For patients with a suspected paradoxical IRIS, the initial consideration is exclusion of a recurrence of the associated infection or development of a new infection. For example, when suspecting paradoxical TB-IRIS, considerations should include non-adherence to TB medications, infection with drug-resistant mycobacteria, new community-acquired pneumonia, PJP and viral infections. Investigations should include sputum microscopy and culture for bacterial and mycobacterial infection, chest X-ray or CT scan of chest or both. Similarly, a patient being considered for paradoxical CM-IRIS, should have a CT scan of brain and lumbar puncture to measure the opening pressure and obtain CSF to determine cell counts and to culture for bacteria, mycobacteria and fungi. When evaluating cultures, it is important to note that while cultures are often negative in an IRIS (in keeping with the concept that non-viable organisms may be antigenic and provoke an immune response), the presence of a positive culture does not exclude an IRIS, as viable pathogens are clearly also antigenic.

After the exclusion of alternative diagnoses, symptomatic management of an IRIS is usually sufficient. For example, therapeutic lumbar punctures and non-steroidal anti-inflammatory drugs often relieve symptoms in paradoxical CM-IRIS. Escalation of antimicrobial therapy is only necessary when there is a clear microbiological relapse of the infection. Importantly, ART should not be ceased unless the patient’s condition becomes critical. While many clinicians consider the use of corticosteroid therapy for an IRIS, the evidence for use of this therapy is not strong and it should only be considered in cases of severe symptomatic IRIS refractory to simple measures. A randomised placebo-controlled trial in South Africa, used 4 weeks of prednisolone (1.5 mg then 0.75 mg/kg/day) in patients with paradoxical pulmonary TB-IRIS, (27) and showed reduction in a combined endpoint of duration of hospitalisation and number of procedures, and improvement in symptoms and wellbeing but increased concurrent infections and glucocorticoid reactions. In PML-IRIS, corticosteroid therapy has been reported to be effective in individual cases (28) but overall, there is insufficient evidence to recommend routine use. Results of randomised controlled trials of corticosteroid therapy for the treatment of PML-IRIS are needed.

Some IRIS manifestations notoriously recur in the setting of decreased corticosteroid dosing, resulting in extremely long durations of therapy and its accompanying risks, including immunosuppression. In this setting, blockade of tumour necrosis factor (TNF) activity through the use of monoclonal antibodies to TNF has been shown to be effective in MAC- and TB-IRIS, though only in case reports (29-31). The CCR5 inhibitor Maraviroc has been advocated as adjunctive ART in patients with severe PML-IRIS on the basis that it will decrease the migration of pathogen-specific memory T cells (which express CXCR5) into the brain, but efficacy has only been demonstrated in a case study (32).

Surgical measures are occasionally necessary, such as drainage or excision of large lymph nodes or abscesses in mycobacterial-IRIS.