Influence of high-dose rifampin on Mycobacterial load and inflammatory mediators in pericardial TB patients - SUMMARY/ABSTRACT
In countries with high tuberculosis (TB) incidence, TB is the most common cause of pericardial effusion.
Pericardial tuberculosis (PCTB) is a severe form of extrapulmonary TB causing hemodynamic instability and
cardiac tamponade requiring pericardiocentesis3. Despite anti-tuberculosis treatment (ATT), complications
remain frequent and mortality high (8-34%, worst in HIV co-infected persons). Death in PCTB is contributed to
both by a high pericardial fluid (PCF) bacillary load that may arise from inadequate penetration of ATT into
pericardium, and by dysregulation of the immune response, which attempts to clear the infection. Thus there is
an important need to improve the current PCTB treatment approach both in terms of efficiency of bacterial killing
and identification of deleterious inflammatory pathways that could be specifically modulated. This collaboration
will therefore determine:
1: Whether high dose rifampin increases drug exposure in PCF and thus results in a greater decline in
Mtb load. The hypothesis is that rifampin (RIF) exposure in PCF will increase with a higher dose (35mg/kg,
RIF35) versus standard (RIF 10mg/kg, RIF10) and that decline in bacteria will correlate with RIF exposure in PCF
and plasma. A randomized controlled clinical trial of 35mg/kg RIF daily in combination with standard doses of
the 3 other antitubercular drugs (pyrazinamide, ethambutol and isoniazid), versus standard of care will be
conducted. This will assess safety and the primary efficacy endpoint of PCF bacillary burden at 0 and 72 hrs.
Secondary endpoints will be a composite of clinical measures and precise cardiovascular magnetic resonance
(CMR) evidence of pericardial inflammation, thickening, effusion, fibrosis or constriction. The pharmacokinetics
and pharmacodynamics of antitubercular drugs in PCF will also be determined.
2: Relationships between pericardial Mtb-specific T cells with bacterial load and treatment outcome in
PCTB. Multiple types of T cells are found in PCF, but it remains unknown which subsets contribute to protection
and/or pathology. The phenotype and function of conventional and donor unrestricted (e.g. MAIT cells, CD1-
restricted T cells, γδ T cells) Mtb-specific T cell subsets in paired blood and PCF from HIV infected and uninfected
persons with PCTB will be investigated. The relationship in PCF of CD4+ T cell biomarkers (CD153, HLA-DR,
CD38, Ki67) with bacillary load and outcome will also be undertaken.
3: Relationships between Mtb-induced markers of host cell death pathways and bacterial load in PCTB.
In model systems, necrotic (cytolytic) cell death benefits dissemination of Mtb, while apoptotic cell death
associates with host bacterial control. It is unknown how the induction of varying cell death pathways relate to
disease in TB patients. Therefore well-defined markers of cytolytic macrophage cell death pathways in PCF (and
blood) will be determined and their correlation with clinical endpoints explored.
