TB-associated immune reconstitution inflammatory syndrome

TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) occurs in two forms, unmasking and paradoxical. Case definitions have been published for resource-limited settings. Disease pathogenesis mechanisms are similar for both forms of TB-IRIS and reflect restoration of an immune response against M. tuberculosis after administration of cART that results in an exaggerated inflammatory response to live or dead bacilli. Unmasking TB-IRIS refers to the clinical manifestations of active TB that occur soon after cART is started in patients with undiagnosed TB. Paradoxical TB-IRIS refers to the worsening of TB after cART is started in patients who are receiving TB treatment. Both forms of TB-IRIS have a wide range of clinical features such as fever, worsening respiratory symptoms, lymphadenopathy (often with suppuration), TB abscesses and serous effusions. Central nervous system TB-IRIS is particularly severe. TB-IRIS can involve multiple sites, reflecting dissemination of TB in patients with profound immunodeficiency. A meta-analysis revealed a summary risk estimate of 18% for paradoxical TB-IRIS with 2% mortality.

Predictors for the occurrence of TB-IRIS include a CD4+ T cell count < 50 cells/µL pre-cART; high pre-cART and lower on-cART HIV viral loads; severity of TB disease (high pathogen burden); and less than 30-day interval between initiation of TB and HIV treatments. Most TB-IRIS occurs within 3 months of the start of TB treatment. There is no diagnostic test for TB-IRIS and alternative diagnoses such as the failure of anti-tuberculosis treatment (drug interactions, non-adherence, drug resistance) and other opportunistic infections must be considered.

Patients with mild or moderately severe TB-IRIS can be managed symptomatically or treated with non-steroidal anti-inflammatory agents (although no clinical data exist to support their use). Patients with more severe TB-IRIS can be treated successfully with corticosteroids. A randomised, placebo-controlled trial demonstrated the benefit of corticosteroids in the management of TB-IRIS symptoms (as measured by decreasing days of hospitalisation and Karnofsky performance score) without adverse consequences. In the presence of TB-IRIS, neither TB therapy nor cART should be stopped because both therapies are necessary for the long-term health of the patient. In patients at high risk of TB-IRIS (CD4+ T cell count <100/mL and commencing cART within 30 days of TB treatment), a randomised trial showed that steroids reduced TB-IRIS without a significant increase in other opportunistic events or mortality. The dosing strategy for prednisolone was 40 mg daily for two weeks, followed by 20 mg daily for two weeks during the first four weeks after initiation of cART. Steroids should be used in cerebral TB as they reduce mortality. In the setting of pericarditis, it is less clear as a randomised controlled trial did not show a reduction in mortality, with a reduction in constrictive pericarditis offset by an increase in some cancers including Kaposi’s sarcoma.