Immune Restoration and Infalmmatory Syndrome - Ins and Outs

Immune Restoration Inflammatory Syndrome (IRIS) Woraphot Tantisiriwat, MD,MPH Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand Overview • Immune reconstitution with potent antiretroviral therapy • Unusual manifestations of OIs after potent antiretroviral therapy • Immune Restoration Syndrome • Case Discussion Effects of potent antiretroviral therapy  Decrease HIV plasma RNA to levels < 50  Increase CD4 cell count T-Cell Changes During HIV Infection Healthy HIV+ Late disease Naive cells Memory cell clones Effector cell clones Source: Goodnow. In: Ciba Foundation Symposium 204: The Molecular Basis of Cellular Defense Mechanisms. John Wiley & Sons; 1997:190-207. Effect of Therapy? Post treatment Late disease Post treatment Naive cells Memory cell clones Effector cell clones CD4+ T-Cell Dynamics With HAART CD4+ T Cells HIV-1–specific T cells Time 8-12 Weeks Changes in OIs Manifestations with HAART (Tantisiriwat W et al : AIDS Reader 122-30,1999) MAC M Kansasi • • Localized lymphadinitis Mediastinal adinitis, osteomyelitis, arthritis Vitritis, retinits with  CD4 Worsening hepatitis CMV • Viral hepatitis (B,C) • TBc VZV • • Paradoxical reaction Acute retinal necrosis,  shingles Cryptococcus • Recurrent of meningitis, Pulmonary and cutaneous cryptococcosis Immune recovery inflammatory syndrome • Retrospective study of 133 patients responding to potent ART • 33 with history of prior OIs developed inflammatory reaction 1-2 mo after starting – recrudescence of HSV – CMV retinitis – Acute HCV hepatitis • zoster •MAC •MTB adenitis • Low baseline CD4 count strong predictor French et al, HIV Med,107-15,2000 Immune Restoration Syndrome = Immune reconstitution syndrome = Immune recovery inflammatory syndrome = Immune reconstitution inflammatory syndrome Immune Restoration Syndrome  Improve CMI with restoration of CD4 cells both memory and naive cells  Increased CD4/CD8 cells detect hidden pathogens which were ignore with deficiency of immunity previously  Result in inflammatory process of the area of occult infections  Usually improved with control of inflammation and specific treatment Potential Impact of Factors Influencing Development of IRIS Stoll M et al: Curr Infect Report 266-76, 2003 Immune Restoration Syndrome Risk factors  Low CD4 cell count  High burden of pathogen or pathologic antigen  Dysregulation of immune process: Shift towards Th-1 cytokine profile with  IFN- MHC gene haplotypes (HLA-B44) Cytokine gene polymorphisms (IL6,12, TNF, etc) Price P, et al: Hum Immunol 157-64, 2001 French M, et al: HIV Med 107-15, 2000 French M, et al: WEST PAC Conference, Perth, 2002 Shelburne SA, et al: Medicine 213-27,2002 Chien J, et al: Chest 933-6, 1998 MAC IRS    Lymphadinitis (within 3 months after HAART) Significant  in memory CD4 + cells with  WC Bx = granulomatous inflammation  Localized lymph node enlargement with caseation Negative blood culture Race et al Lancet 351: 252-5,1998  MAC IRS (cont’)     Necrotizing subcutaneous nodules Endobronchial tumors Small bowel involvement Paravertebral abscesses Brown M, et al: Sex Transm Infect 149-50, 2001 Bartley PB, et al: Int J Tubec Lung Dis 1132-6, 1999 Currier JS, et al: Ann Intern Med 493-503, 2000 del Giudice, et al: Arch Dermatol 1129-30, 1999 Cinti SK, et al: CID 511-4, 2000 MTB IRS 36% of patients with combined MTB + HIV infections after initiation of HAART developed paradoxical clinical deterioration • Prolong fever (>101.5°F) • Increasing respiratory symptoms • Increasing lymphadenopathy • Cutaneous lesions • Ascites • CXR worsening (lymph node, consolidation, effusion) • Tuberculoma Narita M, et al: Am J Respir Crit Care Med 157-61, 1998 McCormack JG, et al: CID 1008-9, 1998 CMV IRS Eye • Intensity of inflammatory response  compared to standard CMV retinitis • Immune recovery vitreitis • Immune recovery uveitis • Inflammatory reaction can lead to proliferative vitreoretinopathy and posterior chamber cataracts resolved in severe visual compromise • Local steroid treatment may be helpful Jacobson M, et al: Lancet 1443-5, 1997 Holland GN. Ocular Immunol Inflamm 215-21, 1999 Postelmans L, et al: Ocular Immunol Inflamm 237-40, 1999 Cassoux N, et al: Ocular Immunol Inflamm 231-5,1999 CMV IRS (cont’) Systemic • Pneumonitis • colitis ***Possible HLA-B44 related Gilquin J, et al: AIDS 1659-60, 1997 Miller RF, et al: Sex Transm Infect 60, 2000 Price P, et al: Hum Immunol 157-64, 2001 Cryptococcal IRS • Presence of cryptococcal Ag without viable organisms can incite significant immune response in HAARTtreated patient • Recurrent meningitis • Pulmonary cryptococcosis • Cutaneous cryptococcosis • Mediastinal and cervical lymphadinitis Shelburne SA, et al: Medicine 213-27,2002 Blanche P, et al: Scand J Infect 615-6, 1998 Lanzafame M, et al: Chest 848-9, 1999 Manfredi R, et al: Mycopathologia 73-8, 1999 Herpes Zoster IRS • 2X – 5X increased in incidence of zoster in patients treated with HAART compared to non treated patients • Mean occurrence ~ week 16 • Longest interval reported = week 103 • Peak CD8 + response in 1 month has been associated with development of zoster • Acute retinal necrosis Andersson J, et al: AIDS F123-29, 1998 Martinez E, et al: CID 1510-3, 1998 Estrada V, et al: AIDS S90, 1998 Hepatitis C IRS • Worsening of hepatitis • Possible related with increase in cytotoxic CD8+ T lymphocytes causing in immune-mediated hepatocyte destruction • Increased in HCV RNA levels, mostly return to baseline within 3 months • ? Drug side effect related Pouti M, et al: J Infect Dis 2033-6, 2000 Rutchmann OT, et al: J Infect Dis 783-5, 1998 Vento S, et al: AIDS 116-7, 1998 Hepatitis B IRS • Worsening of hepatitis • Transient  HBV DNA + clinical hepatitis • Continuation of HAART may lead to clearing of HBsAg and resolution of hepatitis • ? Drug side effect related Mangold C, et al: CID 144-8, 2001 Mastroianni CM, et al: AIDS 1939-40, 1998 Proia LA, et al: Am J Med 249-51, 2000 Velasco M, et al: 1765-66, 1999 JC IRS • With HAART, JC virus in CSF  and also levels of antibody to JC virus • Inflammatory PML variant: MRI enhancement of lesion = extensive demyelination with surrounding inflammation consisting with lymphoplasmoid cells Collazos J, et al: AIDS 1426-8, 1999 Kotecha N, et al: Am J Med 541-3, 1998 PCP IRS • Reports of granulomatous response in stead of usual interstitial mononuclear cell inflammatory cell + debris Bleiweiss IJ, et al: Chest 580-3, 1988 Blumenfeld W, et al: Ann Intern Med 505-7, 1988 Flannary MT, et al: South Med J 409-10, 1996 Klein JS, et al: AJR 753-4, 1989 Sarcoidosis & Kaposi Sarcoma IRS • Worsening of sarcoidosis: IL-2 and  CD4+ T cells Response to steroid, thalidomide Lenner R, et al: Chest 978-81, 2001 • • Usually KS resolved with HAART Report of worsening KS lesion with inflammation + edema Weir A, et al: AIDS 116-7, 1998 Non-infectious IRS Graves Disease • Graves disease after institution of HAART • + thyrotropin receptor antibodies which were negative before HAART • HAART associated thymic-mediated redevelopment of T-cell repertoire abnormality results in proliferation of auto-reactive T cells causing autoreactivity Gilquin J, et al: Lancet 1907-8, 1998 Jubault V, et al: J Clin Endocrinol Metab 4254-7, 2000 Non-infectious IRS (cont’) • • • • • • • SLE Vasculitis Reiter Syndrome Rheumatoid arthritis Polymyositis Alopecia universalis Hyperergic reaction (against tatoos, foreign bodies) Behrens G, et al. Lancet 351:1057-8, 1998 Ward HA, et al. J Am Acad Dermatol 46:284-93, 2002 Bell C et al. Int J STD AIDS 13:580-1, 2002 Sellier P et al. Am J Med 109:510-2, 2000 Sereti I et al. AIDS 15:138-40, 2001 Silvestre JF et al. Arch Dermatol 137:669-70, 2001 Practical concept  Immune Reconstitution Syndrome is common especially in the setting of very low CD4 cell count (<50) and Hx of previous OIs starting on HAART  Screening for hidden OIs before starting HAART would be helpful to avoid unpleasant situation  Unusual/ usual presentations of OIs within 3 months of starting HAART, think of immune reconstitution syndrome and may be beyond  Steroid + specific treatment should be helpful Stoll M et al: Curr Infect Report 266-76, 2003 Clinical Scenario  33 yr old female Dx HIV infection 6 yr ago, husband died from cryptococcal infection  No antiretroviral treatment  On Bactrim ~ 2 yr  Come to see you today for persistent low grade fever x 2 wks  No symptoms except some blurred vision of Rt. eye Clinical Scenario  Fundoscopy = CMV retinitis both eyes, Rt. side is close to macular  CD4 cell count = 10  HIV viral load = 478,000  CBC = Hb 10, WC 1.6 N28 L35 M33 E1 B3, plt 310  LFT = WNL  CXR = no pulmonary infiltrate  Cryptococcal Ag = positive 1:32  Blood culture for MAC : done Clinical Scenario  LP = CSF WC = 8 all mononuclear cell  CSF cryptococcal Ag = negative  Pt underwent ampho B Rx x 2wks follow by fluconazole 400 mg/d  Pt received ganciclovir intraocular Rx  Also received dapsone for PCP prophylaxis and Azithromycin for MAC prophylaxis  Blood culture for MAC = negative Clinical Scenario  Antiretroviral therapy was started (D4T + 3TC + Effavirenz)  Pt complaint for dizziness, confusion after 1 week of antiretroviral therapy  Neurologic symptoms was increased during the next 2-3 weeks  more confusion, behavior change with visual hallucination and weakness of lower limbs Clinical Scenario  MRI brain = Temporal lobe encephalitis  LP: CSF WC 51; mono29 PMN22, protein 650, glucose 59, cryptococcal Ag = negative  CSF herpes PCR = negative  CSF CMV PCR = positive  Systemic ganciclovir IV was started  Clinical improvement with resolution of behavioral change and weakness Clinical Tip: Problems After Initiation of Antiretroviral therapy • Screen for OIs and aware of IRS or hidden OIs especially during the first 3 months of ARV (especially for low CD4 cell count patients) • Understand and aware of short term and long term side effect of use ARV • Aware of interaction of present medication and ARV • Aware of treatment failure Special thank to • William G Powderly, MD Washington University, USA • Carl J Fichtenbaum, MD University of Cincinnati, USA