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; e

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; e

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

6. 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

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
No difference at time of initial CM 1:1024 median CRAG titer.
P=.006
Boulware DR, et al . PLoS Med 2010; e

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; e

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

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; e

11. CSF Differences between IRIS & Relapse

12. 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; e

13. 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).

14. 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; e

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

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

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

18. 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; e
Boulware DR. et al. J Infect Dis. 2010; 202:
Wiesner. Curr Fungal Infect Rep. 2011; 5: 252–261