Immune Reconstitution Inflammatory Syndrome - Overview of IRIS



What Is IRIS?

	• A state of hyperinflammatory response that usually occurs in the first six months of treatment of HIV/AIDS patients.

	• The newly reconstituted immune system may react more strongly to an existing infection, causing a worsening of that disease.



Paradoxical IRIS:

	• The worsening of a previously diagnosed opportunistic infection after initiating antiretroviral therapy.



Unmasking IRIS:

	• Worsening of an unrecognized infection with exaggerated inflammatory features after initiating antiretroviral therapy.



Who Gets It?

	• 10-20% of HIV-infected patients starting on antiretroviral therapy



ART:

	• ART ↓ viral load within the first 1 to 2 weeks after initiation

	• ART ↑ improves CD4 count in 3-6 months



IRIS: Generally Diagnosis of Exclusion!

No specific diagnostic criteria, but the following should be present:

	• AIDS with low pretreatment CD4 count (<100), except TB IRIS which can occur at any CD4 count!

	• Virologic and immunologic response to ART with a decrease in HIV-1 RNA level from baseline or an increase in CD4+ cells from baseline or both

	• Rule out drug-resistant infection, bacterial superinfection, drug reactions, noncompliance

	• Clinical manifestations of inflammation

	• Temporal association between ART initiation and onset of illness features - One week to a few months (median 48 days)



Severity of IRIS Depends On:

	• CD4 count before ART initiation

	• Degree of viral suppression

	• CD4 recovery after ART initiation



Clinical Presentation:

	• Related to the type and location of preexisting opportunistic infection

	• The physical findings of IRIS depend on the pathogen involved



Pathogens:

 • M. TB - Lymphadenitis, pulmonary infiltrates, pleural effusions, CNS tuberculoma meningitis, pericarditis, peritoneal disease, osteitis, cutaneous lesions, serositis peritonitis, bowel perforation, epididymitis, granulomatous nephritis, fevers

 • MAC/NTM - Painful lymphadenitis, pulmonary infiltrates, peritonitis, osteomyelitis, cutaneous abscesses, cavitation

 • Cryptococcus species - Meningoencephalitis, lymphadenitis, cryptococcomas, cavitating pneumonia, skin lesions, ocular

 • PJP - Pneumonitis (fever, cough, hypoxia, and pulmonary infiltrates), organizing PNA

 • Mycobacterium Leprae - Cutaneous lesions

 • Histoplasmosis - Lymphadenitis, cutaneous histoplasmosis, mucocutaneous

 • JC Virus - Progressive multifocal leukoencephalopathy (PML), Confusion, visual symptoms such as double vision, blindness, or gait ataxia

 • Papillomavirus - Molluscum contagiosum

 • Herpes Simplex Virus - Genital ulceration

 • Varicella Zoster - Zoster flare, ocular lesions: keratitis, iritis

 • CMV - Retinitis, immune recovery uveitis, Extraocular symptoms: pneumonitis, colitis, pancreatitis

 • HBV, HCV - Hepatic flare, rapid progression of cirrhosis. Fever, chills, lack of appetite, unintentional weight loss, nausea, jaundice.

 • Kaposi sarcoma, HHV8 - Worsening of cutaneous lesions with swelling, tenderness, and peripheral edema



Other Pathogens Associated with IRIS:

	• Parvovirus B19

	• Candida albicans

	• Epstein Barr Virus

	• Herpes simplex

	• Bartonella henselae

	• Histoplasma capsulatum

	• Dermatophytosis

	• Leprosy

	• Bacillus Calmette-Guérin (BCG)

	• Talaromyces (Penicillium) marneffei

	• Schistosoma mansoni

	• Molluscum contagiosum virus

	• Leishmaniasis



Differential Diagnosis:

	• Drug reaction/ART toxicity

	• Poor adherence to treatment

	• Persistently active infection/drug resistance

	• New opportunistic infection



Treatment:

 • ART is usually continued when patients develop IRIS (exception: encephalitis secondary to IRIS) - Use NSAIDs or corticosteroids for IRIS

 • Treat for opportunistic infection ASAP

 • Paradoxical IRIS:

	• Therapy for previous infection continued

	• If already on ART, continue ART, use NSAIDs or corticosteroids for IRIS with severe symptoms

 • No need to prevent IRIS by delaying ART treatment, unless the patient has known cryptococcal or TB meningitis

	• Guidelines recommend starting ART < 2 weeks for most OI

	• Cryptococcal meningitis: ART 4-6 weeks after antifungal therapy (COAT TRIAL: Deferring ART for 5 weeks improved survival)

	• TB meningitis: ART should be delayed at least four weeks (and initiated within eight weeks) after treatment for TB meningitis is initiated. Corticosteroids should be considered adjuvant treatment



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