Cryptococcal IRIS: Pathogenesis & Pearls for

Clinical Management

David R. Boulware MD, MPH, CTropMedDistinguished Assistant Professor

Infectious Diseases & International MedicineDepartment of MedicineUniversity of Minnesota

What is IRIS?

Two Clinical Scenarios1. “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;10:791–802.

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.

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

Immunology of Cryptococcus: Th1 Response

Differences prior to ART in CSF

<25/mL <50 mg/dLOdds Ratio = 7.2 for IRIS Boulware et al. JID 2010

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

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

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

Predictive Serum Biomarkers for IRISat time of ART initiation

RiskIL-4 (Th2)IL-17 (Th17)

ProtectiveG-CSFGM-CSFMCP-1TNF-aVEGF

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

Pathogen Host

Clinical Outcomes & IRISWiesner DL, et al. Submitted

Research Collaborators

University of Minnesota Infectious Disease InstitutePaul BohjanenDarin WiesnerMelissa Rolfes Kirsten Nielsen Kathy Huppler HullsiekJim Neaton

David MeyaAndrew KambuguYuka Manabe (JHU)

Mbarara University, UgandaConrad Muzoora, Kabanda Taseera

University of ColoradoEdward Janoff

Univ. of Cape Town, South AfricaGraeme 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: 962-970Wiesner. Curr Fungal Infect Rep. 2011; 5: 252–261