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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

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Summary

A prospective study was performed to assess the potential value of interleukin (IL)-8, IL-6, and C-reactive protein (CRP) serum levels to predict fever, gram-negative bacteremia and complicated infection in neutropenic patients with cancer. Serum samples were obtained three times a week during 208 neutropenic episodes following cytotoxic chemotherapy. Fever of any cause developed during 104 out of 191 evaluable episodes. Serum levels of neither cytokine nor CRP were predictive of fever within more than 24 h before its onset. Unlike CRP, both IL-6 and IL-8 serum levels were significantly different between microbiologically documented infections and unexplained fevers. The highest values of IL-6 and IL-8 were observed in episodes of gram-negative bacteremia. Using receiver-operating-characteristic curves, the analysis of cytokine levels measured around the onset of fever indicated that IL-8 is potentially useful for predicting gram-negative bacteremia, with a high negative predictive value of >90% and a moderate positive predictive value of 50% (sensitivity, 70%; specificity, 91%). In patients with persistent fever, predictions of further clinical complications, defined as prolonged fever of more than 7 days’ duration, pneumonia, shock and/or death due to infection, were best predicted by IL-6. With an IL-6 cutoff value of 250 pg/ml in samples obtained 8 to 32 h after onset of fever, the positive predictive value was 92%, the negative predictive value 91% (sensitivity, 85%; specificity, 95%). The positive predictive value of IL-6 in samples obtained another 24h later from patients still febrile remained >90%, but the negative predictive value dropped to 47%. In any of the analyses, the predictive values of CRP levels were poor and inferior to either cytokine. These findings may have clinical value in identifying subgroups of patients requiring different therapeutic approaches.

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References

  1. Pizzo, P. A.: Management of fever in patients with cancer and treatment-induced neutropenia. New Engl. J. Med. 328 (1993) 1323–1332.

    Article  PubMed  CAS  Google Scholar 

  2. The EORTC International Antimicrobial Therapy Cooperative Group: Ceftazidime combined with a short or long course of amikacin for empirical therapy of gram-negative bacteremia in cancer patients with granulocytopenia. N. Engl. J. Med. 317 (1987) 1692–1698.

    Google Scholar 

  3. Rolston, K. V. I., Berkey, P., Bodey, G. P., Anaissie, E. J., Khardori, N. M., Joshi, J. H., Keating, M. J., Holmes, F. A., Cabanillas, F. F., Elting, L.: A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients. Arch. Intern. Med. 152 (1992) 283–291.

    Article  PubMed  CAS  Google Scholar 

  4. Leibovici, L., Paul, M., Poznanski, O., Drucker, M., Samra, Z., Konigsberger, H., Pitlik, S. D.: Monotherapy versus β-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrob. Agents Chemother. 41 (1997) 1127–1133.

    PubMed  CAS  Google Scholar 

  5. Maschmeyer, G., Link, H., Hiddemann, W., Meyer, P., Helmerking, M., Eisenmann, E., Schmitt, J., Adam, D. Pulmonary infiltrations in febrile patients with neutropenia. Risk factors and outcome under empirical antimicrobial therapy in a randomized multicenter study. Cancer 73 (1994) 2296–2304.

    Article  PubMed  CAS  Google Scholar 

  6. Kern, W. V., Maute, B., Engel, A., Heil, G., Kern, P.: Piperacillintazobactam plus netilmicin as empiric treatment for adult patients with acute leukemia, neutropenia, and fever: single-center experience and retrospective comparison with piperacillin plus netilmicin. Curr. Ther. Res. 58 (1997) 56–69.

    Article  CAS  Google Scholar 

  7. Talcott, J. A., Siegel, R. D., Finberg, R., Goldman, L.: Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule. J. Clin. Oncol. 10 (1992) 316–322.

    PubMed  CAS  Google Scholar 

  8. Lucas, K. G., Brown, A. E., Armstrong, D., Chapman, D., Heller, G.: The identification of febrile, neutropenic children with neoplastic disease at low risk for bacteremia and complications of sepsis. Cancer 77 (1996) 791–798.

    Article  PubMed  CAS  Google Scholar 

  9. Viscoli, C., Bruzzi, P., Castagnola, E., Boni, L., and the International Antimicrobial Therapy Cooperative Group of the EORTC. Factors associated with bacteremia in febrile granulocytopenic cancer patients. Eur. J. Cancer 30A (1994), 430–437.

    Article  PubMed  CAS  Google Scholar 

  10. Ligtenberg, P. C., Hoepelman, I. M., Sogtoen, G. A. C., Dckker, A. W., van der Tweel, I., Rozenberg-Arska, M., Verhoef, J.: C-reactive protein in the diagnosis and management of infections in granulocytopenic and non-granulocytopenic patients. Eur J. Clin. Microbiol. Infect. Dis.10 (1991) 25–31.

    Article  PubMed  CAS  Google Scholar 

  11. Katz, J. A., Mustafa, M. M., Bash, R. O., Cash, J. V., Buchanan, G. R.: Value of C-reactive protein determination in the initial diagnostic evaluation of the febrile, neutropenic child with cancer. Pediatr. Infect. Dis. J. 11 (1992) 708–712.

    PubMed  CAS  Google Scholar 

  12. Heney, D., Lewis, I. J. Evans, S. W, Banks, R., Bailey, C. C., Whicher, J. T.: Interleukin-6 and its relationship to C-reactive protein and fever in children with febrile neutropenia. J. Infect. Dis. 165 (1992) 886–890.

    PubMed  CAS  Google Scholar 

  13. Riikonen, P., Saarinen, U. M., Teppo, A. M., Metsärinne, K., Fyhrquist, F., Jalanko, H.: Cytokine and acute-phase reactant levels in serum of children with cancer admitted for fever and neutropenia. J. Infect. Dis. 166 (1992), 432–436.

    PubMed  CAS  Google Scholar 

  14. Manian, F. A.: A prospective study of daily measurement of C-reactive protein in serum of adults with neutropenia. Clin. Infect. Dis. 21 (1995) 114–121.

    PubMed  CAS  Google Scholar 

  15. Cebon, J., Layton, J. E., Maher, D., Morstyn, G.: Endogenous haemopoietic growth factors in neutropenia and infection. Br. J. Haematol. 86 (1994) 265–274.

    Article  PubMed  CAS  Google Scholar 

  16. Hynninen, M., Valtonen, M., Vaara, M., Markkanen, H., Kuusela, P., Saxen, H., Takkunen, O.: Plasma endotoxin and cytokine levels in neutropenic and non-neutropenic bacteremic patients. Eur. J. Clin. Microbiol. Infect. Dis. 14 (1995) 1039–1045.

    Article  PubMed  CAS  Google Scholar 

  17. Steinmetz, H. T., Herbertz, A., Bertram, M., Diehl, V.: Increase in interleukin-6 serum level preceding fever in granulocytopenia and correlation with death from sepsis. J. Infect. Dis. 171 (1995) 225–228.

    PubMed  CAS  Google Scholar 

  18. Günther, G., Gardlund, B., hast, R., Kimby, E. Nordin, M., Wretlind, B.: Endotoxaemia and inflammatory mediators in febrile patients with haematological disease. J. Intern. Med. 237 (1995) 27–33.

    PubMed  Google Scholar 

  19. Antonelli, M., Raponi, G. M., Martino, P., Rosa, G., Conti, G., Jalouk, J., Gasparetto, A.: High IL-6 serum levels are associated with septic shock and mortality in septic patients with severe leukopenia due to hematological malignancies. Scand. J. Infect. Dis. 27 (1995) 381–384.

    Article  PubMed  CAS  Google Scholar 

  20. Engervall, P., Andersson, B., Björkholm, M.: Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia. Br. J. Haematol. 91 (1995) 838–845.

    Article  PubMed  CAS  Google Scholar 

  21. Engel, A., Kern, W. V., Mürdter, G., Kern, P.: Kinetics and correlation with body temperature of circulating interleukin-6, interleukin-8, tumor necrosis factor alpha and interleukin-1 beta in patients with fever and neutropenia. Infection 22 (1994) 160–164.

    Article  PubMed  CAS  Google Scholar 

  22. Kern, W. V., Engel, A., Kern, P.: Soluble tumor necrosis factor receptors in febrile neutropenic cancer patients. Infection 23 (1995) 68–69.

    Article  Google Scholar 

  23. Ostermann, H., Rothenburger, M., Mesters, R. M., van de Loo, J., Kienast, J.: Cytokine response to infection in patients with acute myelogenous leukaemia following intensive chemotherapy. Br. J. Haematol. 88 (1994) 332–337.

    Article  PubMed  CAS  Google Scholar 

  24. Schöhnbohn, H., Schuler, M., Kolbe, K., Peschel, C., Huber, C., Bemb, W., Aulitzky, W. E.: Plasma levels of IL-1, TNF alpha, IL-6, IL-8, G-CSF, and IL1-RA during febrile neutropenia: results of a prospective study in patients undergoing chemotherapy for acute myelogenous leukemia. Ann. Hematol. 71 (1995) 161–168.

    Article  Google Scholar 

  25. Lindemann, A., Tamm, I., Tanodi, K., Mertelsmann, R.: Interleukin-8 serum levels for early detection of infectious episodes in neutropenic patients. J. Infect. Dis. 172 (1995) 610.

    PubMed  CAS  Google Scholar 

  26. Cometta, A., Calandra, T., Gaya, H., Zinner, S. H., de Bock, R., Del Favero, A., Bicaneve, G., Crokaert, F., Kern, W. V., Klastersky, J., Langenaeken, I., Micozzi, A., Padmos, A., Paesmans, M., Viscoli, C., Glauser, M. P., andThe International Antimicrobial Therrapy Cooperative Group of the EORTC and the GIMEMA Infection Program: Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. Antimicrob. Agents Chemother. 40 (1996) 1108–1115.

    PubMed  CAS  Google Scholar 

  27. Kern, W. V., Kurrle, E.: Otloxacin versus trimethoprim-sulfamethaxole for prevention of infection in patients with acute leukemia and granulocytopenia. Infection 19 (1991) 73–80.

    Article  PubMed  CAS  Google Scholar 

  28. Kern, W. V., Hay, B., Kern, P., Marre, R., Arnold, R.: A randomized trial of roxithromycin in patients with acute leukemia and bone marrow transplant recipients receiving fluoroquinolone prophylaxis. Antimicrob. Agents Chemother. 38 (1994) 465–472.

    PubMed  CAS  Google Scholar 

  29. Nettleman, M. D.: Receiver-operator characteristic (ROC) curves. Infect. Control Hosp. Epidemiol. 9 (1988) 374–377.

    Article  PubMed  CAS  Google Scholar 

  30. Zweig, M. H., Campbell, G.: Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical, medicine. Clin. Chem. 39 (1993) 561–577.

    PubMed  CAS  Google Scholar 

  31. Calandra, T., Baumgartner, J. D., Grau, G. E., Wu, M. M., Lambert, P. H., Schellekens, J., Verhoef, J., Glauser, M. P., andthe Swiss-Dutch J5 Immunoglobulin Study Group: Prognostic values of tumor necrosis factor/cachectin, interleukin-1, interferon-α and interferonγ in the serum of patients with septic shock. J. Infect. Dis. 161 (1990) 982–987.

    PubMed  CAS  Google Scholar 

  32. Calandra, T., Gerain, J., Heumann, D., Baumgartner, J. D., Glauser, M. P.: High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. Am. J. Med. 91 (1991) 23–29.

    Article  PubMed  CAS  Google Scholar 

  33. Mackie, P. H., Crockson, R. A., Stuart, J.: C-reactive protein for rapid diagnosis of infection in leukemia. J. Clin. Pathol. 32 (1979) 1253–1256.

    Article  PubMed  CAS  Google Scholar 

  34. Starke, I. D., De Beer, F. C., Donnelly, J. P., Catovsky, D., Goldman, J. M., Galton, D. A. G., Pepys, M. B.: Serum C-reactive protein levels in the management of infection in acute leukemia. Eur. J. Cancer Clin. Oncol. 20 (1984) 319–325.

    Article  PubMed  CAS  Google Scholar 

  35. Hansson, L. O., Lindquist, L.: C-reactive protein: its role in the diagnosis and follow-up of infectious diseases. Curr. Opin. Infect. Dis. 10 (1997) 196–201.

    Article  Google Scholar 

  36. Engervall, P., Granström, M., Andersson, B., Björkholm, M.: Monitoring of endotoxin, interleukin-6 and C-reactive protein serum concentrations in neutropenic patients with fever. Eur. J. Haematol. 54 (1995) 226–234.

    PubMed  CAS  Google Scholar 

  37. Talcott, J. A., Whalen, A., Clark, J., Rieker, P. P., Finberg, R.: Home antibiotic therapy for low-risk cancer patients with fever and neutropenia-a pilot study of 30 patients based on a validated prediction rule. J. Clin. Oncol. 12 (1994) 107–114.

    PubMed  CAS  Google Scholar 

  38. Lau, R. C., Doyle, J. J., Freedman, M. H., King, S. M., Richardson, S. E.: Early discharge of pediatric febrile neutropenic cancer patients by substitution of oral for intravenous antibiotics. Pediatr. Hematol. Oncol. 11 (1994) 417–421.

    Article  PubMed  CAS  Google Scholar 

  39. Sullivan, J. S., Kilpatrick, L., Costarino, A.T., Lee, S. C., Harris M. C.: Correlation of plasma cytokine elevations with mortality rate in children with sepsis. J Pediatr. 120 (1992) 510–515.

    Article  PubMed  CAS  Google Scholar 

  40. Meduri, G. U., Headley, S., Kohler, G., Stentz, F., Tolley, E., Umberger, R., Leeper, K.: Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Chest 107 (1995) 1062–1073.

    Article  PubMed  CAS  Google Scholar 

  41. Örtquist, A., Hedlund, J., Wretlind B., Carlström, A., Kalin, M.: Diagnostic and prognostic value of interleukin-6 and C-reactive protein in community-acquired pneumonia. Scand. J. Infect. Dis. 27 (1995) 457–462.

    Article  Google Scholar 

  42. Hack, C. E., De Groot, E. R., Felt-Bersma, R. J., Nuijens, J. H., Strack van Schijndel, R. J., Eerenberg-Belmer, A. J., Thijs, L. G., Aarden, L. A.: Increased plasma levels of interleukin-6 in sepsis. Blood 74 (1989) 1704–1710.

    PubMed  CAS  Google Scholar 

  43. van Deuren, M., van der Ven-Jongekrijg, J., Bartelink, A. K. M., van Dalen, R., Sauerwein, R. W., van der Meer, J. W. M.: Correlation between proinflammatory cytokines and antiinflammatory mediators and the severity of disease in meningococcal infections. J. Infect. Dis. 172 (1995) 433–439.

    PubMed  Google Scholar 

  44. Waage, A., Brandtzaeg, P., Halstensen, A., Kierulf, P., Espevik, T.: The complex pattern of cytokines in serum from, patients with meningococcal septic shock. J. Exp. Med. 169 (1989) 333–338.

    Article  PubMed  CAS  Google Scholar 

  45. Damas, P., Ledoux, D., Nys, M., Vrindts, Y., de Groote, D., Franchimont, P., Lamy, M.: Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann. Surg. 215 (1992) 356–362.

    Article  PubMed  CAS  Google Scholar 

  46. Gardlund, B., Sjölin, J., Nilsson, A., Roll, M., Wickerts, C. J., Wretlind, B.: Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J. Infect. Dis. 172 (1995) 296–301.

    PubMed  CAS  Google Scholar 

  47. Reinhart, K., Wiegand-Löhnert, C., Grimminger, F., Kaul, M., Withington, S., Treacher, D., Eckart, J., Willatts, S., Bouza, C., Krausch, D., Stockenhuber, F., Eiselstein, J., Daum, L., Kempeni, J., andthe MAK 195F Sepsis Study Group: Assessment of the safety and efficacy of the monoclonal anti-tumor necrosis factor antibody-fragment, MAK 195F, in patients with sepsis and septic shock: a multicenter, randomized, placebo-controlled, dose-ranging study. Crit. Care Med. 24 (1996) 733–742.

    Article  PubMed  CAS  Google Scholar 

  48. Dellinger, R. P., Truman, H. S.: Post hoc analyses in sepsis trial: a formula for disappointment? Crit. Care Med. 24 (1996) 727–729.

    Article  PubMed  CAS  Google Scholar 

  49. Steel, D. M., Whitehead, A. S.: The major acute phase reactants: Creactive protein, serum amyloid P component and serum amyloid A protein. Immunol. Today 15 (1994) 81–88.

    Article  PubMed  CAS  Google Scholar 

  50. Rintala, E., Pulkki, K., Mertsola, J., Nevalainen, T., Nikoskelainen, J.: Endotoxin, interleukin-6 and phospholipase-A2 as marker of sepsis in patients with hematological malignancies. Scand. J. Infect. Dis. 27 (1995) 39–43.

    PubMed  CAS  Google Scholar 

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  1. Medizinische Universitätsklinik und Poliklinik, Oberer Eselsberg, D-89070, Ulm, Germany

    A. Engel, E. Mack, P. Kern & W. V. Kern

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  1. A. Engel
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Engel, A., Mack, E., Kern, P. et al. 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, 213–221 (1998). https://doi.org/10.1007/BF02962366

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