In-hospital outcome of patients with culture-confirmed tuberculous pleurisy: clinical impact of pulmonary involvement
© Shu et al; licensee BioMed Central Ltd. 2011
Received: 17 June 2010
Accepted: 21 February 2011
Published: 21 February 2011
Outcomes for hospitalized patients with tuberculous pleurisy (TP) have rarely been reported, and whether or not pulmonary involvement affects outcomes is uncertain. This study aimed to analyze the in-hospital mortality rate of culture-confirmed TP with an emphasis on the clinical impact of pulmonary involvement.
Patients who were hospitalized for pleural effusion (PE) of unconfirmed diagnosis and finally diagnosed as TP were identified. We classified them according to the disease extent: isolated pleurisy (isolated pleurisy group) and pleurisy with pulmonary involvement (pleuro-pulmonary group).
Among the 205 patients hospitalized before the diagnosis was established, 51 (24.9%) belonged to the isolated pleurisy group. Compared to the pleuro-pulmonary group, patients in the isolated pleurisy group were younger, had fewer underlying co-morbidities, and presented more frequently with fever and chest pain. Fewer patients in the isolated pleurisy group had hypoalbuminemia (< 3.5 g/dL) and anemia. The two groups were similar with regards to PE analysis, resistance pattern, and timing of anti-tuberculous treatment. Patients who had a typical pathology of TP on pleural biopsy received anti-tuberculous treatment earlier than those who did not, and were all alive at discharge. The isolated pleurisy group had a lower in-hospital mortality rate, a shorter length of hospital stay and better short-term survival. In addition, the presence of underlying comorbidities and not receiving anti-tuberculous treatment were associated with a higher in-hospital mortality rate.
In culture-confirmed tuberculous pleurisy, those with pulmonary involvement were associated with a higher in-hospital mortality rate. A typical pathology for TP on pleura biopsy was associated with a better outcome.
Tuberculosis (TB) remains a global health problem even though it has nearly been eradicated in some developed countries [1, 2]. The incidence in 2005 was 76 per 100,000 persons in Taiwan, 80 per 100,000 in the Republic of Korea, and 600 per 100000 in South Africa [3, 4]. TB remains a leading cause of mortality in many countries. The mortality rate has been reported to be 6% in those with pulmonary TB, and as high as 31% in those with disseminated TB [3, 4].
Because of variable manifestations and the difficulty in collecting clinical samples, extra-pulmonary TB is usually difficult to diagnose early . Tuberculous pleurisy (TP) is the second most common extra-pulmonary infection , and accounts for approximately 5% of all forms of TB . The gold standard for the diagnosis of TP is still mycobacterial culture of pleural effusion (PE), pleura tissue and respiratory specimens, which requires weeks to yield. The treatment could thus be delayed, resulting in an increased mortality rate . For those requiring hospitalization, the mortality rate is further increasing due to increasingly severe infections and weaker host states [8, 9].
The prognostic factors for hospitalized patients with TP are unclear. Only limited information is available on whether or not pulmonary involvement has a negative prognostic impact [6, 10]. However, the mortality rate is high in tuberculosis patients if they are not promptly diagnosed and treated . Therefore, we conducted this retrospective study to investigate the in-hospital mortality rate of culture-confirmed TP with an emphasis on the clinical impact of pulmonary involvement.
Subjects of study
This retrospective study was conducted in a tertiary-care referral center in northern Taiwan by reviewing the medical charts as in our previous study . The study was approved by the Institutional Review Board of the Research Ethics Committee of National Taiwan University Hospital (No.: 200809076R). The informed consent was deemed unnecessary for this retrospective study. We reviewed the mycobacterial laboratory registry database of the hospital and identified all patients with PE specimens sent for mycobacterial culture from January 2001 to December 2008. Among them, those who were hospitalized for PE before the diagnosis of TP was established by mycobacterial culture for PE were included for further investigation. Patients were classified into two groups according to the disease extent of TB: the isolated pleurisy group and pleuro-pulmonary group. The former was considered if all respiratory samples from a patient were culture-negative for M tuberculosis and there were no pulmonary parenchymal lesions compatible with active TB on chest radiographs, defined as new patch(es) of consolidation, collapse, lymphadenopathy, mass or nodule, cavitary lesion or infiltrate without other proven etiology . The others were classified into the pleuro-pulmonary group.
Patient data were collected by reviewing medical records and recorded in a standardized case report form by one chest physician, then verified by another physician from July 2009 to December 2009. Data included age, gender, underlying co-morbidities, initial symptoms, laboratory data and radiographic findings when the index PE sample was collected, as well as the course and outcome of anti-tuberculous treatment. Mycobacterial culture and susceptibility testing were performed according to standard procedures [3, 14]. In our hospital, acid-fast smear and mycobacterial culture for pleural effusion samples were routinely performed in cases of lymphocytic pleural exudate by Light's criteria . For patients with adequate cough power, sputum samples were collected by spontaneous expectoration after explanation without supervision. For the others, sputum samples were collected by a nurse using a suction tube inserted through mouth or nasal cavity. We routinely ordered at least three sets of mycobacterial cultures for sputum samples collected from each patient. Bilateral lesions were considered if the contra-lateral lung or pleural cavity were involved. Three histological findings of pleura tissue were considered typical for TP: (1) granulomatous inflammation, (2) caseous necrosis, and (3) the presence of acid fast bacilli .
Patients received standard short-course anti-TB treatment with isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and pyrazinamide (PZA) for the initial 2 months, and INH plus RIF for the following 4 months. The standard regimen was modified if drug resistance or adverse effects were encountered [17, 18]. Patients were followed for at least 6 months after the index PE samples were collected, or until death or loss of follow-up. Residual pleural thickening (RPT) on radiographs after 6 months of treatment was defined as minor if the pleural thickness was less than 10 mm, or major if equal to or greater than 10 mm. One pulmonologist and one radiologist, both blinded to the clinical data, interpreted the chest radiographs. If their opinions differed, the films were further reviewed by another senior pulmonologist blinded to the results.
The inter-group differences were compared by using the independent t test for numerical variables and the chi-square test or Fisher's exact test for categorical variables as appropriate. Survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Variables having a significant difference (p < 0.05) for in-hospital mortality in univariate analysis were further tested by logistic regression with the forward conditional method.
During the 8-year study period, a total of 496 samples from 412 patients out of 24,759 PE samples yielded M. tuberculosis. Among them, 205 patients were hospitalized when TP was culture-confirmed. The indications for hospitalization were intolerant fever or dyspnea in 99, massive and/or loculated PE in 51, prolonged symptoms (> 14 days) in 51, and presence of lung mass in 14. Among the 205 patients, 51 were further classified into the isolated pleurisy group. The other 154, including 97 (63%) whose sputum samples were culture-positive for M. tuberculosis, were classified into the pleuro-pulmonary group. A total of 3,112 patients had culture-confirmed pulmonary TB.
Clinical characteristics of the patients with tuberculous pleurisy
Isolated pleurisy group (N = 51)
Pleuro-pulmonary group (N = 154)
Age ≥ 65 years
Underlying co-morbid condition*
Cirrhosis of liver
Acquired immunodeficiency syndrome#
Laboratory and radiographic findings of the patients with tuberculous pleurisy
Isolated pleurisy group (N = 51)
Pleuro-pulmonary group(N = 154)
Positive AFB in PE
Receiving pleura biopsy
Pretreatment resistance pattern
Total protein (g/dL)
Lactate dehydrogenase (U/L)
Leukocyte > 11000 or < 4000/μL
Albumin < 3.5 g/dL
Total bilirubin > 1.2 mg/dL
Treatment and outcomes
Isolated pleurisy group (N = 51)
Pleuro-pulmonary group (N = 154)
Tube thoracostomy or decortication
Within 2 weeks
More than 2 weeks
Residual pleura thickening*
≥ 10 mm
< 10 mm
In-hospital mortality rate
Length of hospital stay: days
Factors possibly associated with in-hospital mortality
Unlvariate p value
Multivariate OR (95% CI.)
≥ 65 years
< 65 years
Underlying co-morbid illness
Serum albumin level
< 3.5 g/dL
≥ 3.5 g/dL
Days to anti-tuberculous treatment
> 14 days
≤ 14 days
The pleural cavity is a common site of involvement in extra-pulmonary TB [5, 16]; however, the outcomes and prognostic factors are unclear in hospitalized populations. In this retrospective study, those with pleuro-pulmonary TP accounted for three-fourths of all TP patients requiring hospitalization and had a higher in-hospital mortality rate. The in-hospital mortality rate was also higher among patients who had underlying comorbidities, did not receive anti-TB treatment and had no typical pleural pathology for TP.
Although the residual RPT was similar, our analysis showed that the in-hospital mortality rate was six-fold higher in patients with pulmonary involvement than those with isolated pleurisy (24% vs. 4%). Compatible with a previous report showing high mortality in hospitalized TB patients , our previous study revealed that patients with neutrophil-predominant TP had an in-hospital mortality rate of 36% . There are several possible explanations for the high in-hospital mortality rate of patients with TP, especially for those with pulmonary involvement. Because patients with isolated pleurisy are more likely to have local and systemic inflammatory symptoms such as chest pain and fever rather than hypoalbuminemia, pulmonary involvement probably represents an extensive and serious infection in a compromised and malnourished host. Another possible explanation is that TB is usually at the top of the list of the differential diagnoses for lymphocyte-rich pleurisy , whereas it accounts for only 1~2% of the etiologies for pneumonia , thus treatment is frequently delayed. Although a delay in treatment for more than 14 days was not an independent poor prognostic factor, the 19 cases of rapid mortality in our study suggest that TP could be an immediately fatal disease, and timely and effective anti-tuberculous treatment is vital, especially for those with pleuro-pulmonary involvement.
However, two previous studies failed to demonstrate a difference in clinical outcomes between isolated TP and pleuro-pulmonary TB [6, 10]. Again there are several possible explanations. First, the previous studies analyzed survival after completing anti-TB treatment and relapse, rather than in-hospital mortality. These long-term outcomes were more likely to be confounded by other factors, such as age, underlying co-morbidity, and socioeconomic status. Second, those needing admission were probably more severe cases, especially in a referral medical center. Finally, the patients in the previous reports were younger, around the fifth to early sixth decade, and less than 10% of them had underlying comorbid conditions [16, 20].
Our results revealed that histologic examination of the pleural biopsy is the key step for the early diagnosis of TP, because it can effectively demonstrate a typical pathology of TP in more than three-fourths of patients within 3 days, which is higher than the yield rate of mycobacterial cultures for PE samples (11%) . Moreover, even when using the fluorometric BACTEC technique, the results of mycobacterial culture still take one to two weeks . Hence, a typical pleura pathology could result in the early diagnose of TP and improved outcomes. Therefore, for in-patients with lymphocyte-rich PE, the possibility of tuberculosis should be kept in mind and pleural histology should be performed at an early stage if clinically feasible. For the early diagnosis of TP, biomarkers in pleural effusion such as adenosine deaminase and interferon-gamma have been shown to be helpful, but further investigations are needed for the application of nucleic acid amplification tests and interferon-gamma release assays [23, 24].
Our study has several limitations. First, in this retrospective study, the number of patients with culture-confirmed TP could have been underestimated because mycobacterial cultures were not routinely performed for every PE sample, and most studies show the sensitivity to be less than 30% . Therefore, the patients with culture-negative TP might have been missed. However, the selected patients were all true cases of TP and represented a homogenous population for detailed analysis. Second, the 6-month follow-up rate was less than 90%. Third, our study population was selected from a large medical referral center. Whether our findings can be extrapolated to all TP patients should be further confirmed.
Our study revealed that for hospitalized patients with TP, pulmonary involvement, underlying comorbidities, no typical pleura pathology and not receiving anti-TB treatment were associated with a worse in-hospital outcome. Aggressive examination, such as pleural biopsy, for pleural effusion with unknown cause is suggested for the early diagnosis and treatment if clinically appropriate.
We thank Dr. Yao-Wen Kuo for collecting the clinical data and Dr. Huey-Dong Wu and the members of the Taiwan Anti-Mycobacteria Investigation (TAMI) group for data collection and analysis. We are grateful to the Medical Information Management Office of our hospital for their help in reviewing the patient charts. This study was supported by the Institute for Biotechnology and Medicine Industry, Taiwan, and academic grant of National Taiwan University Hospital (NTUH. 100-N1685).
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