Immune reconstitution disease
Bill Powderly MD University College, Dublin Ireland
Slide courtesy of Anton Pozniak
Slide courtesy of Anton Pozniak
Immune Reconstitution Syndrome
Inflammatory response leading to clinical deterioration after the initiation of antiretroviral therapy (ART) Restored capacity of host to mount immune response to infectious agent or self antigen Incidence in cohort studies ranges from 3-25%
French, AIDS 2004
Immune reconstitution disease
Case Definition:
• A paradoxical deterioration in clinical status after initiating highly active antiretroviral therapy (HAART) attributable to the recovery of the immune response to latent or subclinical infectious or non-infectious processes
Other Nomenclature
• Immune reconstitution inflammatory syndrome (IRIS) • Immune restoration/restitution/recovery disease • immune rebound illness
Immune Reconstitution
For many OIs, an inflammatory reaction may occur when treatment for those OIs is started concurrently with ART, often contributing to the morbidity and mortality from these conditions. Initiation of ART also has been associated with inflammatory reactions in patients harboring subclinical infection that becomes clinical in an “atypical” manner several weeks after ART is started.
ART and the treatment of OIs
Patient with OI Treated with ART
Asymptomatic immune recovery Return of original symptoms
New Symptoms
Relapse
IRIS
New OI
Medication Side-effects
IRIS
ART with subclinical infection
ART in advanced HIV disease
Asymptomatic Immune recovery
IRIS
Antiretroviral Therapy Improves Qualitative and Quantitative Immune Defects
Immune suppression/deficiency
HIV replication
Immune activation
Qualitative/functional immune defects
Response to recall antigens
Quantitative immune defects
CD4 counts
Impaired pathogenspecific immunity
OI
Immune Reconstitution
HAART
Qualitative/functional immune defects
Reversal of anergy Lymphocyte proliferative capacity
HIV replication
Immune activation
Quantitative immune defects
Redistribution, death (HIV-, activation-induced), production (peripheral expansion and thymic)
Improved pathogenspecific immunity
Improved immune control
Migueles, Buenos Aires 2003
Many Pathogens and Syndromes
M. avium M. tuberculosis Cryptococcus Pneumocystis Cytomegalovirus Herpes simplex Histoplasmosis Hepatitis B and C •Herpes zoster
•PML (JC virus) •Kaposis sarcoma •Bartonella •Sarcoidosis •Graves disease •Guillain Barre
Adapted from French et al, AIDS 2004
M. Avium and IRS: Usually lymphadenopathy
Lymphadenopathy
• large and painful • intense inflammatory response/caseous necrosis • Few organisms • negative blood cultures • Can have protracted clinical course
Other manifestations
• • • • • pulmonary infiltrates mediastinits liver granuloma osteomyelitis cerebritis
“Paradoxical Reactions” in Tuberculosis
First recognized in 1950s Lymphadenitis (12 – 25 %), pulmonary disease, central nervous system, tuberculomas 1 – 6 months post initiation of therapy Often required steroids
“Paradoxical reactions” in Tuberculosis and HIV Co-infection
More frequent in HIV+ than HIV –
• Mean onset of symptoms is 2 weeks • Mean duration of symptoms is 3 weeks
Most common symptoms include fever, cervical lymphadenopathy, intrathoracic lymphadenopathy Extrathoracic disease has included focal cerebritis, pleural effusions and hepatospenomegaly Associated with restoration of tuberculosis DTH reactivity
Cryptococcal IRS: Usually CNS Disease
CNS Disease: meningitis, cranial nerve palsy, hearing loss Mediastinits Lymphadenitis Subcutaneous abscess Necrotizing pneumonia Can be severe – 3/10 patients died in recent French series
Lortholary AIDS 2005, Shelburne Clin Infect Dis 2005
Worsening PCP with Early ART
Several case series:
• cases of patients starting ART during the acute treatment for PCP.
• Clinical deterioration with the initiation of ART marked by increasing hypoxia and/or new pulmonary infiltrates. • Conclusions limited variable use of corticosteroid therapy at the time of initiating ART.
Risk factors for IRIS
Microbial antigens Host susceptibility
CD4< 50
Adapted from French et al, 2004
Factors Associated with IRS from case series and case-control studies (TB, MAC and cryptococcosis)
Very advanced HIV disease – CD4 counts <50 Unrecognized OI or High microbial burden (fungemia) Early initiation of ART
Management of IRIS
Diagnostic Dilemmas Immune Reconstitution Syndrome Relapse Drug Toxicity New Disease Process Therapeutic Dilemmas Stop or continue ART Stop or change OI therapy Add immunosuppressives
Therapy of Immune Reconstitution Syndrome Therapy
Anti-infective Rx Anti-retroviral Rx Anti-inflammatory NSAIDS Steroids Thalidomide Cytokine Inhibitors
Intervention
Suspicion of active OI Severity of IRIS Validity of ARV need Severity of syndrome
ACTG 5164
ARM A: IMMEDIATE ARV THERAPY OI TREATMENT HIV+ OI or Serious Bacterial Infections ARV THERAPY
ARM B: DELAYED ARV THERAPY OI TREATMENT ARV THERAPY
0
8
24 STUDY WEEK
48