Abstract
Immune modulation may improve outcome in HIV-associated cryptococcal meningitis. Animal studies suggest alternatively activated macrophages are detrimental but human studies are limited. We performed a detailed assessment of the cerebrospinal fluid (CSF) immune response and examined immune correlates of disease severity and poor outcome, and the effects of antiretroviral therapy (ART). We enrolled persons ≥18 years with first episode of HIV-associated cryptococcal meningitis. CSF immune response was assessed using flow cytometry and multiplex cytokine analysis. Principal component analysis was used to examine relationships between immune response, fungal burden, intracranial pressure and mortality, and the effects of recent ART initiation (<12 weeks). CSF was available from 57 persons (median CD4 34/μL). CD206 (alternatively activated macrophage marker) was expressed on 54% CD14 and 35% CD14 monocyte-macrophages. High fungal burden was not associated with CD206 expression but with a paucity of CD4, CD8, and CD4CD8 T cells and lower interleukin-6, G-CSF, and interleukin-5 concentrations. High intracranial pressure (≥30 cm H2O) was associated with fewer T cells, a higher fungal burden, and larger Cryptococcus organisms. Mortality was associated with reduced interferon-gamma concentrations and CD4CD8 T cells but lost statistical significance when adjusted for multiple comparisons. Recent ART was associated with increased CSF CD4/CD8 ratio and a significantly increased macrophage expression of CD206. Paucity of CSF T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIV-associated cryptococcosis. ART had a pronounced effect on the immune response at the site of disease.
Highlights
Host immunity is central to the pathogenesis of cryptococcosis
Paucity of cerebrospinal fluid (CSF) T cell infiltrate rather than alternative macrophage activation was associated with severe disease in HIVassociated cryptococcosis
To better understand the pathophysiology of antiretroviral therapy (ART)-associated cryptococcal meningitis, we examined the effects of recent ART initiation (#12 weeks) on the CSF immune response
Summary
Host immunity is central to the pathogenesis of cryptococcosis. Cryptococcus neoformans is found widely in the environment and serological studies suggest exposure is common.[1,2] Most infections are asymptomatic with the infecting organism contained within pulmonary granulomas.[3]. Previous studies have shown that low cerebrospinal fluid (CSF) levels of proinflammatory cytokines [interferon-g, interleukin (IL)-6, and IL-8] are associated with a higher fungal burden, slower clearance of infection and increased mortality.[8,9] cryptococcosis may be complicated by an over exuberant inflammatory response after the initiation of antiretroviral therapy (ART). This is known as immune reconstitution inflammatory syndrome (IRIS) and either develops during the first manifestation of cryptococcosis (unmasking IRIS) or as a recurrence of meningitis symptoms after successful antifungal treatment (paradoxical IRIS).[10] There are increasing reports from sub-.
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