Table 1.

Summary of the theory of paradoxical cryptococcal immune reconstitution inflammatory syndrome (IRIS) pathogenesis

Phase	Immunologic activity	Evidence in CM-IRIS patients
Baseline (before ART)	Paucity of appropriate inflammation for cryptococcosis and/or Inappropriate (Th2) responses resulting in poor antigen clearance. Increased risk if CSF culture is positive at end of induction fungicidal amphotericin therapy [44•, 46]a	↓ TNF-α, G-CSF, GM-CSF, VEGF in serum; ↓ IFN-γ, G-CSF, TNF-α, IL-6 in CSF [29•] ↑ IL-4 pre-ART [28•] Similar fungal burden at initial infection [28•,50•] Higher CrAg pre-ART [29•]
Early phase (after starting ART)	Increasing pro-inflammatory signaling from APCs due to persisting antigen burden and failure to clear antigen Lack of effector response Secondary activation of coagulation cascade	↑ IL-6 from macrophages [31], then downstream ↑ CRP production; ↑ IL-7 from APCs [28•] No increase in IFN-γ [28•] ↑ D-dimer [28•]
Effector phase (IRIS event)	Cytokine storm of multiple immune pathways of innate and adaptive immune systems Activation of coagulation cascade	Th1: ↑ IFN-γ, VEGF; Th17:↑ IL-17; [28•] Innate: ↑ IL-8, G-CSF, GM-CSF, CRP [28•] ↑ D-dimer [28•]

^aWhether higher dose consolidation therapy with fungicidal doses of fluconazole at ≥800 mg/day is a potential intervention to decrease the risk of IRIS is unknown. Standard consolidation therapy dosing of fluconazole at 400 mg/day is fungistatic [17•].

APCs antigen-presenting cells; ART antiretroviral therapy; CM cryptococcal meningitis; CrAg cryptococcal antigen; CRP C-reactive protein; CSF cerebrospinal fluid; FGF fibroblast growth factor; G-CSF granulocyte colony-stimulating factor; GM-CSF granulocyte-macrophage colony-stimulating factor; IFN interferon; IL interleukin; TNF tumor necrosis factor; VEGF vascular endothelial growth factor.