Abstract
BackgroundAmong the different faces of immune reconstitution inflammatory syndrome (IRIS) developing in HIV-patients, no clinical definition has been reported for Schistosomiasis-IRIS (Schisto-IRIS). Although Schisto-IRIS remains largely uninvestigated, matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) have previously been associated with S. mansoni infection and tuberculosis-IRIS. Here, we aimed to investigate the relevance of these markers in Schisto-IRIS.MethodologyPatients were diagnosed with IRIS related to S. mansoni within a cohort of patients with Schistosomiasis-HIV co-infection, using a clinical working definition of Schisto-IRIS. We compared 9 patients who developed Schisto-IRIS to 9 Schisto+HIV+ controls who did not, and 9 Schisto-HIV+ controls. Plasma levels of MMP-1, MMP-7, MMP-10, TIMP-1, TIMP-2, sCD14, intestinal fatty-acid binding protein, C-reactive protein, and 8 anti-nuclear antibodies (ANA) were analyzed prior to and during 3 months of ART.Principal findingsAlthough no differences were observed for MMP-1 and -7, MMP-10 levels decreased significantly in Schisto+HIV+ controls during 3 months of ART (p = 0.005) while persisting in Schisto-IRIS patients at significantly higher levels compared to Schisto-HIV+ controls (p≤0.030). In contrast TIMP-1 levels only decreased significantly in Schisto-IRIS patients (p = 0.012), while TIMP-2 levels were lower compared to Schisto+HIV+ controls at 2 weeks (p = 0.007), 1 month (p = 0.005) and 3 months (p = 0.031) of ART. Five out of 8 ANAs studied decreased significantly in Schisto-IRIS patients after 1 month of ART(p≤0.039), whereas only 1 ANA decreased for Schisto+HIV+ controls (p = 0.027).Conclusions/SignificanceIn this study, we propose a working definition for the diagnosis of Schisto-IRIS in resource limited settings. We report persistent plasma levels of MMP-10, along with a more pronounced decrease in TIMP-1 and ANA-levels, and low levels of TIMP-2 during 3 months of ART. Corresponding to the clinical symptoms, these data suggest that Schisto-IRIS is marked by unbalanced MMP/TIMP dynamics which favor inflammation.
Highlights
HIV-patients initiating antiretroviral therapy (ART) while dealing with a co-infection are at risk of developing immune reconstitution inflammatory syndrome (IRIS)
This paradoxical immune reconstitution inflammatory syndrome (IRIS) has been abundantly described in common co-infections such as M. tuberculosis (TB-IRIS), whereas IRIS associated with Schistosoma mansoni (Schisto-IRIS) is less well studied
Little is known about the immune dysregulation in Schisto-IRIS, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) have been linked to schistosomiasis and TB-IRIS on account of their role in tissue-destructive inflammation
Summary
HIV-patients initiating antiretroviral therapy (ART) while dealing with a co-infection are at risk of developing immune reconstitution inflammatory syndrome (IRIS). At least three conditions need to be present for an HIV patient to be at risk of IRIS; severe immune suppression, a treated (paradoxical IRIS) -or- undiagnosed (unmasking IRIS) opportunistic infection, and initiation of ART as the trigger. Despite these shared features, IRIS embodies a heterogeneous collection of clinical manifestations [1,2], associated with a plethora of pathogens [3,4]. HIV and Schistosomiasis are highly co-endemic in Sub-Saharan Africa [8] This is especially true in regions with frequent human-water interaction [9,10], e.g. fishing villages along the shores of Lake Victoria. We aimed to investigate the relevance of these markers in Schisto-IRIS
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