Write a short note on immune reconstitution inflammatory syndrome.

Definition

Immune reconstitution inflammatory syndrome is a paradoxical clinical deterioration occurring after starting antiretroviral therapy, caused by the recovering immune system mounting a vigorous inflammatory response against an existing (often subclinical) opportunistic pathogen or antigen — rather than by failure of therapy or by new infection.

The essential paradox to state: the patient gets worse precisely because the treatment is working.

Pathogenesis

Before ART, profound immunosuppression prevents an inflammatory response to opportunistic organisms, so infection may be present but clinically silent or partially treated. With ART:

1. Rapid fall in viral load and recovery of CD4+ T cells, initially memory cells redistributing from lymphoid tissue, later naive cells.

2. Restored capacity to mount a delayed-type hypersensitivity response against residual antigen — living organisms or dead antigenic material.

3. Dysregulated release of pro-inflammatory cytokines produces tissue inflammation at the site of the pathogen, causing clinical deterioration.

Types

Risk Factors

• Low baseline CD4 count (< 50–100/µL) — the strongest predictor
• High baseline viral load, and a rapid fall in viral load with a steep rise in CD4 after starting ART
• Short interval between starting treatment for the opportunistic infection and starting ART
• High pathogen burden at the time of ART initiation
• Disseminated infection, particularly tuberculosis and cryptococcosis
• ART-naive at the time of OI diagnosis

Clinical Features

• Timing: typically within the first 2–12 weeks of starting ART, most often in the first 4–8 weeks.
• The picture is that of inflammation at the site of the underlying pathogen, with fever and constitutional symptoms.
• Crucially, it occurs in the context of a falling viral load and rising CD4 count — evidence that the ART is effective.

Diagnosis

IRIS is a clinical diagnosis of exclusion, requiring:

1. A patient with HIV who has started ART, with evidence of treatment response — falling viral load and/or rising CD4

2. Clinical deterioration with inflammatory features

3. Exclusion of the alternatives, which must be actively pursued:

• Failure of treatment of the opportunistic infection — including drug resistance, which is the critical alternative in tuberculosis
• Poor adherence or malabsorption of OI therapy
• A new, second opportunistic infection
• Drug toxicity or hypersensitivity reaction
• Malignancy

Investigations are directed at excluding these: cultures and sensitivity, drug susceptibility testing (CBNAAT for rifampicin resistance), imaging, and biopsy where needed. There is no confirmatory test for IRIS.

Management

1. CONTINUE ANTIRETROVIRAL THERAPY in almost all cases — this is the central principle. Stopping ART allows the immune system to fail again, risks resistance, and does not treat the underlying problem. ART is interrupted only in life-threatening IRIS unresponsive to all other measures.

2. Continue and optimise treatment of the underlying opportunistic infection; confirm the organism is sensitive and that the patient is absorbing and taking the drugs.

3. Anti-inflammatory therapy:

• NSAIDs for mild disease.
• Corticosteroids for moderate to severe IRIS — particularly effective in tuberculosis-associated IRIS, and used in cryptococcal and CNS disease. Avoid or use with great caution in Kaposi's sarcoma, which they can worsen.

4. Site-specific measures: therapeutic lumbar puncture for raised intracranial pressure in cryptococcal IRIS; drainage of suppurative lymph nodes; ophthalmological management of immune recovery uveitis; airway support for compressive lymphadenopathy.

5. Supportive care and clear explanation to the patient — who will otherwise believe the treatment has failed and may stop it.

Prevention

• Diagnose and treat opportunistic infections BEFORE starting ART, and allow a period of treatment first.
• Optimal timing of ART initiation:
• Most OIs: start ART within 2 weeks, since the benefit of early immune recovery outweighs IRIS risk.
• Tuberculosis: start ATT first, then ART after 2 weeks if CD4 is very low, or up to 8 weeks otherwise.
• Cryptococcal meningitis and TB meningitis: DEFER ART by 4–6 weeks — early initiation in these two conditions increases mortality, because IRIS occurring within the closed cranial cavity is frequently fatal.
• Screen for subclinical infection before starting ART — TB symptom screen and chest X-ray, serum cryptococcal antigen if CD4 is very low, and fundoscopy where CD4 is below 50.