Immune reconstitution inflammatory syndrome (IRIS)

Zambia Specific Information

In Zambia no specific data on incidence/prevalence but IRIS thought to occur in ~10% of all pts on ART, up to 25% when ART started at CD4 <50.
IRIS in Zambia most common with TB, cryptococcosis, and M. avium complex.
2 types of IRIS: 1) “paradoxical” IRIS - HIV+ pts with OI Dx and improving on OI treatment (or have completed treatment) but develop paradoxical worsening or recurrence of OI manifestations (Sx, signs, or radiological features) shortly after starting HAART; and 2) “unmasking” IRIS - HIV+ pts with unrecognized OI begin HAART and subsequently develop clinical manifestations of OI which may have prominent inflammatory component. Both types most common with TB (McIlleron H, Meintjes G, Burman WJ, et al. reference).
Maintain high index of suspicion for IRIS in first weeks to months after starting HAART.
Dx often made clinically, but Bx or Cx of lymph nodes, masses, or abscess fluid useful to confirm Dx.
DDx and general management principles are as listed below.
Specific Management per Zambia National Guidelines on Management and Care for HIV/AIDS 2007:
--If HIV+ pt is severely ill with TB , other stage 3/4 disease or CD4 < 200, hold ART until TB medications are tolerated (usually 2-3 wks); if HIV+ pt with TB and CD4 200-350 or clinical deterioration, start ART after intensive phase of TB treatment; if HIV+ pt with TB has CD4 > 350 or clinically stable, consider ART after completion of TB treatment.
--General Management of IRIS: ART should be continued; however, if continuation impossible, temporarily interrupt ART and restart same regimen after OI or inflammatory condition treated.
--Corticosteroid treatment in moderate to severe cases: prednisolone or prednisone 0.5 mg/kg/day for 5-10 days. (Author note: longer courses may sometimes be necessary depending on clinical response to taper or discontinuation)

Zambia Information Author: David Riedel, M.D.

CLINICAL

Paradoxical deterioration in clinical status after ART initiation despite improved immune function due to inflammatory response against infectious antigen, which may or may not have been Dx'd at initiation of ART.

Typically occurs in pts with low initial CD4 (usually <50) and rapid decline in viral load; onset usually within 6 wks of ART initiation, but sometimes several mos later.

Inciting pathogens: M. avium complex, (30% of cases), and other Mycobacteria, CMV, Cryptococcus, PCP, Leishmania, HSV, VZV, hepatitis B and C, JC virus, HHV8 (Kaposi's and Castleman's), JC virus (PML), and others.

Common Sx (varies according to causative pathogen): fever, localized lymphadenophathy/lymphadenitis, abscesses, pneumonia, vitritis, CNS disease, hepatitis, and dermatologic manifestations.

Presentations of OIs may be atypical (eg, MAC: localized granulomatous lymphadenopathy without mycobacteremia; CMV: vitritis; PML: enhancing CNS lesions; Cryptococcus: marked CSF leukocytosis).

Autoimmune diseases (e.g.sarcoidosis, Grave's disease) may be exacerbated

Despite high risk (>25%) of paradoxical worsening in pts with active TB after initiation of ART, overall mortality improved in coinfected pts with CD4<100 treated with ART.

TREATMENT

General principles

Treat underlying active infection (refer to specific pathogen module)

Continue ART, unless inflammatory response is life threatening

Anti-inflammatory therapy (NSAIDS and/or corticosteroids)

Response to corticosteroids typically rapid. Slow taper may be required

Initiation of ART during the treatment of an active OIs is controversial. Timing of ART depends on severity of OI and degree of immunosuppression. Studies in progress.

Pathogen-specific considerations

MAC (lymphadenitis): NSAIDS, if Sx persist, 20-40 mg/d prednisone with slow taper, titrating to recurrence of symptoms. Abscesses may be surgically drained.

: prednisone 20-40 mg/d for 2 wks with slow taper. In pts with active TB not on antiretrovirals, consider treating TB for >2 mos before starting HAART unless CD4<100. Delayed ART in TB-HIV co-infected pts with CD4 <100 associated with high risk of morbidity and mortality in African studies.

CMV vitritis: systemic or periocular steroids, 50% respond

Hepatitis: consider using TDF + either 3TC or FTC in pts infected with HBV coinfection. Consider discontinuing ART if serious drug toxicity suspected. Risk of reversible drug-related hepatotoxicity highest with full-dose RTV (rarely used), but tends to occur >6 wks into therapy. NVP hepatotoxicity occurs early (within 6 wks), may be associated with rash and can be fatal, but rarely observed with pre-treatment CD4 <250.

Cryptococcal meningitis: usually Cx negative, but higher CSF opening pressure. Steroids, serial LPs to manage elevated CSF pressure. Interruption of ART may be necessary in severe or unresponsive cases.

Zambia Specific Information

CLINICAL

DIAGNOSIS

TREATMENT

REFERENCED WITHIN THIS GUIDE