Research Article: Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study

Date Published: December 21, 2010

Publisher: Public Library of Science

Author(s): David R. Boulware, David B. Meya, Tracy L. Bergemann, Darin L. Wiesner, Joshua Rhein, Abdu Musubire, Sarah J. Lee, Andrew Kambugu, Edward N. Janoff, Paul R. Bohjanen, David G. Lalloo

Abstract: David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome).

Partial Text: Cryptococcal meningitis (CM), caused by the fungal organism Cryptococcus neoformans (commonly termed simply “cryptococcus”) is the most common fatal central nervous system (CNS) infection in persons with AIDS and is the initial AIDS-defining illness in 20%–30% of AIDS patients in Africa, causing 20%–40% of AIDS-attributable mortality [1]–[4]. The US Centers for Disease Control (CDC) estimates approximately 1 million CM cases occur annually, with 70% in sub-Saharan Africa [5]. The incidence of CM among Ugandans with CD4 counts <200 cells/µl is 10% annually without antiretroviral therapy (ART) [1], and without ART, almost all persons with CM die within 6 mo [6]. Although ART availability has led to improved CM survival in Africa [7]–[9], mortality after CM is still high, in part due to paradoxical HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated inflammatory response causing a subset of persons with recent CM to paradoxically deteriorate on ART in the presence of improving immune function [10]–[14]. Paradoxical CM-IRIS incidence has been reported as 10%–42% among ART-naïve persons with CM, with a pooled average of 18% (95% CI 14%–23%) [7],[14]–[17]. CM-IRIS is of grave concern because of its high incidence and mortality (33%–66%) [7],[14],[17],[18]. In many resource-limited regions, particularly sub-Saharan Africa where CM is the second most common AIDS-defining opportunistic infection [1]–[4], CM-IRIS is a major clinical problem. In this prospective cohort study of patients with AIDS and recent CM in Uganda, we characterized the incidence and clinical features of CM-IRIS and identified serum biomarkers that can diagnose IRIS and can stratify the risk for IRIS or death. CM-IRIS is a common complication of ART in sub-Saharan Africa, with an incidence reported in the literature ranging from 10% to 31% [11],[14]–[18],[50]. In our cohort with <1% loss to follow up, the incidence of CM-IRIS was 45%, two-thirds of whom experienced characteristic CNS manifestations (30%). Unlike many other forms of IRIS, which produce less dramatic consequences, CM-IRIS is exceptional for its substantial morbidity and mortality [11],[50]–[52]. The 36% CM-IRIS mortality in our study is consistent with other CM-IRIS studies [14],[15],[17],[18],[52],[53]. Such dire outcomes may derive from the increased inflammation that accompanies CM-IRIS in the anatomically constrained compartment of the CNS. Source: http://doi.org/10.1371/journal.pmed.1000384

 

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