Immune Reconstitution Inflammatory Syndrome (IRIS)

Definition

Types of IRIS

Key distinction for exams: In paradoxical IRIS, the OI was known and treated. In unmasking IRIS, the OI was hidden and ART reveals it.

Pathophysiology

• Initiating ART restores both quantitative (CD4+ T-cell count) and qualitative (pathogen-specific immune responses) immunity.
• The recovering immune system mounts an exaggerated inflammatory response against antigens of dead/dying pathogens or subclinical infections.
• Involves restoration of CD4+ Th1 responses, which drive cytokine storms (TNF-α, IFN-γ, IL-6, IL-12).
• Antigens released from dying organisms act as the trigger — the inflammatory response is often disproportionate to the actual pathogen burden.
• More common in patients with severely depleted CD4+ counts at baseline, where the immune system is almost completely naive to the OI.

Timing

• Typically occurs 1–3 months after ART initiation, though some cases occur within 4 weeks.
• Earlier ART initiation (i.e., before fully treating the OI) = higher IRIS risk.
• Unmasking IRIS usually within 3 months of ART start.

Risk Factors

Incidence

• Occurs in approximately 10% of HIV-TB co-infected patients on ART.
• Occurs in 5–10% of HIV-infected children within 4 weeks of ART initiation.
• Cryptococcal IRIS: ~30% of patients with cryptococcal meningitis who start ART.

Common Pathogens Causing IRIS

Clinical Features

General

• Fever (most common feature)
• Lymphadenopathy (particularly cervical, mediastinal)
• Weight loss despite ART adherence

TB-IRIS (Most Tested)

• Worsening pulmonary infiltrates
• New or enlarging pleural effusions
• Lymph node enlargement/suppuration
• CNS involvement (tuberculoma, meningitis)

Cryptococcal IRIS (Most Dangerous)

• Recurrence of headache, meningismus
• Markedly elevated intracranial pressure (ICP)
• CSF often shows sterile inflammation (no viable Cryptococcus, but positive antigen)
• Can be rapidly fatal if ICP not managed

MAC-IRIS

• Suppurative, fluctuant lymphadenitis
• Fever, abdominal pain (mesenteric adenitis)
• May require surgical drainage

CMV-IRIS

• Immune recovery uveitis — vitritis, macular edema, epiretinal membrane
• Can cause visual loss despite cleared CMV viremia

Diagnosis

Diagnostic Criteria (International Network for the Study of HIV-associated IRIS — INSHI)

1. Temporal relationship — new or worsening symptoms after ART initiation
2. Evidence of immune recovery — rise in CD4+ count and/or fall in HIV viral load
3. Symptoms consistent with an inflammatory condition or known OI
4. Not explained by a newly acquired infection, expected course of OI, drug toxicity, or non-adherence to OI treatment

Key Investigations

Differential Diagnosis

• Treatment failure (resistant OI, non-adherence) — most important to exclude
• New opportunistic infection
• Drug toxicity/hypersensitivity (e.g., Stevens-Johnson syndrome)
• Malignancy (lymphoma, KS)
• Non-infectious inflammatory disease

Management

Principles

1. Do NOT discontinue ART unless life-threatening — this is a core exam point.
2. Do NOT stop OI treatment — continue antimicrobial therapy.
3. Treat the inflammation.

Stepwise Approach

Corticosteroid Evidence

• The COAT trial (Cryptococcal IRIS) — steroids increased mortality in cryptococcal IRIS; use with extreme caution.
• For TB-IRIS — prednisone significantly reduces symptoms, duration of hospitalization (supported by RCT evidence).
• For other IRIS — corticosteroid use is based largely on expert opinion.

Prevention of IRIS

Timing of ART in OIs — High-Yield Table

Prognosis

• Most IRIS episodes are self-limiting and resolve over weeks to months.
• Mortality is relatively low but can occur, primarily in patients with:
  • High pre-existing mortality risk
  • CNS involvement (especially cryptococcal IRIS with uncontrolled ICP)
  • Severe TB-IRIS with respiratory failure
• ART should be maintained even through IRIS episodes when possible, as the benefits outweigh risks.

High-Yield Exam Summary Points