The advent of antiretroviral therapy (ART) revolutionised the care of patients with human immunodeficiency virus (HIV) infection. However, from the late 1980s, when zidovudine monotherapy was introduced, through to the late 1990s, when combination ART became standard of care, clinicians began to recognise that some patients experienced an exacerbation of a previously treated opportunistic infection or initial presentation of a new infection despite increased CD4+ T cell counts after commencing ART (1, 2). These disease episodes were characterised by exaggerated and/or atypical inflammation and involved a wide variety of opportunistic pathogens, including non-tuberculous mycobacteria (NTM), Mycobacterium tuberculosis, Pneumocystis, Cryptococcus, varicella zoster virus (VZV), John Cunningham (JC) virus and cytomegalovirus (CMV). Notably, Mycobacterium avium complex (MAC) disease was associated with the restoration of immune responses against mycobacteria. These conditions were therefore referred to as immune restoration disease to differentiate them from immunodeficiency disease, though the term immune reconstitution inflammatory syndrome (IRIS) is now more commonly used (3). IRIS events occur in patients who are very immunodeficient when ART is commenced, mostly in the first 6 months of therapy but may also occur in the setting of ART intensification. Importantly, IRIS is not limited to individuals with HIV infection but also occurs in non-HIV settings, particularly solid organ transplant and haematopoietic stem cell transplant recipients in the setting of immune recovery after withdrawal of immunosuppressant drug therapy (4, 5), and in multiple sclerosis patients who experience progressive multifocal leucoencephalopathy (PML) during natalizumab therapy and an exacerbation of PML with inflammatory features after natalizumab withdrawal (6).