General IRIS case definition proposed by French, et al. (2004)

Diagnosis requires two major criteria (A+B) or major criterion (A) plus two minor criteria to be fulfilled:

Major criteria

A. Atypical presentation of opportunistic infections or tumor’s in patients responding to ART, manifested by any of the following:
• Localized disease
• Exaggerated inflammatory reaction
• Atypical inflammatory response in affected tissues
• Progression of organ dysfunction or enlargement of preexisting lesions after definite clinical improvement       with pathogen-specific therapy prior to ART and exclusion of treatment toxicity and new diagnoses
B. Decrease in plasma HIV RNA level >1 log10 copies/ml

Minor criteria

• Increase in CD4 count after ART
• Increase in an immune response specific to the relevant pathogen
• Spontaneous resolution of disease with continuation of ART

General IRIS case definition proposed by Robertson, et al. (2006)

Required criterion

• Worsening symptoms of inflammation/infection
• Temporal relationship with starting antiretroviral treatment
• Symptoms not explained by newly acquired infection or disease or the usual course of a previously acquired disease
• >1 log10 decrease in plasma HIV load

Supportive criterion

• Increase in CD4+ cell count of ≥25 cells/μl
• Biopsy demonstrating well-formed granulomatous inflammation or unusually exuberant inflammatory response

Percent calorie needs: % of calories from PN; TPN: Total Parenteral Nutrition; BMI: Body-Mass-Index percentile; Yr: year

Table 1:General case definitions for IRIS [3]


Clinical features of IRIS


Mycobacterium tuberculosis

Fever, lymphadenitis, new/ worsening pulmonary infiltrates, pleural effusions, hepatomegaly, paradoxical or unmasking TBM/ tuberculoma


Fever, lymphadenitis (painful/suppurative), pulmonary infiltrates and cavitation, inflammatory masses

Bartonella spp.

Granulomatous splenitis

Chlamydia trachomatis

Reiter’s syndrome

Herpes viruses


Immune recovery uveitis (usually following previous history of retinitis), retinitis (typically unmasking)


Dermatologic reactivation (shingles), encephalitis, transverse myelitis, stromal keratitis

HSV-1, HSV-2

Mucocutaneous ulceration, encephalomyelitis


New presentation of non-Hodgkins’s lymphoma, Burkitt’s lymphoma


Kaposi’s sarcoma- IRIS, multicentric Castleman’s disease

Hepatitis B, Hepatitis C

Hepatitis flare, rapidly progressive cirrhosis


JC virus

Paradoxical PML (clinical deterioration, progression of lesions) or unmasking PML (new diagnosis)

BK virus


Molluscum contagiosum virus

Acute new or recurrent cutaneous papules with florid/ extensive distribution

Parvovirus B19

Pure red cell aplasia, encephalitis


Warts (acute recurrence/ relapse or enlargement)


Cryptococcus neoformans

Meningitis with raised intracranial pressure,lymphadenitis, pneumonitis, ocular and soft tissue inflammation

Pneumocystis jirovecii

Unmasking PCP, paradoxical deterioration during or shortly after treatment with worsening hypoxia and new pulmonary infiltrates, organizing pneumonia (rare)

Histoplasma spp

Acute fistulous lymphadenopathy

Candida spp

Typically unmasking; mucocutaneous (oral/oesophageal)


Toxoplasma gondii

New or enlarging intracerebral lesions (ring-enhancing appearance on contrast neuroimaging)

Schistosoma mansoni

Eosinophilia, enteritis, colitis/polyposis

Leishmania sp

Leishmania major

Cutaneous, uveitis

Leishmania infantum

Post-kala-azar dermal leishmaniasis, visceral leishmaniasis

Leishmania braziliensis

Cutaneous, mucosal


Gastrointestinal or disseminated presentation; pneumonitis, enteritis, eosinophilia, hepatitis

Cryptosporidium spp

Terminal ileitis, duodenitis, cholangitis, gastrointestinal ulceration

Microsporidium spp




May occur as a new presentation, or an exacerbation of existing autoimmune condition

Grave’s disease
Guillain -Barré Syndrome
Rheumatoid arthritis
Relapsing polychondritis


Inflammatory presentation

Eosinophilic folliculitis
Seborrheic dermatitis
Pruritic papular eruption




New or recurrent granulomatous inflammation, typically late (around 12 months post-ART initiation) in patients with CD4 counts .200 cells/mm3; typically pulmonary presentation, but may be cutaneous (erythema nodosum, papular lesions) and/or intra-abdominal

Lymphoid interstitial pneumonitis

Fever, respiratory distress, negative microbiological tests (may mimic PCP)


Leukoencephalopathy, demyelination, cerebral edema

Percent calorie needs: % of calories from PN; TPN: Total Parenteral Nutrition; BMI: Body-Mass-Index percentile; Yr: year

Table 2:Pathogens and key clinical features of associated IRIS [1]