Cryptococcal IRIS: Pathogenesis & Pearls for Clinical Management David R. Boulware MD, MPH, CTropMed...
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Cryptococcal IRIS: Pathogenesis & Pearls for Clinical Management David R. Boulware MD, MPH, CTropMed Distinguished Assistant Professor Infectious Diseases
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
Slide 2
What is IRIS? Two Clinical Scenarios 1.Unmasking IRIS (new,
subclinical OI) Subclinical infection with detectable +CRAG
Preventable by pre-ART CRAG screening 2.Paradoxical IRIS
(paradoxical reactions) Haddow. Lancet Infect Dis.
2010;10:791802.
Slide 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.
Slide 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.
Slide 5
Immunology of Cryptococcus: Th1 Response
Slide 6
Differences prior to ART in CSF
Slide 7
Pre-ART Serum CRAG titer P=.006 Median Initial CSF CRAG Titer
at Meningitis diagnosis (5 weeks prior) Initial CSF Titers Boulware
DR, et al. PLoS Med 2010; e1000384. No IRIS on ART Future
CM-IRIS
Slide 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.
Slide 9
Inflammatory Changes on ART Grey shading is 95% CI for cohort
controls without CM-IRIS Boulware DR, et al. PLoS Med 2010;
e1000384.
Slide 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.
Slide 11
CSF Differences between IRIS & Relapse
Slide 12
PhaseImmunologic ActivityEvidence 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- , G-CSF, GM-CSF, VEGF (serum) IFN- , G-CSF,
TNF- 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- , VEGF; TH17
IL-17 Innate: IL-8, G-CSF, GM-CSF d-dimer FGF-2 Boulware DR, et al.
PLoS Med 2010; e1000384.
Slide 13
Differences prior to ART at time of the initial Cryptococcal
meningitis Predictive of IRIS Predictive of Survival
Slide 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; e1000384.
Slide 15
Biomarkers for Mortality IL-17 CRP GM-CSF Boulware DR, et al.
PLoS Med 2010; e1000384.
Slide 16
C-Reactive Protein (CRP) vs. Mortality Boulware DR, et al. PLoS
Med 2010; e1000384.
Slide 17
Pathogen Influence on Host Immune Response Pathogen Host
Clinical Outcomes & IRIS Wiesner DL, et al. Submitted
Slide 18
Research Collaborators University of MinnesotaInfectious
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.
Georges (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: 252261
