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

Table

Laboratory findings of patients with MAS, HLH, or EVD and their association with fatal EVD outcomes*

Laboratory finding MAS diagnostic value HLH diagnostic value EVD Associated with fatal EVD outcome References
Cytopenia >2 cell types
Anemia, g/dL <9 Rarely No (24,25)
Thrombocytopenia, x 103/mL <181 <100 Sometimes No (24,25)
Neutropenia, cells/mL

<1,000
Rarely
No
(16,26)
Hyperferritinemia, ng/mL >684 >500 Yes Yes (3,18)
Hypofibrinogenemia, mg/dL <360 <150 Sometimes Unknown (18)
Hypertriglyceridemia, mg/dL
>156
>265
Sometimes
Yes
This study
sIL-2R (sCD25), U/mL >2,400 Yes No (18); this study
Low or absent NK cell activity Yes Yes (27)
Hemophagocytosis in BM, spleen, or LN None reported (2)
Soluble CD163 Yes Yes This study
Elevated AST/ALT, U/L >48 Yes Yes (28)
Elevated D-dimer Yes Yes (3,18,28)

*ALT, alanine aminotransferase; AST, aspartate aminotransferase; BM, bone marrow; EVD, Ebola virus disease; HLH, hemophagocytic lymphohistiocytosis; LN, lymph node; MAS, macrophage activation syndrome; NK, natural killer; sIL-2R, soluble interleukin 2 receptor; –, feature not included in disease diagnostic criteria.

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;163:237182. DOIPubMed
  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;235:15374. DOIPubMed
  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;210:55866. DOIPubMed
  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. DOIPubMed
  5. Hutchinson  KL, Rollin  PE. Cytokine and chemokine expression in humans infected with Sudan Ebola virus. J Infect Dis. 2007;196(Suppl 2):S35763. DOIPubMed
  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;128:1638. DOIPubMed
  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):S18891. DOIPubMed
  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. DOIPubMed
  9. George  MR. Hemophagocytic lymphohistiocytosis: review of etiologies and management. J Blood Med. 2014;5:6986. DOIPubMed
  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. DOIPubMed
  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;83:736. DOIPubMed
  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;69:915. DOIPubMed
  13. Grom  AA, Horne  A, De Benedetti  F. Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol. 2016;12:25968. DOIPubMed
  14. Ab-Rahman  HA, Rahim  H, AbuBakar  S, Wong  PF. Macrophage activation syndrome-associated markers in severe dengue. Int J Med Sci. 2016;13:17986. DOIPubMed
  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;112:471924. DOIPubMed
  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. DOIPubMed
  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. DOIPubMed
  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;63:4607. DOIPubMed
  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;30:94750.PubMed
  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):S3647. DOIPubMed
  21. Lehmberg  K, Ehl  S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;160:27587. DOIPubMed
  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;48:12431. DOIPubMed
  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;68:56676. DOIPubMed
  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;374:63646. DOIPubMed
  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;15:12929. DOIPubMed
  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;145:65763.PubMed
  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. DOIPubMed
  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):S36471. DOIPubMed
  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;371:2394401. DOIPubMed
  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):S27580. DOIPubMed
  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;533:1004. DOIPubMed
  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;56:96571. DOIPubMed
  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;74:610. DOIPubMed
  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:e869. DOIPubMed
  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. DOIPubMed
  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;11:1118. DOIPubMed
  37. McElroy  AK, Mühlberger  E, Muñoz-Fontela  C. Immune barriers of Ebola virus infection. Curr Opin Virol. 2018;28:15260. DOIPubMed
  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;45:82833. DOIPubMed
  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;116:157484. DOIPubMed
  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;39:5206. DOIPubMed
  41. Feingold  KR, Hardardóttir  I, Grunfeld  C. Beneficial effects of cytokine induced hyperlipidemia. Z Ernahrungswiss. 1998;37(Suppl 1):6674.PubMed
  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;214:1198204. DOIPubMed
  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;80:2635. DOIPubMed
  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;72:7117.PubMed
  45. Sun  YY, Li  XF, Meng  XM, Huang  C, Zhang  L, Li  J. Macrophage phenotype in liver injury and repair. Scand J Immunol. 2017;85:16674. DOIPubMed
  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. DOIPubMed
  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;284:205. DOIPubMed
  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;75:1102533. DOIPubMed
  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. DOIPubMed

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