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 23, Number 8—August 2017
Research

Clinical Laboratory Values as Early Indicators of Ebola Virus Infection in Nonhuman Primates

Ronald B. Reisler, Chenggang Yu, Michael J. Donofrio, Travis K. Warren, Jay B. Wells, Kelly S. Stuthman, Nicole L. Garza, Sean A. Vantongeren, Ginger C. Donnelly, Christopher D. Kane, Mark G. Kortepeter, Sina Bavari, and Anthony P. CardileComments to Author 
Author affiliations: United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, Maryland, USA

Main Article

Table 2

Results of selected laboratory tests for 3 nonhuman primate models at various days after challenge with EBOV*

Laboratory variable, d Models of infection
Rhesus macaque with
 p value‡ Cynomolgus macaque with Kikwit strain, mean (range), n = 6 p value§
Kikwit strain, mean (range), n = 18† Makona strain, mean (range), n = 6
BUN, mg/dL
0 16.1 (11–22) 15.2 (10–19) 0.544 17.8 (16–23) 0.217
3 15.3 (11–20) 14.3 (8–19) 0.615 17.3 (13–21) 0.215
5 20.0 (10–39) 14.2 (10–17) 0.365 38.5 (15–116) 0.124
7
 58.7 (11–108)
 17.2 (11–24)
 0.050
 112.6 (58–135)
 0.015
Creatinine, mg/dL
0 0.6 (0.5–0.8) 0.5 (0.5–0.6) 0.012 0.6 (0.5–0.9) 0.871
3 0.6 (0.5, 0.8) 0.5 (0.4–0.6) 0.030 0.6 (0.4–0.9) 0.662
5 1.1 (0.6–2.6) 0.6 (0.5–0.7) 0.005 1.8 (0.8–5.2) 0.094
7
 2.3 (0.7–5.6)
 0.8 (0.7–1.0)
 0.055
 24.3 (1.7 to >56.0)
 0.037
AST, U/L
0 37.9 (22– 62) 35.8 (26– 53) 0.702 64.7 (37– 151) 0.192
3 49.4 (32, 74) 42.0 (31–57) 0.230 95.7 (47–145) 0.002
5 411.6 (46–1,716) 47.0 (33–56) 0.001¶ 423.2 (116–743) 0.386
7
 991.4 (145–1,585)
 244.5 (113–398)
 0.009
 1,626.6 (752 to >3,400)
 0.624
ALT, U/L
0 32.1 (10–64) 17.5 (7–27) 0.009 53.8 (36–94) 0.078
3 45.2 (10–87) 25.0 (10–38) 0.009 60.2 (51–81) 0.028
5 137.2 (19–554) 29.0 (13–46) 0.008 87.8 (51–138) 0.790
7
 299.4 (68–606)
 67.2 (21–108)
 0.016
 610.0 (154–2,087)
 0.955
CRP, mg/L
0 5.6 (0–20) 5.2 (5–6) 0.651 6.8 (4–11) 0.385
3 10.1 (5–31) 5.2 (5–6) 0.013 19.7 (8–59) 0.047
5 71.2 (43–83) 17.2 (6–44) <0.001¶ 73.8 (70–78) 0.764
7
 59.5 (44–74)
 57.3 (32–71)
 0.960
 48.2 (13–72)
 0.533
LDH, IU/L
0 510.8 (366–679) 456.0 (390–537) 0.083 964.7 (653–1,267) 0.008
3 641.0 (381–829) 563.3 (454–775) 0.110 1,511.5 (894–2,532) <0.001¶
5 3,897.2 (670 to >9,000) 700.8 (551–826) 0.001¶ 5,799.8 (1,667 to >9,000) 0.229
7
 7,965.7 (1,531 to >9,000)
 5,524.3 (1,562 to >9,000)
 0.042
 9,000 (>9,000 to >9,000)
 0.353
CPK, U/L
0# 435.2 (55–915) 214.7 (84–395) 0.006 ND
3 507.3 (181–874) 557.0 (333–897) 0.594 ND
5 1,721.3 (183–5157) 494.5 (287–755) 0.014 ND
7
 4,599.1(320 to >6,400)
 2,459.3 (700–5,692)
 0.065
 ND
Platelets, × 103/mm3
0 347.5 (240–502) 274.3 (220–318) 0.002 312.5 (278–373) 0.102
3 330.4 (223–557) 285.7 (244–330) 0.193 288.2 (237–352) 0.217
5 172.0 (91–303) 253.7 (199–286) 0.006 197.3 (144–312) 0.350
7
 89.6 (34–161)
 112.3 (26–191)
 0.482
 142.4 (106–195)
 0.047
PT, s
0 11.2 (10.4–14.9) 11.4 (10.8–12.2) 0.374 10.6 (9.8–11.3) 0.010
3 10.7 (9.8–12.7) 10.9 (10.1–12.0) 0.365 10.4 (9.7–10.9) 0.545
5 13.9 (10.9–18.1) 10.4 (10.0–10.9) <0.001¶ 14.1 (12.6–17.1) 0.739
7
 15.7 (12–19.6)
 12.4 (11.7–13.8)
 0.004
 18.0 (14.6–22.8)
 0.282
APTT, s
0 27.0 (24.5–32.0) 27.5 (26.8–29.6) 0.440 25.8 (24.4–27.5) 0.095
3 26.7 (23.8–31.5) 26.1 (25.0–28.5) 0.841 27.1 (25.0–32.9) 0.947
5 43.4 (31.5–62.6) 27.6 (24.7–31.8) <0.001¶ 41.2 (35.2–48.4) 0.571
7
 60.4 (42.3–111.1)
 41.9 (34.9–47.6)
 0.012
 62.5 (51.3–67.4)
 0.532
AT, %
0 101.8 (85.8–116.9) 105.7 (90.5–121.6) 0.450 100.5 (92.0–118.6) 0.768
3 104.2 (76.0–127.3) 110.0 (98.8–119.8) 0.286 103.0 (92.8–115.3) 0.689
5 76.9 (55.5–100.9) 113.8 (103.1–129.2) <0.001¶ 73.5 (70.4–83.3) 0.505
7 67.7 (38.5–94.8) 103.1 (95.5–116.0) <0.001¶ 49.4 (34.0–55.9) 0.031

*ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; AT, antithrombin; BUN, blood urea nitrogen; CPK, creatine phosphokinase; CRP, C-reactive protein; EBOV, Ebola virus; LDH, lactate dehydrogenase; ND, not done; PT, prothrombin time.
†Results for 6 macaques in the EBOV Kikwit strain group were previously reported as a mean difference from day 7 to day 0 (28).
‡For results for rhesus macaque model of infection with EBOV Kikwit strain vs. Makona strain. Bold indicates p<0.05.
§For rhesus macaque model with EBOV Kikwit strain vs. cynomolgus macaque model with EBOV Kikwit strain. Bold indicates p<0.05.
¶Adjusted p value of <0.001, based upon a simplified Bonferroni correction for multiple comparisons.
#In the 24 nonhuman primates infected with EBOV for whom CPK values were analyzed, 16 (67%) had levels >5,000 U/L during the course of disease.

Main Article

References
  1. Centers for Disease Control and Prevention. 2014 Ebola outbreak in West Africa—case counts [cited 2016 Dec 5]. https://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html
  2. Kortepeter  MG, Bausch  DG, Bray  M. Basic clinical and laboratory features of filoviral hemorrhagic fever. J Infect Dis. 2011;204(Suppl 3):S810–6. DOIPubMedGoogle Scholar
  3. Faye  O, Andronico  A, Faye  O, Salje  H, Boëlle  PY, Magassouba  N, et al. Use of viremia to evaluate the baseline case fatality ratio of Ebola virus disease and inform treatment studies: a retrospective cohort study. PLoS Med. 2015;12:e1001908. DOIPubMedGoogle Scholar
  4. Towner  JS, Rollin  PE, Bausch  DG, Sanchez  A, Crary  SM, Vincent  M, et al. Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J Virol. 2004;78:4330–41. DOIPubMedGoogle Scholar
  5. Schieffelin  JS, Shaffer  JG, Goba  A, Gbakie  M, Gire  SK, Colubri  A, et al.; KGH Lassa Fever Program; Viral Hemorrhagic Fever Consortium; WHO Clinical Response Team. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N Engl J Med. 2014;371:2092–100. DOIPubMedGoogle Scholar
  6. de La Vega  M-A, Caleo  G, Audet  J, Qiu  X, Kozak  RA, Brooks  JI, et al. Ebola viral load at diagnosis associates with patient outcome and outbreak evolution. J Clin Invest. 2015;125:4421–8. DOIPubMedGoogle Scholar
  7. Lanini  S, Portella  G, Vairo  F, Kobinger  GP, Pesenti  A, Langer  M, et al.; INMI-EMERGENCY EBOV Sierra Leone Study Group. Blood kinetics of Ebola virus in survivors and nonsurvivors. J Clin Invest. 2015;125:4692–8. DOIPubMedGoogle Scholar
  8. Crowe  SJ, Maenner  MJ, Kuah  S, Erickson  BR, Coffee  M, Knust  B, et al. Prognostic indicators for Ebola patient survival. Emerg Infect Dis. 2016;22:217–23. DOIPubMedGoogle Scholar
  9. Fitzpatrick  G, Vogt  F, Moi Gbabai  OB, Decroo  T, Keane  M, De Clerck  H, et al. The contribution of Ebola viral load at admission and other patient characteristics to mortality in a Médecins Sans Frontières Ebola case management centre, Kailahun, Sierra Leone, June–October 2014. J Infect Dis. 2015;212:1752–8. DOIPubMedGoogle Scholar
  10. 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
  11. Janvier  F, Foissaud  V, Cotte  J, Aletti  M, Savini  H, Cordier  PY, et al.; Healthcare Workers Ebola Treatment Center Medical Team. Monitoring of prognostic laboratory markers in Ebola virus disease. J Infect Dis. 2016;213:1049. DOIPubMedGoogle Scholar
  12. Haaskjold  YL, Bolkan  HA, Krogh  KØ, Jongopi  J, Lundeby  KM, Mellesmo  S, et al. Clinical features of and risk factors for fatal Ebola virus disease, Moyamba District, Sierra Leone, December 2014–February 2015. Emerg Infect Dis. 2016;22:1537–44. DOIPubMedGoogle Scholar
  13. Xu  Z, Jin  B, Teng  G, Rong  Y, Sun  L, Zhang  J, et al. Epidemiologic characteristics, clinical manifestations, and risk factors of 139 patients with Ebola virus disease in western Sierra Leone. Am J Infect Control. 2016;44:1285–90. DOIPubMedGoogle Scholar
  14. Wong  JY, Zhang  W, Kargbo  D, Haque  U, Hu  W, Wu  P, et al. Assessment of the severity of Ebola virus disease in Sierra Leone in 2014-2015. Epidemiol Infect. 2016;144:1473–81. DOIPubMedGoogle Scholar
  15. Qin  E, Bi  J, Zhao  M, Wang  Y, Guo  T, Yan  T, et al. Clinical features of patients with Ebola virus disease in Sierra Leone. Clin Infect Dis. 2015;61:491–5. DOIPubMedGoogle Scholar
  16. Sadek  RF, Khan  AS, Stevens  G, Peters  CJ, Ksiazek  TG. Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995: determinants of survival. J Infect Dis. 1999;179(Suppl 1):S24–7. DOIPubMedGoogle Scholar
  17. Agua-Agum  J, Ariyarajah  A, Blake  IM, Cori  A, Donnelly  CA, Dorigatti  I, et al.; WHO Ebola Response Team. Ebola virus disease among male and female persons in West Africa. N Engl J Med. 2016;374:96–8. DOIPubMedGoogle Scholar
  18. 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
  19. Barry  M, Touré  A, Traoré  FA, Sako  FB, Sylla  D, Kpamy  DO, et al. Clinical predictors of mortality in patients with Ebola virus disease. Clin Infect Dis. 2015;60:1821–4. DOIPubMedGoogle Scholar
  20. Barry  M, Traoré  FA, Sako  FB, Kpamy  DO, Bah  EI, Poncin  M, et al. Ebola outbreak in Conakry, Guinea: epidemiological, clinical, and outcome features. Med Mal Infect. 2014;44:491–4. DOIPubMedGoogle Scholar
  21. Martins  K, Cooper  C, Warren  T, Wells  J, Bell  T, Raymond  J, et al. Characterization of clinical and immunological parameters during Ebola virus infection of rhesus macaques. Viral Immunol. 2015;28:32–41. DOIPubMedGoogle Scholar
  22. Warren  TK, Trefry  JC, Marko  ST, Chance  TB, Wells  JB, Pratt  WD, et al. Euthanasia assessment in ebola virus infected nonhuman primates. Viruses. 2014;6:4666–82. DOIPubMedGoogle Scholar
  23. Marzi  A, Feldmann  F, Hanley  PW, Scott  DP, Günther  S, Feldmann  H. Delayed disease progression in cynomolgus macaques infected with Ebola virus Makona strain. Emerg Infect Dis. 2015;21:1777–83. DOIPubMedGoogle Scholar
  24. Wong  G, Qiu  X, de La Vega  MA, Fernando  L, Wei  H, Bello  A, et al. Pathogenicity comparison between the Kikwit and Makona Ebola virus variants in rhesus macaques. J Infect Dis. 2016;214(suppl 3):S281–9. DOIPubMedGoogle Scholar
  25. McElroy  AK, Spiropoulou  CF. Biomarkers for understanding Ebola virus disease. Biomarkers Med. 2014;8:1053–6. DOIPubMedGoogle Scholar
  26. Villinger  F, Rollin  PE, Brar  SS, Chikkala  NF, Winter  J, Sundstrom  JB, et al. Markedly elevated levels of interferon (IFN)-γ, IFN-α, interleukin (IL)-2, IL-10, and tumor necrosis factor-α associated with fatal Ebola virus infection. J Infect Dis. 1999;179(Suppl 1):S188–91. DOIPubMedGoogle Scholar
  27. Leroy  EM, Baize  S, Lu  CY, McCormick  JB, Georges  AJ, Georges-Courbot  MC, et al. Diagnosis of Ebola haemorrhagic fever by RT-PCR in an epidemic setting. J Med Virol. 2000;60:463–7. DOIPubMedGoogle Scholar
  28. Warren  TK, Jordan  R, Lo  MK, Ray  AS, Mackman  RL, Soloveva  V, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381–5. DOIPubMedGoogle Scholar
  29. Geisbert  TW, Lee  AC, Robbins  M, Geisbert  JB, Honko  AN, Sood  V, et al. Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet. 2010;375:1896–905. DOIPubMedGoogle Scholar
  30. Qiu  X, Wong  G, Audet  J, Bello  A, Fernando  L, Alimonti  JB, et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514:47–53.PubMedGoogle Scholar
  31. Pettitt  J, Zeitlin  L, Kim  DH, Working  C, Johnson  JC, Bohorov  O, et al. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci Transl Med. 2013;5:199ra113. DOIPubMedGoogle Scholar
  32. Colubri  A, Silver  T, Fradet  T, Retzepi  K, Fry  B, Sabeti  P. Transforming clinical data into actionable prognosis models: machine-learning framework and field-deployable app to predict outcome of Ebola patients. PLoS Negl Trop Dis. 2016;10:e0004549. DOIPubMedGoogle Scholar
  33. Hasanoglu  I, Guner  R, Carhan  A, Kocak Tufan  Z, Yagci-Caglayik  D, Guven  T, et al. Crucial parameter of the outcome in Crimean Congo hemorrhagic fever: Viral load. J Clin Virol. 2016;75:42–6. DOIPubMedGoogle Scholar
  34. Ozturk  B, Tutuncu  E, Kuscu  F, Gurbuz  Y, Sencan  I, Tuzun  H. Evaluation of factors predictive of the prognosis in Crimean-Congo hemorrhagic fever: new suggestions. Int J Infect Dis. 2012;16:e89–93. DOIPubMedGoogle Scholar
  35. Gai  ZT, Zhang  Y, Liang  MF, Jin  C, Zhang  S, Zhu  CB, et al. Clinical progress and risk factors for death in severe fever with thrombocytopenia syndrome patients. J Infect Dis. 2012;206:1095–102. DOIPubMedGoogle Scholar
  36. Sirikutt  P, Kalayanarooj  S. Serum lactate and lactate dehydrogenase as parameters for the prediction of dengue severity. J Med Assoc Thai. 2014;97(Suppl 6):S220–31.PubMedGoogle Scholar
  37. Adeva-Andany  M, López-Ojén  M, Funcasta-Calderón  R, Ameneiros-Rodríguez  E, Donapetry-García  C, Vila-Altesor  M, et al. Comprehensive review on lactate metabolism in human health. Mitochondrion. 2014;17:76–100. DOIPubMedGoogle Scholar
  38. Guzmán-de la Garza  FJ, Ibarra-Hernández  JM, Cordero-Pérez  P, Villegas-Quintero  P, Villarreal-Ovalle  CI, Torres-González  L, et al. Temporal relationship of serum markers and tissue damage during acute intestinal ischemia/reperfusion. Clinics (Sao Paulo). 2013;68:1034–8. DOIPubMedGoogle Scholar
  39. Yasuda  H, Okita  Y, Imaoka  H, Fujikawa  H, Ohi  M, Araki  T, et al. Intestinal necrosis due to norovirus enteritis. Clin J Gastroenterol. 2015;8:10–3. DOIPubMedGoogle Scholar
  40. de Villiers  FPR, Driessen  M. Clinical neonatal rotavirus infection: association with necrotising enterocolitis. S Afr Med J. 2012;102:620–4. DOIPubMedGoogle Scholar
  41. Lynn  LA. Combined endothelial and epithelial barrier disruption of the colon may be a contributing factor to the Ebola sepsis-like syndrome. Patient Saf Surg. 2015;9:1. DOIPubMedGoogle Scholar
  42. Kortepeter  MG, Lawler  JV, Honko  A, Bray  M, Johnson  JC, Purcell  BK, et al. Real-time monitoring of cardiovascular function in rhesus macaques infected with Zaire ebolavirus. J Infect Dis. 2011;204(Suppl 3):S1000–10. DOIPubMedGoogle Scholar
  43. Zein  JG, Lee  GL, Tawk  M, Dabaja  M, Kinasewitz  GT. Prognostic significance of elevated serum lactate dehydrogenase (LDH) in patients with severe sepsis. Chest. 2004;126(4_Meeting Abstracts):873S. DOIGoogle Scholar
  44. Kruse  O, Grunnet  N, Barfod  C. Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med. 2011;19:74. DOIPubMedGoogle Scholar
  45. Vincent  JL, Quintairos E Silva  A, Couto  L Jr, Taccone  FS. The value of blood lactate kinetics in critically ill patients: a systematic review. Crit Care. 2016;20:257. DOIPubMedGoogle Scholar
  46. Duman  A, Akoz  A, Kapci  M, Ture  M, Orun  S, Karaman  K, et al. Prognostic value of neglected biomarker in sepsis patients with the old and new criteria: predictive role of lactate dehydrogenase. Am J Emerg Med. 2016;34:2167–71. DOIPubMedGoogle Scholar
  47. Erez  A, Shental  O, Tchebiner  JZ, Laufer-Perl  M, Wasserman  A, Sella  T, et al. Diagnostic and prognostic value of very high serum lactate dehydrogenase in admitted medical patients. Isr Med Assoc J. 2014;16:439–43.PubMedGoogle Scholar
  48. Johnson  E, Jaax  N, White  J, Jahrling  P. Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus. Int J Exp Pathol. 1995;76:227–36.PubMedGoogle Scholar

Main Article

Page created: July 17, 2017
Page updated: July 17, 2017
Page reviewed: July 17, 2017
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