Prednisolone does not reduce poor outcomes in TB pericarditis

Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis.

Mayosi BM, Ntsekhe M, Bosch J, Pandie S, Jung H, Gumedze F, Pogue J, Thabane L, Smieja M, Francis V, Joldersma L, Thomas KM, Thomas B, Awotedu AA, Magula NP, Naidoo DP, Damasceno A, Chitsa Banda A, Brown B, Manga P, Kirenga B, Mondo C, Mntla P, Tsitsi JM, Peters F, Essop MR, Russell JB, Hakim J, Matenga J, Barasa AF, Sani MU, Olunuga T, Ogah O, Ansa V, Aje A, Danbauchi S, Ojji D, Yusuf S; IMPI Trial Investigators. N Engl J Med. 2014 Sep 18;371(12):1121-30. doi: 10.1056/NEJMoa1407380. Epub 2014 Sep 1.

Background: Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered. We evaluated the effects of adjunctive glucocorticoid therapy and Mycobacterium indicus pranii immunotherapy in patients with tuberculous pericarditis.

Methods: Using a 2-by-2 factorial design, we randomly assigned 1400 adults with definite or probable tuberculous pericarditis to either prednisolone or placebo for 6 weeks and to either M. indicus pranii or placebo, administered in five injections over the course of 3 months. Two thirds of the participants had concomitant human immunodeficiency virus (HIV) infection. The primary efficacy outcome was a composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

Results: There was no significant difference in the primary outcome between patients who received prednisolone and those who received placebo (23.8% and 24.5%, respectively; hazard ratio, 0.95; 95% confidence interval [CI], 0.77 to 1.18; P=0.66) or between those who received M. indicus pranii immunotherapy and those who received placebo (25.0% and 24.3%, respectively; hazard ratio, 1.03; 95% CI, 0.82 to 1.29; P=0.81). Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04). Both prednisolone and M. indicus pranii, each as compared with placebo, were associated with a significant increase in the incidence of cancer (1.8% vs. 0.6%; hazard ratio, 3.27; 95% CI, 1.07 to 10.03; P=0.03, and 1.8% vs. 0.5%; hazard ratio, 3.69; 95% CI, 1.03 to 13.24; P=0.03, respectively), owing mainly to an increase in HIV-associated cancer.

Conclusions: In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis.

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Editor’s notes: Tuberculous pericarditis remains an important and serious complication of HIV disease. Previous studies have suggested that treatment with steroids, in addition to standard TB treatment, reduces the risk of serious complications such as constrictive pericarditis. However, previous studies have been small, and have included few HIV-positive people.

This randomised controlled trial across eight countries in Africa tested two treatments for people with either definite or probable TB pericarditis. These included high dose steroid treatment, and injections of Mycobacterium indicus pranii. Mycobacterium indicus pranii is an environmental mycobacterium suggested to have a possible effect to reduce inflammation among people with TB. Two-thirds of the 1400 study participants were HIV-positive, most of whom were not taking antiretroviral therapy at the time of enrolment. The median CD4 count at enrolment was around 150 cells/µl. The primary outcome of the study was a composite of death, cardiac tamponade requiring drainage, and constrictive pericarditis. 

The death rate overall was high at 18%, and the main causes of death were considered to be pericarditis, TB, and HIV disease. Immunotherapy with Mycobacterium indicus pranii had no beneficial effects on any outcome. There was no overall difference in the composite primary outcome among people receiving prednisolone compared to placebo. However, people receiving prednisolone were less likely to develop constrictive pericarditis or to be hospitalised. There were more cancers (primarily Kaposi’s sarcoma among HIV-positive people) in people receiving either prednisolone or Mycobacterium indicus pranii, although the absolute rate was low. This is in keeping with previous observations.

Limitations of the study include that most people did not have microbiological confirmation of their TB diagnosis, so could potentially have had other causes of pericarditis for which prednisolone would not be expected to improve outcomes.

The results of this trial suggest that guidelines concerning use of prednisolone for TB pericarditis should be reviewed, particularly for people living with HIV. The poor outcomes among this group of people with TB and advanced HIV disease highlight the need for earlier HIV diagnosis, initiation of antiretroviral therapy, and TB preventive therapy.

Avoid TB deaths
Comorbidity, HIV Treatment
Africa
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