Abstract
The introduction of combination antiretroviral therapy for HIV infection has prolonged the lives of patients with AIDS. It is increasingly being recognized, however, that following initiation of this therapy some patients can develop a paradoxical neurological deterioration, despite dramatic improvements in HIV viral load and CD4+ T-cell counts. This immune reconstitution inflammatory syndrome (IRIS) in the CNS is emerging as an important neurological complication, particularly as antiretroviral therapy is now becoming readily available worldwide. Currently, there are no guidelines for prevention, diagnosis or treatment of the CNS manifestations of IRIS. Even in patients with an acute presentation, the diagnosis can be challenging. Furthermore, it is possible that more-chronic forms of the syndrome exist but remain unrecognized. Here, we review the various clinical presentations of CNS IRIS, and discuss options for their management.
Key Points
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Immune reconstitution inflammatory syndrome (IRIS) is a worsening of an HIV patient's clinical condition that is paradoxically attributable to recovery of the immune system after initiation of highly active antiretroviral therapy (HAART)
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IRIS is set to emerge as an important neurological complication of HIV and HAART, and is likely to have a serious impact on the ability of clinicians to treat large populations with HAART
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The clinician must be most vigilant for IRIS during the first few months after initiation of HAART
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A diagnosis of IRIS should be considered even in cases of new occurrence of fever, if the fever occurs soon after starting HAART
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Histopathology shows a preponderance of CD8+ T cells in IRIS lesions
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Stopping HAART is not recommended, and the use of systemic corticosteroids is controversial; however, when the inflammatory response from IRIS is causing (or is likely to cause) life-threatening symptoms, systemic corticosteroids may be used
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References
Kaplan JE et al. (2000) Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy. Clin Infect Dis 30 (Suppl 1): S5–S14
d'Arminio Monforte A et al. (2004) Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol 55: 320–328
Sacktor N et al. (2001) HIV-associated neurologic disease incidence changes: multicenter AIDS cohort study 1990–1998. Neurology 56: 257–260
Mocroft A et al. (2003) Decline in the AIDS and death rates in the EuroSIDA study: an observational study. Lancet 362: 22–29
Robertson J et al. (2006) Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis 42: 1639–1646
Shelburne SA et al. (2002) Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 81: 213–227
Shelburne SA et al. (2006) Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother 57: 167–170
Lederman MM and Valdez H (2000) Immune restoration with antiretroviral therapies: implications for clinical management. JAMA 284: 223–228
Keane NM et al. (2001) An evaluation of serum soluble CD30 levels and serum CD26 (DPPIV) enzyme activity as markers of type 2 and type 1 cytokines in HIV patients receiving highly active antiretroviral therapy. Clin Exp Immunol 126: 111–116
Wang T et al. (2006) Granzyme B mediates neurotoxicity through a G-protein-coupled receptor. FASEB J 20: 1209–1211
Shelburne SA et al. (2005) Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19: 399–406
Stoll M and Schmidt RE (2004) Immune restoration inflammatory syndromes: apparently paradoxical clinical events after the initiation of HAART. Curr HIV/AIDS Rep 1: 122–127
French MA et al. (2004) Immune restoration disease after antiretroviral therapy. AIDS 18: 1615–1627
Price P et al. (2002) Polymorphisms in cytokine genes define subpopulations of HIV-1 patients who experienced immune restoration diseases. AIDS 16: 2043–2047
French MAH et al. (1992) Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 6: 1293–1297
Narita M et al. (1998) Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med 158: 157–161
Kumarasamy N et al. (2004) Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 37: 1574–1576
Lawn SD et al. (2005) Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 5: 361–373
Crump JA et al. (1998) Miliary tuberculosis with paradoxical worsening of intracranial tuberculomas complicating human immunodeficiency virus infection in a patient receiving highly active antiretroviral therapy. Clin Infect Dis 26: 1008–1009
Murray R et al. (2001) Cerebral Mycobacterium avium infection in an HIV-infected patient following immune reconstitution and cessation of therapy for disseminated Mycobacterium avium infection. Eur J Clin Microbiol Infect Dis 20: 199–201
Navas E et al. (2002) Paradoxical reactions of tuberculosis in patients with the acquired immunodeficiency syndrome who are treated with highly active antiretroviral therapy. Arch Intern Med 162: 97–99
Breen RAM et al. (2004) Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax 59: 704–707
Katrak SM et al. (2000) The clinical, radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. J Neurol Sci 181: 118–126
Blanche P et al. (1998) HIV combination therapy: immune restitution causing cryptococcal lymphadenitis dramatically improved by anti-inflammatory therapy. Scand J Infect Dis 30: 615–616
Jenny-Avital ER and Abadi M (2002) Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy. Clin Infect Dis 35: e128–e133
Skiest DJ et al. (2005) Cryptococcal immune reconstitution syndrome: report of four cases and review of the literature. J Infect 51: e289–e297
Lortholary O et al. (2005) Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 19: 1043–1049
Trevenzoli M et al. (2002) Mediastinitis due to cryptococcal infection: a new clinical entity in the HAART era. J Infect 45: 173–179
Woods ML Jr et al. (1998) HIV combination therapy: partial immune restitution unmasking latent cryptococcal infection. AIDS 12: 1491–1494
Boelaert JR et al. (2004) Relapsing meningitis caused by persistent cryptococcal antigens and immune reconstitution after the initiation of highly active antiretroviral therapy. AIDS 18: 1223–1224
King MD et al. (2002) Paradoxical recurrent meningitis following therapy of cryptococcal meningitis: an immune reconstitution syndrome after initiation of highly active antiretroviral therapy. Int J STD AIDS 13: 724–726
York J et al. (2005) Raised intracranial pressure complicating cryptococcal meningitis: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease? J Infect 51: 165–171
Shelburne SA III et al. (2005) The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 40: 1049–1052
Lawn SD et al. (2005) Cryptococcal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS 19: 2050–2052
Breton G et al. (2002) Paradoxical intracranial cryptococcoma in a human immunodeficiency virus-infected man being treated with combination antiretroviral therapy. Am J Med 113: 155–157
Cattelan AM et al. (2004) Multiple cerebral cryptococcomas associated with immune reconstitution in HIV-1 infection. AIDS 18: 349–351
Venkataramana A et al. (2006) Immune reconstitution inflammatory syndrome in the CNS of HIV infected patients. Neurology 67: 383–388
Cinque P et al. (2001) The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 7: 358–363
Safdar A et al. (2002) Fatal immune restoration disease in human immunodeficiency virus type-1 infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 35: 1250–1257
Vendrely A et al. (2005) Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol 109: 449–455
Nuttall JJC et al. (2004) Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome. Pediatr Infect Dis J 23: 683–685
Kastrup O et al. (2005) Evolution of purely infratentorial PML under HAART—negative outcome under rapid immune reconstitution. Clin Neurol Neurosurg 107: 509–513
Kotecha N et al. (1998) Enhancing progressive multifocal leukoencephalopathy: an indicator of improved immune status? Am J Med 105: 541–543
Collazos J et al. (1999) Contrast-enhancing progressive multifocal leukoencephalopathy as an immune reconstitution event in AIDS patients. AIDS 13: 1426–1428
Miralles P et al. (2001) Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS 15: 1900–1902
Hoffmann C et al. (2003) Progressive multifocal leukoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 74: 1142–1144
Tulius M et al. (2005) Inflammatory progressive multifocal leukoencephalopathy after antiretroviral treatment. AIDS 20: 469–471
Du Pasquier RA and Koralnik IJ (2003) Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 9 (Suppl 1): S25–S31
Jabs DA et al. (2002) Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol 133: 48–61
Jacobson MA et al. (1997) Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet 349: 1443–1445
Zegans ME et al. (1998) Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol 125: 292–300
Karavellas MP et al. (2001) Immune recovery vitritis and uveitis in AIDS: clinical predictors, sequelae, and treatment outcomes. Retina 21: 1–9
Goldberg DE et al. (2005) HIV-associated retinopathy in the HAART era. Retina 25: 633–649
Karavellas MP et al. (1998) Immune recovery vitritis associated with inactive CMV retinitis: a new syndrome. Arch Ophthalmol 116: 169–175
Karavellas MP et al. (1999) Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis 179: 697–700
Song M-K et al. (2003) Effect of anti-cytomegalovirus therapy on the incidence of immune recovery uveitis in AIDS patients with healed cytomegalovirus retinitis. Am J Ophthalmol 136: 696–702
Henderson HWA and Mitchell SM (1999) Treatment of immune recovery vitritis with local steroids. Br J Ophthalmol 83: 540–545
Miller RF et al. (2004) Cerebral CD8+ lymphocytosis in HIV-1 infected patients with immune restoration induced by HAART. Acta Neuropathol 108: 17–23
Langford TD et al. (2002) Severe, demyelinating leukoencephalopathy in AIDS patients on antiretroviral therapy. AIDS 16: 1019–1029
Shelburne SA and Hamill RJ (2003) The immune reconstitution inflammatory syndrome. AIDS Rev 5: 67–79
Lipman M and Breen R (2006) Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis 19: 20–25
McComsey GA et al. (2001) Placebo-controlled trial of prednisone in advanced HIV-1 infection. AIDS 16: 321–327
Acknowledgements
The authors' work is supported in part by NIH grants P01MH70056, P01MH070306, R01NS039253 and K08DA016160.
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Riedel, D., Pardo, C., McArthur, J. et al. Therapy Insight: CNS manifestations of HIV-associated immune reconstitution inflammatory syndrome. Nat Rev Neurol 2, 557–565 (2006). https://doi.org/10.1038/ncpneuro0303
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DOI: https://doi.org/10.1038/ncpneuro0303
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