Immune Reconstitution Inflammatory Syndrome (IRIS)

V. LUVIRA

IRIS
a clinical entity characterized by an excessive

inflammatory response to a preexisting antigen of pathogen and paradoxical deterioration in clinical status after initiation of antiretroviral therapy

Nomenclature
Immune restoration/restitution/ recovery disease Immune rebound syndrome HAART attacks

Outline
Pathogenesis Definition Incidence Thailand Treatment Disease specific IRIS

Pathogenesis
First phase (initial 3 mo ) : shift of memory CD4+from lymphoid cause pro-inflammatory response

 Second phase (after 3 mo) :increase Nave CD4+

quantitative &qualitative improves host immune response

AIDS Research and Therapy 2007, 4:9

Risk Factor

AIDS 2004, 18:16151627

Retrospective study IRIS developed in 57/180 (31.7%) Incidence 15.1/100 patientyears HAART

AIDS 2005, 19:399406

AIDS 2005, 19:399406

Risk Factor

AIDS Research and Therapy 2007, 4:9

Definition
There is no single agreed upon definition for IRIS There are 2 presentations
Paradoxical

IRIS: worsoning of symptoms of a known disease during ART Unmasking IRIS: present of an occult opportunistic infection , in which disease that was not clinically apperent prior to ART, manifests during ART

Definition:

AIDS 2004, 18:16151627

Definition:

Clinical Infectious Diseases 2006; 42:163946

Definition:
Need fulfill of clinical criterias

Clinical Infectious Diseases 2009; 49:142432

Definition:
Need fulfill of clinical criterias

Clinical Infectious Diseases 2009; 49:142432

Incidence
10-23% of all individuals who started ART 8-43% of all individuals with an existing

opportunistic infection

IRIS in Thailand
Retrospective study at Chonburi 11/174 cases(6.3%) 4.2/100 patient-yeasrs HAART (7 TB, 2 mycobacterium infection, 1 cryptococcosis, 1 CMV) IRIS occur within 90 days in majority of cases (72.7%)
Southeast Asian Trop Hyg 2010; 41(1); 138-145

IRIS in Thailand
Initial rapid increase in CD4 does not necessary predict IRIS

More hospitalization no interruption of HAART No difference of outcome (treatment success and weight gain)
Southeast Asian Trop Hyg 2010; 41(1); 138-145

Treatment& Prognosis
Significant more require admission and interventions

No difference in mortality rate

Greater likelihood of immune reconstitution

Adapted from AIDS 2005, 19:399406

Treatment& Prognosis
Depend on severity Treatment options Observation NSAIDS Corticosteroids Temporary cessation of ART Surgical debulking

Disease Specific IRIS

CID 2004; 38:115966

Disease Specific IRIS

TB IRIS The paradoxical reaction that follows the commencement of anti-TB therapy for pulmonary TB is usually characterized by fever, malaise, weight loss, and worsening respiratory symptoms Patients with extrapulmonary TB infection may develop worsening lymphadenitis, new pleural effusions, or expansion of preexisting intracranial tuberculomas, as well as a variety of other neurological symptoms after anti-tuberculosis therapy is begun Most occur within 2 months of ART initiation
J Infect Dis 2009; 199:437 J Infect Dis 2004; 190:1670 Clin Infect Dis 1994; 19:1092

ART was initiated at a median (IQR) duration of 2.2 (1.4-3.7) mo after TB Rx Median CD4 36 cell/ml IRIS was identified in 21/167 (12.6%) 15 pts developed IRIS within 2mo of ART 11/21(52.4%) need steroid Rx(deteriorated symptoms) The mortality rate in patients with and without IRIS was not different (9.5% versus 2.1%, P = 0.119).

Median time 32 days

Treatment:
Double blinded placebo-control RCT South Africa, only 48% confirmed by culture, Rifampicin

resistant rate 10/110 Inclusion: paradoxical TB IRIS

New or recurrent one of following: infiltration on CXR, enlarge LN, serous effusion, cold abscess <18 years, Rifampicin resistant, previous glucocorticoid Rx, prior ART, pregnancy, uncontrolled DM, KS, immediate life threatening TB IRIS

Exclusion:

Intervention: prednisolone 1.5 mg/kg/d x2

weeks0.75mg/kg/d x 2 weeks Primary outcome: hospital day

AIDS 2010, 24:23812390

Treatment:

AIDS 2010, 24:23812390

Treatment:

AIDS 2010, 24:23812390

Treatment:

AIDS 2010, 24:23812390

Disease Specific IRIS

MAC IRIS In the majority of cases, IRIS due to MAC manifests as fever and painful lymphadenitis that occurs one to eight weeks after HAART is commenced Individual case reports or small case series also exist describing IRIS syndrome manifesting as necrotic subcutaneous nodules, osteomyelitis, bursitis, granulomatous hepatitis, paravertebral abscesses, brain abscess, worsening lung infiltrates, or diffuse intestinal involvement presenting with abdominal pain

Disease Specific IRIS

Cryptococcus IRIS IRIS associated with preexisting cryptococcal infection & HIV-infected patients previously infected with Cryptococcus spp. may develop symptoms of IRIS localized to the central nervous system (CNS) or the lungs Symptoms often occur within two months after commencement of therapy, but may be delayed for more than six months Despite the use of concurrent antifungal therapy, patients with preexisting cryptococcal meningoencephalitis may develop fever, increased headache, nausea, eye pain, photophobia, and nuchal rigidity following the initiation of HAART

Disease Specific IRIS

Cryptococcus IRIS Repeat lumbar puncture in patients with IRIS associated with cryptococcal meningitis often reveals more inflammatory cells than were found prior to the initiation of antifungal therapy and HAART Cultures usually remain sterile Patients with IRIS-related cryptococcal meningitis had significantly higher opening pressures, CD4 cell counts, and lower HIV viral loads HIV-infected patients with preexisting cryptococcal pulmonary infection may develop cavitary lung lesions, hypoxia, respiratory failure, and ARDS following the initiation of HAART Rarely, patients with disseminated cryptococcal infections may develop mediastinal lymphadenitis, hypercalcemia, and cutaneous abscesses as part of the IRIS syndrome

Thank You