Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis

Department of Clinical Immunology and Immunogenetics, Royal Perth Hospital, Australia
HIV Medicine (Impact Factor: 3.99). 04/2008; 9(5):307 - 316. DOI: 10.1111/j.1468-1293.2008.00565.x
Source: PubMed


Objectives A proportion of HIV patients beginning antiretroviral therapy (ART) develop immune restoration disease (IRD). Immunological characteristics of IRD were investigated in a cohort of HIV patients beginning therapy in Kuala Lumpur, Malaysia.Methods Peripheral blood mononuclear cells were collected at weeks 0, 6, 12, 24 and 48 of ART from five patients experiencing IRD [two with cryptococcal and three with Mycobacterium tuberculosis (Mtb) disease], eight non-IRD controls who had begun ART with CD4 T-cell counts of <100 cells/μL and 17 healthy controls. Leukocytes producing interferon-gamma (IFNγ) were quantified by enzyme-linked immunospot assay after stimulation with purified protein derivative (PPD), early secretory antigenic target-6 (ESAT-6), Cryptococcus neoformans or Cytomegalovirus antigens. Plasma immunoglobulin (IgG) antibodies reactive with these antigens were assessed by enzyme-linked immunosorbent assay. Proportions of activated (HLA-DRhi) and regulatory (CD25 CD127lo and CTLA-4+) CD4 T-cells were quantified by flow cytometry.Results Plasma HIV RNA declined and CD4 T-cell counts rose within 8–27 weeks on ART. Mtb IRD patients displayed elevated IFNγ responses and/or plasma IgG to PPD, but none responded to ESAT-6. Cryptococcal IRD occurred in patients with low baseline CD4 T-cell counts and involved clear IFNγ and antibody responses to cryptococcal antigen. Proportions of activated and regulatory CD4 T-cells declined on ART, but remained higher in patients than in healthy controls. At the time of IRD, proportions of activated CD4 T-cells and regulatory CD4 T-cells were generally elevated relative to other patients.Conclusions Cryptococcal and Mtb IRD generally coincide with peaks in the proportion of activated T-cells, pathogen-specific IFNγ responses and reactive plasma IgG. IRD does not reflect a paucity of regulatory CD4 T-cells.

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Available from: Dino Bee Aik Tan
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    • "Only one study observed no difference in IL-2 and IL-12 production in TB-IRIS and non-IRIS individuals [32]. Regarding humoral immune responses, two out of three patients with TB-IRIS evaluated by Tan et al (2008) had an increase of anti-PPD IgG compared to TB patients not infected with HIV [30]. Anti-PGL-Tb1 was found only in non-IRIS individuals [21]. "
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    • "Risk factors for IRIS include disseminated OI disease; recent OI treatment; low baseline CD4 with rapid rise after starting cART; and high baseline HIV VL with rapid decline after starting cART [14] [17] [20] [21]. Paradoxical IRIS in HIV-positive patients with previously treated cryptococcal disease has been estimated between 4 and 30% and is associated with an exaggerated T-cell mediated production of interferon-gamma to pathogen specific antigens [10] [12] [18] [22] [23]. The most common presentations of cryptococcal IRIS are either meningitis or lymphadenitis [24]. "
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    ABSTRACT: Background. HIV-positive people starting combined antiretroviral therapy may develop immune reconstitution to latent or treated opportunistic infections. Immune reconstitution to cerebral Cryptococcus is poorly understood and can be fatal. Case Presentation. A 33-year-old Zimbabwean female presented with cryptococcal meningitis and newly diagnosed HIV with a CD4 count of 51 cells/μL (4%). She was treated with amphotericin and flucytosine. Combined antiretroviral therapy was started four weeks later and she showed early improvement. However, over the ensuing 18 months, her clinical course was marked by periodic worsening with symptoms resembling cryptococcal meningitis despite having achieved CD4 counts ≥400 cells/μL. Although initially treated for relapsing cryptococcal immune reconstitution syndrome, a brain biopsy taken 17 months after initial presentation showed budding Cryptococci. Conclusion. This unusually protracted case highlights the difficulties in differentiating relapsing cryptococcal meningitis from immune reconstitution and raises questions concerning the optimum timing of initiation of combined antiretroviral therapy in such patients.
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    • "CD4+ counts and preexisting opportunistic infection are reliable predictors of IRIS development [39–41]. The immune pathology of IRIS is largely determined by the infecting organisms where CD8+ T cells dominate lesions of viral origins; granulomatous inflammation usually dominates IRIS of fungi, protozoa, and mycobacterial conditions [42–50]. IRIS manifests when there is an abrupt shift from an anti-inflammatory and immuno-suppressive state mediated by TNF-α and IL-10 to a pro-inflammatory state mediated by variable levels of IL-2, IL-12 and IFN-γ [38, 51–55]. "
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