Immune reconstitution syndrome refers to a paradoxical worsening of a patient’s clinical status that can occur after the initiation of ART.¹³⁰ The worsening of symptoms is due to improved function of the patient’s immune system, resulting in the system’s ability to mount an inflammatory response to infectious pathogens and neoplasms.¹³¹ Immune reconstitution syndromes have been reported in patients with Mycobacterium avium complex, ¹³² TB, ¹³³ Cryptococcus neoformans,¹³⁴ cytomegalovirus (CMV),¹³⁵ PCP,¹³⁶ and a host of other AIDS-related malignancies.¹³⁷ The differential diagnosis of a patient who presents with worsening symptoms and is newly started on ART should include an adverse reaction to a drug, a new or previously unrecognized OI, and failure of OI therapy. Once other causes of worsening symptoms have been ruled out, management of patients almost always includes continuation of ART, treatment directed at the specific OI affecting the patient’s immune system, and the occasional use of anti-inflammatory agents. Care should follow the approach outlined in Protocol 3.26.¹³⁸