Cryptococcal IRIS: Pathogenesis & Pearls for Clinical Management David R. Boulware MD, MPH, CTropMed Distinguished Assistant Professor Infectious Diseases & International Medicine Department of Medicine University of Minnesota

What is IRIS? Two Clinical Scenarios “Unmasking” IRIS (new, subclinical OI) Subclinical infection with detectable +CRAG Preventable by pre-ART CRAG screening “Paradoxical” IRIS (paradoxical reactions) Haddow. Lancet Infect Dis. 2010;10:791–802.

Theoretical Model of IRIS Pre-ART Phase (at time of OI) Pre-IRIS Phase (on ART) IRIS Event Boulware DR, et al . PLoS Med 2010; e1000384.

Theoretical Model of IRIS Pre-ART Phase Lack of inflammation, or inappropriate (Th2) Poor antigen clearance / immune control TB-LAM,  HBV viral load, CrAg, Drug Resistance Pre-IRIS Phase Increasing signaling related to antigen burden IL-6 => CRP IRIS Event Generalized cytokine storm (Th1, Th17, gen) Boulware DR, et al . PLoS Med 2010; e1000384.

Immunology of Cryptococcus: Th1 Response Boulware DR, et al . PLoS Med 2010; e1000384.

Differences prior to ART in CSF Initial CSF WBCs <25 cells/mL and protein <50 mg/dL were associated with development of IRIS (OR=7.2, 95%CI: 2.7 to 18.7, P<.001). <25/mL <50 mg/dL Odds Ratio = 7.2 for IRIS Boulware et al. JID 2010

Pre-ART Serum CRAG titer No IRIS on ART Median Initial CSF CRAG Titer at Meningitis diagnosis (5 weeks prior) Initial CSF Titers Future CM-IRIS No difference at time of initial CM 1:1024 median CRAG titer. P=.006 Boulware DR, et al . PLoS Med 2010; e1000384.

Theoretical Model of IRIS Pre-ART Phase Lack of inflammation, or inappropriate (Th2) Poor antigen clearance / immune control TB-LAM,  HBV viral load, CrAg, Drug Resistance Pre-IRIS Phase Increasing signaling related to antigen burden IL-6 => CRP => d-dimer IRIS Event Generalized cytokine storm (Th1, Th17, gen) Boulware DR, et al . PLoS Med 2010; e1000384.

Inflammatory Changes on ART Grey shading is 95% CI for cohort controls without CM-IRIS Boulware DR, et al . PLoS Med 2010; e1000384.

Theoretical Model of IRIS Pre-ART Phase Lack of inflammation, or inappropriate (Th2) Poor antigen clearance / immune control TB-LAM,  HBV viral load, CrAg, Drug Resistance Pre-IRIS Phase Increasing signaling related to antigen burden IL-6 => CRP => d-dimer IRIS Event Generalized cytokine storm (Th1, Th17, general) Boulware DR, et al . PLoS Med 2010; e1000384.

CSF Differences between IRIS & Relapse

Evidence in CM-IRIS Subjects Phase Immunologic Activity Evidence in CM-IRIS Subjects Prior to HIV Therapy Paucity of appropriate inflammation for cryptococcosis and/or Inappropriate (Th2) responses resulting in: Poor antigen clearance, pre-ART  TNF-a, G-CSF, GM-CSF, VEGF (serum)  IFN-g, G-CSF, TNF-a, IL-6 in CSF [46] IL-4 pre-ART Similar CSF CRAG at initial infection [46] Higher CRAG pre-ART After Starting HIV Therapy Increasing pro-inflammatory signaling from antigen presenting cells due to persisting antigen burden and failure to clear antigen Secondary activation of coagulation cascade  IL6 from macrophages,[56] then downstream  CRP production  IL-7 from antigen presenting cells  d-dimer, At IRIS Storm of multiple immune pathways of innate and adaptive immune systems Activation of coagulation cascade Neuronal cell activation and damage Th1  INF-g, VEGF; TH17  IL-17 Innate:  IL-8, G-CSF, GM-CSF  d-dimer  FGF-2 Boulware DR, et al . PLoS Med 2010; e1000384.

Differences prior to ART at time of the initial Cryptococcal meningitis Predictive of IRIS Predictive of Survival Initial CSF WBCs <25 cells/mL and protein <50 mg/dL were associated with development of IRIS (OR=7.2, 95%CI: 2.7 to 18.7, P<.001).

Predictive Serum Biomarkers for IRIS at time of ART initiation  Risk IL-4 (Th2) IL-17 (Th17) Protective G-CSF GM-CSF MCP-1 TNF-a VEGF Boulware DR, et al . PLoS Med 2010; e1000384.

Biomarkers for Mortality  IL-17  CRP GM-CSF Boulware DR, et al . PLoS Med 2010; e1000384.

C-Reactive Protein (CRP) vs. Mortality Boulware DR, et al . PLoS Med 2010; e1000384.

Pathogen Influence on Host Immune Response Clinical Outcomes & IRIS Wiesner DL, et al. Submitted

Research Collaborators University of Minnesota Infectious Disease Institute Paul Bohjanen Darin Wiesner Melissa Rolfes Kirsten Nielsen Kathy Huppler Hullsiek Jim Neaton David Meya Andrew Kambugu Yuka Manabe (JHU) Mbarara University, Uganda Conrad Muzoora, Kabanda Taseera University of Colorado Edward Janoff Univ. of Cape Town, South Africa Graeme Meintjes, Charlotte Schutz St. George’s (UK) Tom Harrison, Tihana Bicanic Boulware DR, et al . PLoS Med 2010; e1000384. Boulware DR. et al. J Infect Dis. 2010; 202: 962-970 Wiesner. Curr Fungal Infect Rep. 2011; 5: 252–261