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Cryptococcal IRIS: Pathogenesis & Pearls for Clinical Management

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

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Cryptococcal IRIS: Pathogenesis & Pearls for Clinical Management

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  1. 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

  2. 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.

  3. 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.

  4. 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.

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

  6. Differences prior to ART in CSF <25/mL <50 mg/dL Odds Ratio = 7.2 for IRIS Boulware et al. JID 2010

  7. 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 P=.006 Boulware DR, et al . PLoS Med 2010; e1000384.

  8. 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.

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

  10. 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.

  11. CSF Differences between IRIS & Relapse

  12. Boulware DR, et al . PLoS Med 2010; e1000384.

  13. Differences prior to ART at time of the initial Cryptococcal meningitis • Predictive of IRIS • Predictive of Survival

  14. Predictive Serum Biomarkers for IRISat 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.

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

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

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

  18. Research Collaborators 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

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