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Immune reconstitution inflamatory syndrome

Immune restoration disease
sindroma pemulihan imun pada ART

Samuel M Baso Sp.PD FINASIM

SMF IPD RSU Jayapura
The first define IRIS by Joseph A. DeSimone in Sept 2000
edition Ann Int of Med
Syndrome due to reaction against (antigen, non antigen
and neoplasma) in patients who have started ART and
undergo a restoration of their immune response .
Frequency 10-30 % patients who initiated HAART
Frequently occured in patient CD<50 cell/mm
and viral load >100.000 copy/mm
Timing typically 2-12 weeks but can fisrt week and more
than 1 yeart after initiating ART
Most common IRIS events 60% are TB, MAC and
Cryptococcal disease

Natural Course of HIV Infection and Host Responses

CD4+ T-cells Anti-HIV Ab

Relative Levels

HIV-CTL+CD8 activi

Plasma HIV Viremia

Months Years After HIV Infection

Acute HIV infection Symptom AIDS-related illness

Natural Course of HIV Infection and Common Complications

900 Asymptomatic
CD4+ cell Count

CD4+ T cells
700 TB
Acute HIV
600 infection
400 Relative level of OHL
300 Plasma HIV-RNA
200 PPE
100 TB CM
0 1 2 3 4 5 1 2 3 4 5 6 7 8 9 10 11
Months Years After HIV Infection
Oportunistic Infection
Pathogenesis of IRIS
Pathogenesis remains largely speculative
Current theories concerning pathogenesis are combination of
underlying antigenic burden, degree of immune restoration following
HAART and host genetic susceptibility.
These pathogenesis mechanism may interact and likely depend on
underlying burden of infection or noninfection agent.
Increased immune function (rapidly increased CD4 and decreased
Viral load)
Inflamatory reaction more likely to occur in patients low CD4 cont
(<50 copy) and high viral load (>100.000 copy)
High proliferation of Lymphonode
IRIS has 2 classification reaction :
1. Unmasking
2. Paradoxical
Some report frequent in PI treatment
Causes of IRIS
Infectious and non infectiuos causes of IRIS in HIV-infected patients

Infectious Etiologies Noninfectious etiologies

Mycobacteria : Autoimmune :

M . Tuberkulosis Reumatoid artritis, SLE

M . Avium kompleks Grave diseases
Mikobakterium lain AIDS related lymphoma
Cytomegalo virus Sarkoidosis dan rekasi Granlomatosis
Herpes viruses Gullain Barresyndrome
Cryptokokkus neoformans Interstitial lymphoid pneumositis
Pneumocystis jirovecii pneumonia
Histoplasmosis capsulatum
Hepatitis B dan C virus
Progressive multifocal leukoencephalitis
Parvovirus B
Molluscum contagiosum and genital warts
Clinical factors associated with the development of IRIS

R i s k factors

Male sex
Younger age
Lower CD4 cell count at ART initiation
Higher RNA at ART initiation
Lower CD4 cell percentage at ART initiation
Lower CD4 : CD8 ratio at ART initition
More rapid initial fall in HIV RNA on ART
Antiretroviral nave at time of OI diagnosis
Shorter interval between OI theraphy initition and ART initition
Manifestation of IRIS
More than 75% patients symptomatic for IRIS ;
manifestation within 90 days after initition ART
60% of IRIS events are due to Mycobacterium
tuberculosis, Mycobacterium avium complex (MAC) or
Crytococcal disease
Symptoms vary from mild to severe
Common clinical manifestation depend on basic OI
Worsening of coexisting infection such as flare of
Hepatitis B or C
IRIS may be mild and resolve without treatment
Continue ART if the patients can tolerate it. In severe cases (live
threatining) may be temporary interuption until of ART until the
patients is stable.
The consensus is that ART should not be stop in almost all cases of
paradoxical inflamation.
Treatment unmasked OI such TB,MAC and Crytococcal disesae
Corticisteroid treatment to suppress exaggerated inflamatory
response for moderate and severe cases of IRIS
Prednison 0.5 mg/kg/day for 5-10 days.
Double-blind, placebo controlled trial people with TB-associated
IRIS to 4 meeks prednison (1.5 mgr/kg/day for 2 weeks then 0.75
mg/kg/day for 2 weeks), p =0.04.
Antiretroviral Drugs 2003
zidovudine (ZDV) nevirapine (NVP) saquinavir (SQV)
didanosine (ddI) efavirenz (EFV) ritonavir (RTV)
zalcitabine (ddC) delavirdine (DLV) indinavir (IDV)

stavudine (d4T) nelfinavir (NFV)

lamivudine (3TC) NtRTI amprenavir (APV)

abacavir (ABC) tenofovir lopinavir/r (LPV/r)

emtricitabine atazanavir (ATV)

Fusion inhibitors - enfuvitide
Disease-spesific manifestation of IRIS
Mycobacterium tuberculosis
Cryptococcus neoformans
Varcella zoster virus
Coinfection Hepatitis B dan C
Pneumocystis jiroveci pneumonia
Progressive multifocal leokoencephalopathy
Clinical manifestation TB of IRIS

The common clinical manifestation are

fever,lymphadenopathy, pulmonary infitrates,
mediastinal lymphadenopathy and pleural effusion
Disseminated TB
Intracranial tuberculoma,meningitis
SIRS (systemic inflamatory response)
Treatment depend on unmasking or paradoxical?
Atypical mycobacterial IRIS
Lymphadenitis, with or without abscess formation and
Respiratory failure or ARDS
Treatment : surgical excision , Ethambutol and
Claritromycine for 2 month.
Cryptococcus neoformans IRIS
Mostly cryptococcal IRIS cases present as Meningitis
Common clinical manifestation is severe headache
Treatment are LP and antifungal combination
(amphotericin B and flucytocine)
Jamur Cryptococcus neoformans
berkapsul (CSF dengan pewarna
Atypical cryptococcosis IRIS

Intrathoracic Lymphadenopathy Infiltrate with

Source: CID 2002:35, Jenny-Avital and Abadi
Cytomegalovirus IRIS
CMV retinitis
lost of visual acuity
Macular edema, papillitis and vitritis
Treatment : gancyclovir or valgancyclovir
Retinitis karena CMV
Varcella zoster IRIS
Encephalitis, myelitis, cranial and peripheral
nerve palsies
Treatment acyclovir