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. 2019 Feb;25(2):290-298.
doi: 10.3201/eid2502.181326.

Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1

Anita K McElroy, Punya Shrivastava-Ranjan, Jessica R Harmon, Roosecelis B Martines, Luciana Silva-Flannery, Timothy D Flietstra, Colleen S Kraft, Aneesh K Mehta, G Marshall Lyon, Jay B Varkey, Bruce S Ribner, Stuart T Nichol, Sherif R Zaki, Christina F Spiropoulou

Macrophage Activation Marker Soluble CD163 Associated with Fatal and Severe Ebola Virus Disease in Humans1

Anita K McElroy et al. Emerg Infect Dis. 2019 Feb.

Abstract

Ebola virus disease (EVD) is associated with elevated cytokine levels, and hypercytokinemia is more pronounced in fatal cases. This type of hyperinflammatory state is reminiscent of 2 rheumatologic disorders known as macrophage activation syndrome and hemophagocytic lymphohistiocytosis, which are characterized by macrophage and T-cell activation. An evaluation of 2 cohorts of patients with EVD revealed that a marker of macrophage activation (sCD163) but not T-cell activation (sCD25) was associated with severe and fatal EVD. Furthermore, substantial immunoreactivity of host tissues to a CD163-specific antibody, predominantly in areas of extensive immunostaining for Ebola virus antigens, was observed in fatal cases. These data suggest that host macrophage activation contributes to EVD pathogenesis and that directed antiinflammatory therapies could be beneficial in the treatment of EVD.

Keywords: CD163; Ebola; Ebola virus; Ebola virus disease; HLH; MAS; T cells; activation marker; hemophagocytic lymphohistiocytosis; humans; hyperferritinemia; hypertriglyceridemia; inflammation; macrophage; macrophage activation syndrome; sCD163; sCD25; severe disease; viruses; zoonoses.

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Figures

Figure 1
Figure 1
Laboratory findings of patients with EVD that are consistent with laboratory findings in patients with macrophage activation syndrome or hemophagocytic lymphohistiocytosis. A, B) Triglycerides; C, D) ferritin; E, F) sIL-2R; and G, H) sCD163. Levels were measured in the plasma of a series of 86 Sudan virus–infected patients (left column) or 4 Ebola virus–infected patients (right column). Solid horizontal lines indicate means. Gray shaded areas represent the level of the analyte detected in 10 healthy donors. Dotted lines indicate limit of detection. C) From McElroy AK, Erickson BR, Flietstra TD, Rollin PE, Nichol ST, Towner JS, et al. Ebola hemorrhagic fever: novel biomarker correlates of clinical outcome. J Infect Dis. 2014;210:558–66 (3); reproduced with permission. D, F) From McElroy AK, Harmon JR, Flietstra TD, Campbell S, Mehta AK, Kraft CS, et al. Kinetic analysis of biomarkers in a cohort of US patients with Ebola virus disease. Clin Infect Dis. 2016;63:460–7 (18); reproduced with permission. *Statistically significant difference between fatal and nonfatal cases (p<0.05). EVD, Ebola virus disease; sCD163, soluble CD163; sIL-2R, soluble interleukin 2 receptor.
Figure 2
Figure 2
Immunohistochemical stains of tissue from patients with fatal cases of Ebola virus (EBOV) disease showing EBOV (red) and CD163 (brown) antigens. A) Hematoxylin and eosin stain of liver showing hepatocellular necrosis with intracytoplasmic eosinophilic inclusions (arrow). B) EBOV antigens in hepatocytes and CD163 antigens in macrophages. C) High magnification image of double immunohistochemical staining of liver tissue showing colocalization of EBOV and CD163 antigens in macrophage (arrow). D) Colocalization of EBOV and CD163 antigen in macrophage of spleen (arrow). E) Staining of EBOV and interstitial macrophages (CD163) in heart. EBOV found in some cardiomyocytes. F) EBOV and CD163 antigen in endothelial cells (arrowhead) and macrophages of testis (arrow). Original magnification ×20 (A, B, D, E, F); ×63 (C).
Figure 3
Figure 3
Double immunohistochemical staining of Ebola virus (red) and CD163 antigen (brown) in tissues of patients who died of noninfectious causes. CD163 antigens in macrophages of heart (A), liver (Kupffer cells) (B), spleen (C), and testicle (D). Original magnification ×20.
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