.Deaths were found in 5 (6.2 %) cases; among these 5 cases, 4 were affected with co-morbid condition (3 patients were pleuritis TB plys HIV/AIDS and 1 with diabetes mellitus).Similar default and failure rate have been reported by Sharma et al [23].

Limitations of the study
All registered cases from January 2006 to December 2008 in the cited clinic were part of study.Due to the retrospective nature of the study, some social factors were, however, considered "Unknown" where they were unconfirmed.

CONCLUSION
The incidence of pleura TB was higher in males than in females and higher in Chinese race than other ethnic group.Fever, cough, chest pain, shortness of breathing, night sweat were clinically proven symptoms.The study confirms early detection by simple tests and ensuring complete treatment using direct observe therapy short course (DOTS) strategy.DOTS strategy is an effective treatment modality for TB pleurisy, achieving a high treatment completion rate, low default and failure rates.HIV/AIDS, diabetes mellitus, COPD and asthma are co-morbidity which makes treatment more complicated.

Table 3 :
Laboratory test results for patients (N = 80)

Table 4 :
Categorization of patients according to treatment outcomes