Intensive Care Medicine

, Volume 39, Issue 2, pp 319–326 | Cite as

Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock

  • Xiao-Jun Xu
  • Yong-Min Tang
  • Chan Liao
  • Hua Song
  • Shi-Long Yang
  • Wei-Qun Xu
  • Shu-Wen Shi
  • Ning Zhao
Pediatric Original



We performed a prospective study to evaluate the ability of inflammatory cytokines in discriminating gram-negative from gram-positive bacteremia in septic shock.


During the study period, the serum inflammatory cytokine levels were measured at the onset of septic shock by flow cytometry in pediatric hematology/oncology patients with septic shock.


One hundred episodes of septic shock were enrolled. Of 97 episodes of monomicrobial infection, 73.2 % were caused by gram-negative bacteremia and 26.8 % by gram-positive bacteremia. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were closely related to the pediatric index of mortality 2 (PIM2) score and mortality. However, although the PIM2 score and mortality were comparable, the IL-6, IL-10, and TNF-α levels were significantly higher in patients with gram-negative bacteremia (GNB) than those with gram-positive bacteremia (median levels, pg/mL: IL-6: 784.1 vs. 254.4, P = 0.001; IL-10: 192.2 vs. 19.7, P < 0.001; TNF-α: 4.2 vs. 2.0, P < 0.001). Of the three cytokines, IL-10 was the most useful biomarker for GNB prediction in the derivation cohort and a cutoff value of 50 pg/mL showed a sensitivity of 70.8 % and a specificity of 80.0 %, with a positive predictive value of 89.5 %. When this cutoff value was applied to the validation cohort, the sensitivity, specificity, and positive predictive value were 80.9, 75.0, and 90.5 %, respectively.


Flow cytometry-based inflammatory cytokine measurement is a helpful adjuvant approach for early and quick discrimination of gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock which might be useful for evaluating the severity of shock and the selection and/or timely withdrawal or switch of antibiotics.


Cytokine Septic shock Gram-negative bacteremia Interleukin-10 Flow cytometry 


  1. 1.
    Watson RS, Carcillo JA, Linde-Zwirble WT, Clermont G, Lidicker J, Angus DC (2003) The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med 167:695–701PubMedCrossRefGoogle Scholar
  2. 2.
    Shime N, Kawasaki T, Saito O, Akamine Y, Toda Y, Takeuchi M, Sugimura H, Sakurai Y, Iijima M, Ueta I, Shimizu N, Nakagawa S (2012) Incidence and risk factors for mortality in paediatric severe sepsis: results from the national paediatric intensive care registry in Japan. Intensive Care Med 38:1191–1197PubMedCrossRefGoogle Scholar
  3. 3.
    Lin MY, Weinstein RA, Hota B (2008) Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia. Antimicrob Agents Chemother 52:3188–3194PubMedCrossRefGoogle Scholar
  4. 4.
    Vandijck DM, Depuydt PO, Offner FC, Nollet J, Peleman RA, Steel E, Noens LA, Decruyenaere JM, Benoit DD (2010) Impact of organ dysfunction on mortality in ICU patients with hematologic malignancies. Intensive Care Med 36:1744–1750PubMedCrossRefGoogle Scholar
  5. 5.
    Opal SM, Cohen J (1999) Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med 27:1608–1616PubMedCrossRefGoogle Scholar
  6. 6.
    Gao H, Evans TW, Finney SJ (2008) Bench-to-bedside review: sepsis, severe sepsis and septic shock—does the nature of the infecting organism matter? Crit Care 12:213PubMedCrossRefGoogle Scholar
  7. 7.
    Feezor RJ, Oberholzer C, Baker HV, Novick D, Rubinstein M, Moldawer LL, Pribble J, Souza S, Dinarello CA, Ertel W, Oberholzer A (2003) Molecular characterization of the acute inflammatory response to infections with gram-negative versus gram-positive bacteria. Infect Immun 71:5803–5813PubMedCrossRefGoogle Scholar
  8. 8.
    Bjerre A, Brusletto B, Hoiby EA, Kierulf P, Brandtzaeg P (2004) Plasma interferon-gamma and interleukin-10 concentrations in systemic meningococcal disease compared with severe systemic Gram-positive septic shock. Crit Care Med 32:433–438PubMedCrossRefGoogle Scholar
  9. 9.
    Engel A, Mack E, Kern P, Kern WV (1998) An analysis of interleukin-8, interleukin-6 and C-reactive protein serum concentrations to predict fever, gram-negative bacteremia and complicated infection in neutropenic cancer patients. Infection 26:213–221PubMedCrossRefGoogle Scholar
  10. 10.
    Lehrnbecher T, Venzon D, de Haas M, Chanock SJ, Kuhl J (1999) Assessment of measuring circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble Fc gamma receptor type III, and mannose-binding protein in febrile children with cancer and neutropenia. Clin Infect Dis 29:414–419PubMedCrossRefGoogle Scholar
  11. 11.
    Kern WV, Heiss M, Steinbach G (2001) Prediction of gram-negative bacteremia in patients with cancer and febrile neutropenia by means of interleukin-8 levels in serum: targeting empirical monotherapy versus combination therapy. Clin Infect Dis 32:832–835PubMedCrossRefGoogle Scholar
  12. 12.
    Soker M, Colpan L, Ece A, Devecioglu C, Haspolat K (2001) Serum levels of IL-1 beta, sIL-2R, IL-6, IL-8, and TNF-alpha in febrile children with cancer and neutropenia. Med Oncol 18:51–57PubMedCrossRefGoogle Scholar
  13. 13.
    Spasova MI, Terzieva DD, Tzvetkova TZ, Stoyanova AA, Mumdzhiev IN, Yanev IB, Genev ED (2005) Interleukin-6, interleukin-8, interleukin-10, and C-reactive protein in febrile neutropenia in children with malignant diseases. Folia Med (Plovdiv) 47:46–52Google Scholar
  14. 14.
    Prat C, Sancho JM, Dominguez J, Xicoy B, Gimenez M, Ferra C, Blanco S, Lacoma A, Ribera JM, Ausina V (2008) Evaluation of procalcitonin, neopterin, C-reactive protein, IL-6 and IL-8 as a diagnostic marker of infection in patients with febrile neutropenia. Leuk Lymphoma 49:1752–1761PubMedCrossRefGoogle Scholar
  15. 15.
    Tang Y, Liao C, Xu X, Song H, Shi S, Yang S (2012) Th1/Th2 cytokine profiles in G+/G− bacteremia in pediatric hematology/oncology patients. Pediatr Blood Cancer 58:50–54PubMedCrossRefGoogle Scholar
  16. 16.
    Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6:2–8PubMedCrossRefGoogle Scholar
  17. 17.
    Slater A, Shann F, Pearson G (2003) PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Med 29:278–285PubMedGoogle Scholar
  18. 18.
    Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, Pan B, Zhao F, Liao C, Luo C (2008) Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol 143:84–91PubMedCrossRefGoogle Scholar
  19. 19.
    Gogos CA, Drosou E, Bassaris HP, Skoutelis A (2000) Pro- versus anti-inflammatory cytokine profile in patients with severe sepsis: a marker for prognosis and future therapeutic options. J Infect Dis 181:176–180PubMedCrossRefGoogle Scholar
  20. 20.
    Bozza FA, Salluh JI, Japiassu AM, Soares M, Assis EF, Gomes RN, Bozza MT, Castro-Faria-Neto HC, Bozza PT (2007) Cytokine profiles as markers of disease severity in sepsis: a multiplex analysis. Crit Care 11:R49PubMedCrossRefGoogle Scholar
  21. 21.
    Carrol ED, Thomson AP, Jones AP, Jeffers G, Hart CA (2005) A predominantly anti-inflammatory cytokine profile is associated with disease severity in meningococcal sepsis. Intensive Care Med 31:1415–1419PubMedCrossRefGoogle Scholar
  22. 22.
    Tang Y, Liao C, Xu X, Song H, Shi S, Yang S, Zhao F, Xu W, Chen X, Mao J, Zhang L, Pan B (2011) Evaluation of Th1/Th2 cytokines as a rapid diagnostic tool for severe infection in paediatric haematology/oncology patients by the use of cytometric bead array technology. Clin Microbiol Infect 17:1666–1673PubMedCrossRefGoogle Scholar
  23. 23.
    Abe R, Oda S, Sadahiro T, Nakamura M, Hirayama Y, Tateishi Y, Shinozaki K, Hirasawa H (2010) Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia. Crit Care 14:R27PubMedCrossRefGoogle Scholar
  24. 24.
    Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R (1997) Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 278:234–240PubMedCrossRefGoogle Scholar
  25. 25.
    Finney SJ, Leaver SK, Evans TW, Burke-Gaffney A (2012) Differences in lipopolysaccharide- and lipoteichoic acid-induced cytokine/chemokine expression. Intensive Care Med 38:324–332PubMedCrossRefGoogle Scholar
  26. 26.
    Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34:17–60PubMedCrossRefGoogle Scholar
  27. 27.
    Jaramillo-Bustamante JC, Marin-Agudelo A, Fernandez-Laverde M, Bareno-Silva J (2012) Epidemiology of sepsis in pediatric intensive care units: first Colombian multicenter study. Pediatr Crit Care Med 13:501–508PubMedCrossRefGoogle Scholar
  28. 28.
    Labelle A, Juang P, Reichley R, Micek S, Hoffmann J, Hoban A, Hampton N, Kollef M (2012) The determinants of hospital mortality among patients with septic shock receiving appropriate initial antibiotic treatment. Crit Care Med 40:2016–2021PubMedCrossRefGoogle Scholar
  29. 29.
    Richens JL, Urbanowicz RA, Metcalf R, Corne J, O’Shea P, Fairclough L (2010) Quantitative validation and comparison of multiplex cytokine kits. J Biomol Screen 15:562–568PubMedCrossRefGoogle Scholar
  30. 30.
    Leng SX, McElhaney JE, Walston JD, Xie D, Fedarko NS, Kuchel GA (2008) ELISA and multiplex technologies for cytokine measurement in inflammation and aging research. J Gerontol A Biol Sci Med Sci 63:879–884PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg and ESICM 2012

Authors and Affiliations

  • Xiao-Jun Xu
    • 1
    • 2
  • Yong-Min Tang
    • 1
    • 2
  • Chan Liao
    • 1
  • Hua Song
    • 1
  • Shi-Long Yang
    • 1
  • Wei-Qun Xu
    • 1
  • Shu-Wen Shi
    • 1
  • Ning Zhao
    • 1
    • 2
  1. 1.Division of Hematology-OncologyChildren’s Hospital of Zhejiang University School of MedicineHangzhouPeople’s Republic of China
  2. 2.Key Laboratory of Reproductive Genetics, Zhejiang University, Ministry of EducationHangzhouPeople’s Republic of China

Personalised recommendations