1. 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

2. 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

3. 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:
Longley et al. Curr Opin Infect Dis. 2013;26(1) : 26–34

4. 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

5. 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:
Maziarz & Perfect: Infect Dis Clin N Am ;30:

6. 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

7. 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:

8. 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

9. 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

10. END