Serological biomarkers of risk for cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) in patients with human immunodeficiency virus (HIV) - associated cryptococcal meningitis (CM) have not been identified. We determined the relationship between Cryptococcus neoformans(CN) specific and non-specific antibody levels and risk for C-IRIS.
We determined CN glucuronoxylomannan (GXM) and laminarin (Lam, a β 1–3 cell wall glucan) antibody titers by ELISA and total immunoglobulin levels by a luminex-based assay in plasma samples obtained before initiation of antiretroviral therapy (ART) ~ 18 days after the start of antifungal therapy from a previously reported cohort of 89 patients with HIV-associated CM (Chang CC, et al. AIDS 2013, 27:2089-99) that included 26 patients who developed C-IRIS after ART initiation and 63 patients who did not (no-C-IRIS). Statistical analysis was performed using logistic regression models with adjustment for age, sex, HIV viral load and CD4 level.
CD4 cell counts were lower in the C-IRIS than no-C-IRIS group (medians: 14 vs. 35 cells/µL respectively; P=0.06). GXM IgM, Lam IgM, Lam IgG and total IgM were each significantly inversely associated with C-IRIS independent of each adjustment factor including CD4 level. The strongest association with C-IRIS was log2 total IgM (odds ratioadjusted=0.3; 95% confidence interval=0.2-0.6; P=0.0002).
Lower levels of pre-ART GXM IgM, Lam IgM, Lam IgG, and total IgM were each associated with development of C-IRIS independent of CD4 level. Deficiency of serum IgM and B-1 B cells has been associated with aberrant pulmonary inflammatory patterns and fungal dissemination from lungs to brain in mice. As B-1 B cells produce natural and Lam IgM in mice, reduced total and/or Lam IgM in patients could reflect a loss of IgM memory B cells. This question along with the biological function of circulating IgM and Lam antibodies are now under investigation in our laboratory. Further work to determine whether reduced IgM and/or Lam antibodies portend risk for ART-associated C-IRIS is warranted.
H. A. Yoon,
A. Nakouzi, None
C. Chang, None
M. French, None
L. A. Pirofski, None