Cryptococcal Immune Reconstitution Inflammatory Syndrome Dr. Tihana Bicanic Reader and Consultant in Infectious Diseases Centre for Global Health, Institute of Infection and Immunity, St. George’s, University of London; St George's Hospital NHS Foundation Trust

Intended Learning Outcomes To understand what immune reconstitution inflammatory syndrome is To be aware of the predictors for C-IRIS To be aware of the different manifestations of C-IRIS To understand the management and prevention of C-IRIS

Immune Reconstitution Inflammatory Syndrome Rapid reversal of immunodeficiency leads to restoration of T-cell mediated Cryptococcus- specific immune responses, promoting an (exaggerated) inflammatory reaction to antigens (dead or alive) Two clinical scenarios: 1. “Unmasking” IRIS: NEW presentation of subclinical/ latent OI 2. “Paradoxical” IRIS: symptom recurrence in previously treated OI (clinical/ microbiologic response) Incidence: Paradoxical: 6-45% in HIV+ (usually 1-2 months post start of ART), 5-11% solid organ transplant recipients) Acute mortality 0-36%: lower if recognised early and managed appropriately Haddow et al. Lancet Infect Dis 2010; 10:791-802 Longley et al. Curr Opin Infect Dis. 2013;26(1) : 26–34

Immune Reconstitution Inflammatory Syndrome CNS presentation most common: headache, meningism, seizures Lumbar Puncture: CSF WBC, protein, glucose; fungal cultures sterile (paradoxical) or positive (unmasking) Non CNS Pneumonitis Lymphadenitis (including mediastinal) Rarely: skin, soft tissue, bone and joint lesions

Immune Reconstitution Inflammatory Syndrome Diagnostic criteria New appearance or worsening of the following: Clinical or radiographic manifestations consistent with an inflammatory process Histopathology showing granulomatous lesions Symptoms occurring during receipt of appropriate antifungal therapy with no alternative cause identified on investigation Negative results of cultures, or stable or reduced biomarkers for the initial fungal pathogen during the diagnostic workup for the inflammatory process (Unmasking= NEW presentation with cultures positive) Haddow et al. Lancet Infect Dis. 2010; 10:791-802 Maziarz & Perfect: Infect Dis Clin N Am . 2016;30:179-206

Immune Reconstitution Inflammatory Syndrome Predictors: High fungal burden at diagnosis and at start of ART: baseline CrAg titre >1:1024, fungaemia + poor fungal clearance  positive CSF cultures prior to ART start Host immune factors: rapid immune reconstitution (decline in HIV viral load , increasing CD4 count); poor CNS inflammatory responses (CSF WBC and cytokine responses pre-ART including TNF alpha and IFN gamma) Longley et al. Curr Opin Infect Dis. 2013; 26(1): 26–34

Immune Reconstitution Inflammatory Syndrome Management of C-IRIS No trials: based on expert opinion Check adherence to fluconazole/ ART Do LP / investigate to seek alternative explanations Modification of antifungals not indicated; Continue ART Minor cases improve without specific treatment Corticosteroid therapy if persistent/ severe CNS manifestations: 0.5–1.0 mg/kg per day of prednisolone or dexamethasone: 2-6 weeks reducing Anti-TNF-α/ thalidomide case reports Therapeutic LPs if raised CSF OP Longley et al. Curr Opin Infect Dis. 2013; 26(1): 26–34 Maziarz & Perfect: Infect Dis Clin N Am. 2016;30:179-206

Prevention of IRIS Paradoxical: Use best available initial induction CM treatment regimen to sterilise the CSF (AmB 1mg/kg/d+5FC 100mg/kg/d OR Fluconazole 1200mg/d+5FC) Perform LP at 2 weeks to assess CSF culture status Prompt ART initiation: aim to start at 4-6 weeks from CM diagnosis: when CNS symptoms (incl raised ICP) resolved and CSF cultures sterile Unmasking Screen for serum CrAg in patients with CD4<100/uL: if positive, LP if symptoms; treat pre-emptively with fluconazole

Summary C-IRIS is due to exaggerated immune responses to Cryptococcus after immune restoration Can be both unmasking and paradoxical: diagnosis challenging (case definition) CNS manifestation most common (raised ICP, seizures) Corticosteroids for refractory symptoms; mortality low if recognised early and managed Can be prevented by good induction CM treatment, appropriate ART timing and CRAG screening programmes

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