Skip directly to site content Skip directly to page options Skip directly to A-Z link Skip directly to A-Z link Skip directly to A-Z link
Volume 25, Number 2—February 2019
Research

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

Anita K. McElroyComments to Author , 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, and Christina F. Spiropoulou
Author affiliations: University of Pittsburgh, Pittsburgh, Pennsylvania, USA (A.K. McElroy); Centers for Disease Control and Prevention, Atlanta (A.K. McElroy, P. Shrivastava-Ranjan, J.R. Harmon, R.B. Martines, L Silva-Flannery, T.D. Flietstra, S.T. Nichol, S.R. Zaki, C.F. Spiropoulou); Emory University School of Medicine, Atlanta, Georgia, USA (A.K. McElroy, C.S. Kraft, A.K. Mehta, G.M. Lyon, J.B. Varkey, B.S. Ribner)

Main Article

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 hea

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.

Main Article

References
  1. Geisbert  TW, Young  HA, Jahrling  PB, Davis  KJ, Larsen  T, Kagan  E, et al. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am J Pathol. 2003;163:2371–82. DOIPubMedGoogle Scholar
  2. Martines  RB, Ng  DL, Greer  PW, Rollin  PE, Zaki  SR. Tissue and cellular tropism, pathology and pathogenesis of Ebola and Marburg viruses. J Pathol. 2015;235:153–74. DOIPubMedGoogle Scholar
  3. 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. DOIPubMedGoogle Scholar
  4. Wauquier  N, Becquart  P, Padilla  C, Baize  S, Leroy  EM. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl Trop Dis. 2010;4:e837. DOIPubMedGoogle Scholar
  5. Hutchinson  KL, Rollin  PE. Cytokine and chemokine expression in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196(Suppl 2):S357–63. DOIPubMedGoogle Scholar
  6. Baize  S, Leroy  EM, Georges  AJ, Georges-Courbot  MC, Capron  M, Bedjabaga  I, et al. Inflammatory responses in Ebola virus-infected patients. Clin Exp Immunol. 2002;128:163–8. DOIPubMedGoogle Scholar
  7. Villinger  F, Rollin  PE, Brar  SS, Chikkala  NF, Winter  J, Sundstrom  JB, et al. Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J Infect Dis. 1999;179(Suppl 1):S188–91. DOIPubMedGoogle Scholar
  8. van der Ven  AJ, Netea  MG, van der Meer  JW, de Mast  Q. Ebola virus disease has features of hemophagocytic lymphohistiocytosis syndrome. Front Med (Lausanne). 2015;2:4. DOIPubMedGoogle Scholar
  9. George  MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:69–86. DOIPubMedGoogle Scholar
  10. Dowd  JB, Palermo  T, Brite  J, McDade  TW, Aiello  A. Seroprevalence of Epstein-Barr virus infection in U.S. children ages 6-19, 2003-2010. PLoS One. 2013;8:e64921. DOIPubMedGoogle Scholar
  11. Tasdelen Fisgin  N, Fisgin  T, Tanyel  E, Doganci  L, Tulek  N, Guler  N, et al. Crimean-Congo hemorrhagic fever: five patients with hemophagocytic syndrome. Am J Hematol. 2008;83:73–6. DOIPubMedGoogle Scholar
  12. Wan Jamaludin  WF, Periyasamy  P, Wan Mat  WR, Abdul Wahid  SF. Dengue infection associated hemophagocytic syndrome: Therapeutic interventions and outcome. J Clin Virol. 2015;69:91–5. DOIPubMedGoogle Scholar
  13. Grom  AA, Horne  A, De Benedetti  F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12:259–68. DOIPubMedGoogle Scholar
  14. Ab-Rahman  HA, Rahim  H, AbuBakar  S, Wong  PF. Macrophage activation syndrome-associated markers in severe dengue. Int J Med Sci. 2016;13:179–86. DOIPubMedGoogle Scholar
  15. McElroy  AK, Akondy  RS, Davis  CW, Ellebedy  AH, Mehta  AK, Kraft  CS, et al. Human Ebola virus infection results in substantial immune activation. Proc Natl Acad Sci U S A. 2015;112:4719–24. DOIPubMedGoogle Scholar
  16. Younan  P, Iampietro  M, Nishida  A, Ramanathan  P, Santos  RI, Dutta  M, et al. Ebola virus binding to TIM-1 on T lymphocytes induces a cytokine storm. MBio. 2017;8:e00845-17. DOIPubMedGoogle Scholar
  17. Olejnik  J, Forero  A, Deflubé  LR, Hume  AJ, Manhart  WA, Nishida  A, et al. Ebolaviruses associated with differential pathogenicity induce distinct host responses in human macrophages. J Virol. 2017;91:e00179-17. DOIPubMedGoogle Scholar
  18. 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. DOIPubMedGoogle Scholar
  19. Ksiazek  TG, Rollin  PE, Jahrling  PB, Johnson  E, Dalgard  DW, Peters  CJ. Enzyme immunosorbent assay for Ebola virus antigens in tissues of infected primates. J Clin Microbiol. 1992;30:947–50.PubMedGoogle Scholar
  20. Zaki  SR, Shieh  WJ, Greer  PW, Goldsmith  CS, Ferebee  T, Katshitshi  J, et al. A novel immunohistochemical assay for the detection of Ebola virus in skin: implications for diagnosis, spread, and surveillance of Ebola hemorrhagic fever. Commission de Lutte contre les Epidémies à Kikwit. J Infect Dis. 1999;179(Suppl 1):S36–47. DOIPubMedGoogle Scholar
  21. Lehmberg  K, Ehl  S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;160:275–87. DOIPubMedGoogle Scholar
  22. Henter  JI, Horne  A, Aricó  M, Egeler  RM, Filipovich  AH, Imashuku  S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31. DOIPubMedGoogle Scholar
  23. Ravelli  A, Minoia  F, Davì  S, Horne  A, Bovis  F, Pistorio  A, et al.; Paediatric Rheumatology International Trials Organisation; Childhood Arthritis and Rheumatology Research Alliance; Pediatric Rheumatology Collaborative Study Group; Histiocyte Society. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 2016;68:566–76. DOIPubMedGoogle Scholar
  24. Uyeki  TM, Mehta  AK, Davey  RT Jr, Liddell  AM, Wolf  T, Vetter  P, et al.; Working Group of the U.S.–European Clinical Network on Clinical Management of Ebola Virus Disease Patients in the U.S. and Europe. Clinical management of Ebola virus disease in the United States and Europe. N Engl J Med. 2016;374:636–46. DOIPubMedGoogle Scholar
  25. Hunt  L, Gupta-Wright  A, Simms  V, Tamba  F, Knott  V, Tamba  K, et al. Clinical presentation, biochemical, and haematological parameters and their association with outcome in patients with Ebola virus disease: an observational cohort study. Lancet Infect Dis. 2015;15:1292–9. DOIPubMedGoogle Scholar
  26. Finch  CA, Bellotti  V, Stray  S, Lipschitz  DA, Cook  JD, Pippard  MJ, et al. Plasma ferritin determination as a diagnostic tool. West J Med. 1986;145:657–63.PubMedGoogle Scholar
  27. Cimini  E, Viola  D, Cabeza-Cabrerizo  M, Romanelli  A, Tumino  N, Sacchi  A, et al. Different features of Vδ2 T and NK cells in fatal and non-fatal human Ebola infections. PLoS Negl Trop Dis. 2017;11:e0005645. DOIPubMedGoogle Scholar
  28. Rollin  PE, Bausch  DG, Sanchez  A. Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196(Suppl 2):S364–71. DOIPubMedGoogle Scholar
  29. Kreuels  B, Wichmann  D, Emmerich  P, Schmidt-Chanasit  J, de Heer  G, Kluge  S, et al. A case of severe Ebola virus infection complicated by gram-negative septicemia. N Engl J Med. 2014;371:2394–401. DOIPubMedGoogle Scholar
  30. Lüdtke  A, Ruibal  P, Becker-Ziaja  B, Rottstegge  M, Wozniak  DM, Cabeza-Cabrerizo  M, et al. Ebola virus disease is characterized by poor activation and reduced levels of circulating CD16+ monocytes. J Infect Dis. 2016;214(suppl 3):S275–80. DOIPubMedGoogle Scholar
  31. Ruibal  P, Oestereich  L, Lüdtke  A, Becker-Ziaja  B, Wozniak  DM, Kerber  R, et al. Unique human immune signature of Ebola virus disease in Guinea. Nature. 2016;533:100–4. DOIPubMedGoogle Scholar
  32. Bleesing  J, Prada  A, Siegel  DM, Villanueva  J, Olson  J, Ilowite  NT, et al. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor α-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheum. 2007;56:965–71. DOIPubMedGoogle Scholar
  33. Schaer  DJ, Schleiffenbaum  B, Kurrer  M, Imhof  A, Bächli  E, Fehr  J, et al. Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol. 2005;74:6–10. DOIPubMedGoogle Scholar
  34. Santos-Arroyo  A, Barrera-Llaurador  J, Sánchez  JE, Martín-García  R, Sánchez  JL. Role of skin biopsies in the diagnosis of hemophagocytic lymphohistiocytosis. Am J Dermatopathol. 2017;39:e86–9. DOIPubMedGoogle Scholar
  35. Wang  J, Guo  W, Du  H, Yu  H, Jiang  W, Zhu  T, et al. Elevated soluble CD163 plasma levels are associated with disease severity in patients with hemorrhagic fever with renal syndrome. PLoS One. 2014;9:e112127. DOIPubMedGoogle Scholar
  36. Bogner  MP, Voss  SD, Bechhofer  R, Hank  JA, Roper  M, Poplack  D, et al. Serum CD25 levels during interleukin-2 therapy: dose dependence and correlations with clinical toxicity and lymphocyte surface sCD25 expression. J Immunother (1991). 1992;11:111–8. DOIPubMedGoogle Scholar
  37. McElroy  AK, Mühlberger  E, Muñoz-Fontela  C. Immune barriers of Ebola virus infection. Curr Opin Virol. 2018;28:152–60. DOIPubMedGoogle Scholar
  38. Wormsbecker  AJ, Sweet  DD, Mann  SL, Wang  SY, Pudek  MR, Chen  LY. Conditions associated with extreme hyperferritinaemia (>3000 μg/L) in adults. Intern Med J. 2015;45:828–33. DOIPubMedGoogle Scholar
  39. Cohen  LA, Gutierrez  L, Weiss  A, Leichtmann-Bardoogo  Y, Zhang  DL, Crooks  DR, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116:1574–84. DOIPubMedGoogle Scholar
  40. Naz  N, Moriconi  F, Ahmad  S, Amanzada  A, Khan  S, Mihm  S, et al. Ferritin L is the sole serum ferritin constituent and a positive hepatic acute-phase protein. Shock. 2013;39:520–6. DOIPubMedGoogle Scholar
  41. Feingold  KR, Hardardóttir  I, Grunfeld  C. Beneficial effects of cytokine induced hyperlipidemia. Z Ernahrungswiss. 1998;37(Suppl 1):66–74.PubMedGoogle Scholar
  42. Knudsen  TB, Ertner  G, Petersen  J, Møller  HJ, Moestrup  SK, Eugen-Olsen  J, et al. Plasma soluble CD163 level independently predicts all-cause mortality in HIV-1–infected individuals. J Infect Dis. 2016;214:1198–204. DOIPubMedGoogle Scholar
  43. Weaver  LK, Hintz-Goldstein  KA, Pioli  PA, Wardwell  K, Qureshi  N, Vogel  SN, et al. Pivotal advance: activation of cell surface Toll-like receptors causes shedding of the hemoglobin scavenger receptor CD163. J Leukoc Biol. 2006;80:26–35. DOIPubMedGoogle Scholar
  44. Hintz  KA, Rassias  AJ, Wardwell  K, Moss  ML, Morganelli  PM, Pioli  PA, et al. Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol. 2002;72:711–7.PubMedGoogle Scholar
  45. Sun  YY, Li  XF, Meng  XM, Huang  C, Zhang  L, Li  J. Macrophage phenotype in liver injury and repair. Scand J Immunol. 2017;85:166–74. DOIPubMedGoogle Scholar
  46. Barros  MH, Hauck  F, Dreyer  JH, Kempkes  B, Niedobitek  G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013;8:e80908. DOIPubMedGoogle Scholar
  47. Gupta  M, Mahanty  S, Ahmed  R, Rollin  PE. Monocyte-derived human macrophages and peripheral blood mononuclear cells infected with ebola virus secrete MIP-1α and TNF-α and inhibit poly-IC-induced IFN-α in vitro. Virology. 2001;284:20–5. DOIPubMedGoogle Scholar
  48. Ströher  U, West  E, Bugany  H, Klenk  HD, Schnittler  HJ, Feldmann  H. Infection and activation of monocytes by Marburg and Ebola viruses. J Virol. 2001;75:11025–33. DOIPubMedGoogle Scholar
  49. Younan  P, Ramanathan  P, Graber  J, Gusovsky  F, Bukreyev  A. The toll-like receptor receptor 4 antagonist eritoran protects mice from lethal filovirus challenge. MBio. 2017;8:e00226-17. DOIPubMedGoogle Scholar

Main Article

1Preliminary results from this study were presented at the American Association of Immunology annual meeting, May 4-8, 2018, Austin, Texas, USA.

Page created: January 16, 2019
Page updated: January 16, 2019
Page reviewed: January 16, 2019
The conclusions, findings, and opinions expressed by authors contributing to this journal do not necessarily reflect the official position of the U.S. Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors' affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.
file_external