Skip to main content
Top
Published in: Supportive Care in Cancer 10/2013

01-10-2013 | Original Article

Substantially elevated C-reactive protein (CRP), together with low levels of procalcitonin (PCT), contributes to diagnosis of fungal infection in immunocompromised patients

Authors: Markéta Marková, Helena Brodská, Karin Malíčková, Veronika Válková, Petr Cetkovský, Michal Kolář, Martin Haluzík

Published in: Supportive Care in Cancer | Issue 10/2013

Login to get access

Abstract

Purpose

Serum procalcitonin (PCT) has become a routinely utilized parameter with a high prediction value of the severity of bacterial infectious complications and their immediate outcomes. Whereas the utility of PCT in differentiating between bacterial and viral infection is generally accepted, its significance in fungal infections has yet to be determined. The aim of the study was to determine the role of PCT testing in patients at high risk for invasive fungal infections.

Methods

Immunocompromised hematological patients undergoing cyclic chemotherapy treatment or allogeneic hemopoietic stem cell transplantation with infectious complications in which the infectious agents were identified during the disease course were evaluated. In patients with bacterial infection, positive hemocultures were documented, and in patients with fungal infection, the presence of either proven or probable disease was confirmed according to Ascioglu criteria. C-reactive protein (CRP) and PCT were prospectively assessed from the day following fever onset, for four consecutive days.

Results

Overall, 34 patients were evaluated, 21 with bacterial and 13 with fungal infections. Significant elevations of CRP concentrations (i.e., above the upper normal limit) were observed in all patients, with a tendency toward higher levels in bacterial (both gram-positive [Gr+] and Gr-negative [Gr−]) than in fungal infections. PCT levels were significantly elevated in patients with bacterial infections (e.g., predominantly in Gr− compared to Gr+), whereas in patients with fungal infections, we identified minimal or no PCT elevations, p < 0.01. For the fungal infections, according to constructed receiver operating characteristic curves, a combination of PCT <0.5 μg/L and CRP 100–300 mg/L offers the best specificity, sensitivity and positive and negative predictive values (81, 85, 73, and 89 %, respectively).

Conclusion

Altogether, our data suggest that the finding of substantially elevated CRP combined with low PCT in immunocompromised patients may indicate systemic fungal infection. The use of this combination might simplify the diagnostic process, which otherwise can often be lengthy and arduous.
Appendix
Available only for authorised users
Literature
1.
go back to reference Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer, Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34(1):7–14CrossRefPubMed Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ, Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer, Mycoses Study Group of the National Institute of Allergy and Infectious Diseases (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34(1):7–14CrossRefPubMed
2.
go back to reference Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS, the CLSI Subcommittee for Antifungal Testing (2011) Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat(Feb 23) Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, Motyl M, Perlin DS, the CLSI Subcommittee for Antifungal Testing (2011) Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat(Feb 23)
3.
go back to reference Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore R, Smith J, Bueid A, Moore CB, Bowyer P, Perlin DS (2011) High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis 52(9):1123–1129CrossRefPubMed Denning DW, Park S, Lass-Florl C, Fraczek MG, Kirwan M, Gore R, Smith J, Bueid A, Moore CB, Bowyer P, Perlin DS (2011) High-frequency triazole resistance found in nonculturable Aspergillus fumigatus from lungs of patients with chronic fungal disease. Clin Infect Dis 52(9):1123–1129CrossRefPubMed
4.
go back to reference Howard SJ, Arendrup MC (2011) Acquired antifungal drug resistance in Aspergillus fumigatus: epidemiology and detection. Med Mycol 49(Suppl 1):S90–S95CrossRefPubMed Howard SJ, Arendrup MC (2011) Acquired antifungal drug resistance in Aspergillus fumigatus: epidemiology and detection. Med Mycol 49(Suppl 1):S90–S95CrossRefPubMed
5.
go back to reference Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, Walsh TJ (2004) Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 190(3):641–649CrossRefPubMed Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, Walsh TJ (2004) Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 190(3):641–649CrossRefPubMed
6.
go back to reference Maertens J, Buvé K, Theunissen K, Meersseman W, Verbeken E, Verhoef G, Van Eldere J, Lagrou K (2009) Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer 115(2):355–362CrossRefPubMed Maertens J, Buvé K, Theunissen K, Meersseman W, Verbeken E, Verhoef G, Van Eldere J, Lagrou K (2009) Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer 115(2):355–362CrossRefPubMed
7.
go back to reference Hope WW, Kruhlak MJ, Lyman CA, Petraitiene R, Petraitis V, Francesconi A, Kasai M, Mickiene D, Sein T, Peter J, Kelaher AM, Hughes JE, Cotton MP, Cotten CJ, Bacher J, Tripathi S, Bermudez L, Maugel TK, Zerfas PM, Wingard JR, Drusano GL, Walsh TJ (2007) Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy. J Infect Dis 195(3):455–466CrossRefPubMed Hope WW, Kruhlak MJ, Lyman CA, Petraitiene R, Petraitis V, Francesconi A, Kasai M, Mickiene D, Sein T, Peter J, Kelaher AM, Hughes JE, Cotton MP, Cotten CJ, Bacher J, Tripathi S, Bermudez L, Maugel TK, Zerfas PM, Wingard JR, Drusano GL, Walsh TJ (2007) Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: implications for antifungal therapy. J Infect Dis 195(3):455–466CrossRefPubMed
8.
go back to reference Becker MJ, de Marie S, Willemse D, Verbrugh HA, Bakker-Woudenberg IA (2000) Quantitative galactomannan detection is superior to PCR in diagnosing and monitoring invasive pulmonary aspergillosis in an experimental rat model. J Clin Microbiol 38(4):1434–1438PubMed Becker MJ, de Marie S, Willemse D, Verbrugh HA, Bakker-Woudenberg IA (2000) Quantitative galactomannan detection is superior to PCR in diagnosing and monitoring invasive pulmonary aspergillosis in an experimental rat model. J Clin Microbiol 38(4):1434–1438PubMed
9.
go back to reference Buchheidt D, Hummel M (2005) Aspergillus polymerase chain reaction (PCR) diagnosis. Med Mycol 43(Suppl 1):S139–S145CrossRefPubMed Buchheidt D, Hummel M (2005) Aspergillus polymerase chain reaction (PCR) diagnosis. Med Mycol 43(Suppl 1):S139–S145CrossRefPubMed
10.
go back to reference Khot PD, Ko DL, Hackman RC, Fredricks DN (2008) Development and optimization of quantitative PCR for the diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. BMC Infect Dis 8:73CrossRefPubMed Khot PD, Ko DL, Hackman RC, Fredricks DN (2008) Development and optimization of quantitative PCR for the diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. BMC Infect Dis 8:73CrossRefPubMed
11.
go back to reference Vincent JL, Donatelo K, Schmidt X (2011) Biomarkers in the critically ill patient: C-reactive protein. Crit Care Clin 27:241–251CrossRefPubMed Vincent JL, Donatelo K, Schmidt X (2011) Biomarkers in the critically ill patient: C-reactive protein. Crit Care Clin 27:241–251CrossRefPubMed
12.
go back to reference Reinhard K, Meisner M (2011) Biomarkers in the critically ill patient: procalcitonin. Crit Care Clin 27:253–263CrossRef Reinhard K, Meisner M (2011) Biomarkers in the critically ill patient: procalcitonin. Crit Care Clin 27:253–263CrossRef
13.
go back to reference Ortega M, Rovira M, Filella X, Almela M, Puig de la Bellacasa J, Carreras E, Mensa J (2004) Prospective evaluation of procalcitonin in adults with febrile neutropenia after haematopoietic stem cell transplantation. Br J Haematol 126(3):372–376CrossRefPubMed Ortega M, Rovira M, Filella X, Almela M, Puig de la Bellacasa J, Carreras E, Mensa J (2004) Prospective evaluation of procalcitonin in adults with febrile neutropenia after haematopoietic stem cell transplantation. Br J Haematol 126(3):372–376CrossRefPubMed
14.
go back to reference Christofilopoulou S, Charvalos E, Petrikkos G (2002) Could procalcitonin be a predictive biological marker in systemic fungal infections? Study of 14 cases. Eur J Intern Med 13(8):493–495CrossRefPubMed Christofilopoulou S, Charvalos E, Petrikkos G (2002) Could procalcitonin be a predictive biological marker in systemic fungal infections? Study of 14 cases. Eur J Intern Med 13(8):493–495CrossRefPubMed
15.
go back to reference Petrikkos GL, Christofilopoulou SA, Tentolouris NK, Charvalos EA, Kosmidis CJ, Daikos GL (2005) Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infections. Eur J Clin Microbiol Infect Dis 24(4):272–275CrossRefPubMed Petrikkos GL, Christofilopoulou SA, Tentolouris NK, Charvalos EA, Kosmidis CJ, Daikos GL (2005) Value of measuring serum procalcitonin, C-reactive protein, and mannan antigens to distinguish fungal from bacterial infections. Eur J Clin Microbiol Infect Dis 24(4):272–275CrossRefPubMed
16.
go back to reference Charles PE, Dalle F, Aho S, Quenot JP, Doise JM, Aube H, Olsson NO, Blettery B (2006) Serum procalcitonin measurement contribution to the early diagnosis of candidemia in critically ill patients. Intensive Care Med 32(10):1577–1583CrossRefPubMed Charles PE, Dalle F, Aho S, Quenot JP, Doise JM, Aube H, Olsson NO, Blettery B (2006) Serum procalcitonin measurement contribution to the early diagnosis of candidemia in critically ill patients. Intensive Care Med 32(10):1577–1583CrossRefPubMed
17.
go back to reference Hambach L, Eder M, Dammann E, Schrauder A, Sykora KW, Dieterich C, Kirschner P, Novotny J, Ganser A, Hertenstein B (2002) Diagnostic value of procalcitonin serum levels in comparison with C-reactive protein in allogeneic stem cell transplantation. Haematologica 87(6):643–651PubMed Hambach L, Eder M, Dammann E, Schrauder A, Sykora KW, Dieterich C, Kirschner P, Novotny J, Ganser A, Hertenstein B (2002) Diagnostic value of procalcitonin serum levels in comparison with C-reactive protein in allogeneic stem cell transplantation. Haematologica 87(6):643–651PubMed
18.
go back to reference Gérard Y, Hober D, Petitjean S, Assicot M, Bohuon C, Mouton Y, Wattré P (1995) High serum procalcitonin level in a 4-year-old liver transplant recipient with a disseminated candidiasis. Infection 23(5):310–311CrossRefPubMed Gérard Y, Hober D, Petitjean S, Assicot M, Bohuon C, Mouton Y, Wattré P (1995) High serum procalcitonin level in a 4-year-old liver transplant recipient with a disseminated candidiasis. Infection 23(5):310–311CrossRefPubMed
19.
go back to reference Beaune G, Bienvenu F, Pondarré C, Monneret G, Bienvenu J, Souillet G (1998) Serum procalcitonin rise is only slight in two cases of disseminated aspergillosis. Infection 26(3):168–169CrossRefPubMed Beaune G, Bienvenu F, Pondarré C, Monneret G, Bienvenu J, Souillet G (1998) Serum procalcitonin rise is only slight in two cases of disseminated aspergillosis. Infection 26(3):168–169CrossRefPubMed
20.
go back to reference Halekoh U, Højsgaard S, Yan J (2006) The R package geepack for generalized estimating equations. J Stat Softw 15(2):1–11 Halekoh U, Højsgaard S, Yan J (2006) The R package geepack for generalized estimating equations. J Stat Softw 15(2):1–11
21.
go back to reference Siegel S, Castellan NJ (1988) Nonparametric statistics for the behavioral sciences, 2nd edn. McGraw-Hill, New York Siegel S, Castellan NJ (1988) Nonparametric statistics for the behavioral sciences, 2nd edn. McGraw-Hill, New York
22.
go back to reference Blijlevens NM, Donnelly JP, Meis JF, De Keizer MH, De Pauw BE (2000) Procalcitonin does not discriminate infection from inflammation after allogeneic bone marrow transplantation. Clin Diagn Lab Immunol 7(6):889–892PubMed Blijlevens NM, Donnelly JP, Meis JF, De Keizer MH, De Pauw BE (2000) Procalcitonin does not discriminate infection from inflammation after allogeneic bone marrow transplantation. Clin Diagn Lab Immunol 7(6):889–892PubMed
23.
go back to reference Dornbusch HJ, Strenger V, Kerbl R, Lackner H, Schwinger W, Sovinz P, Urban C (2005) Procalcitonin—a marker of invasive fungal infection? Support Care Cancer 13(5):343–346CrossRefPubMed Dornbusch HJ, Strenger V, Kerbl R, Lackner H, Schwinger W, Sovinz P, Urban C (2005) Procalcitonin—a marker of invasive fungal infection? Support Care Cancer 13(5):343–346CrossRefPubMed
24.
go back to reference Martini A, Gottin L, Menestrina N, Schweiger V, Simion D, Vincent JL (2010) Procalcitonin levels in surgical patients at risk of candidemia. J Infect 60(6):425–430CrossRefPubMed Martini A, Gottin L, Menestrina N, Schweiger V, Simion D, Vincent JL (2010) Procalcitonin levels in surgical patients at risk of candidemia. J Infect 60(6):425–430CrossRefPubMed
25.
go back to reference Montagna MT, Coretti C, Caggiano G (2011) Procalcitonin: a possible marker of invasive fungal infection in high risk patients? J Prev Med Hyg 52(1):38–39PubMed Montagna MT, Coretti C, Caggiano G (2011) Procalcitonin: a possible marker of invasive fungal infection in high risk patients? J Prev Med Hyg 52(1):38–39PubMed
26.
go back to reference Charles PE, Tinel C, Barbar S, Aho S, Prin S, Doise JM, Olsson NO, Blettery B, Quenot JP (2009) Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome. Crit Care 13(2):R38CrossRefPubMed Charles PE, Tinel C, Barbar S, Aho S, Prin S, Doise JM, Olsson NO, Blettery B, Quenot JP (2009) Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome. Crit Care 13(2):R38CrossRefPubMed
27.
go back to reference Suberviola B, Castellanos-Ortega A, González-Castro A, García-Astudillo LA, Fernández-Miret B (2012) Prognostic value of procalcitonin, C-reactive protein and leukocytes in septic shock. Med Intensiva 36(3):177–184CrossRefPubMed Suberviola B, Castellanos-Ortega A, González-Castro A, García-Astudillo LA, Fernández-Miret B (2012) Prognostic value of procalcitonin, C-reactive protein and leukocytes in septic shock. Med Intensiva 36(3):177–184CrossRefPubMed
28.
go back to reference Simon L, Gauvin F, Saint Louis P, Lacroix J (2004) Serum procalcitonin and C-reactive levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 39:206–217CrossRefPubMed Simon L, Gauvin F, Saint Louis P, Lacroix J (2004) Serum procalcitonin and C-reactive levels as markers of bacterial infection: a systematic review and meta-analysis. Clin Infect Dis 39:206–217CrossRefPubMed
29.
go back to reference Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C (1993) High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341(8844):515–518CrossRefPubMed Assicot M, Gendrel D, Carsin H, Raymond J, Guilbaud J, Bohuon C (1993) High serum procalcitonin concentrations in patients with sepsis and infection. Lancet 341(8844):515–518CrossRefPubMed
30.
go back to reference Becker KL, Snider R, Nylen ES (2008) Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 36(3):941–952CrossRefPubMed Becker KL, Snider R, Nylen ES (2008) Procalcitonin assay in systemic inflammation, infection, and sepsis: clinical utility and limitations. Crit Care Med 36(3):941–952CrossRefPubMed
31.
go back to reference Schuetz P, Christ-Crain M, Müller B (2007) Biomarkers to improve diagnostic and prognostic accuracy in systemic infections. Curr Opin Crit Care 13(5):578–585CrossRefPubMed Schuetz P, Christ-Crain M, Müller B (2007) Biomarkers to improve diagnostic and prognostic accuracy in systemic infections. Curr Opin Crit Care 13(5):578–585CrossRefPubMed
32.
go back to reference Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B, ProHOSP Study Group (2009) Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 302(10):1059–1066CrossRefPubMed Schuetz P, Christ-Crain M, Thomann R, Falconnier C, Wolbers M, Widmer I, Neidert S, Fricker T, Blum C, Schild U, Regez K, Schoenenberger R, Henzen C, Bregenzer T, Hoess C, Krause M, Bucher HC, Zimmerli W, Mueller B, ProHOSP Study Group (2009) Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 302(10):1059–1066CrossRefPubMed
33.
go back to reference Tang H, Huang T, Jing J, Shen H, Cui W (2009) Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection 37(6):497–507CrossRefPubMed Tang H, Huang T, Jing J, Shen H, Cui W (2009) Effect of procalcitonin-guided treatment in patients with infections: a systematic review and meta-analysis. Infection 37(6):497–507CrossRefPubMed
34.
go back to reference Bucova M, Zahorec R, Buc M (2006) Immunomodulatory effect of recombinant human procalcitonin on mitogenic activity of lymphocytes. Cent Eur J Immunol 31(3–4):87–93 Bucova M, Zahorec R, Buc M (2006) Immunomodulatory effect of recombinant human procalcitonin on mitogenic activity of lymphocytes. Cent Eur J Immunol 31(3–4):87–93
35.
go back to reference Wei JX, Verity A, Garle M, Mahajan R, Wilson V (2008) Examination of the effect of procalcitonin on human leucocytes and the porcine isolated coronary artery. Br J Anaesth 100(5):612–621CrossRefPubMed Wei JX, Verity A, Garle M, Mahajan R, Wilson V (2008) Examination of the effect of procalcitonin on human leucocytes and the porcine isolated coronary artery. Br J Anaesth 100(5):612–621CrossRefPubMed
36.
go back to reference Liappis AP, Gibbs KW, Nylen ES, Yoon B, Snider RH, Gao B, Becker KL (2011) Exogenous procalcitonin evokes a pro-inflammatory cytokine response. Inflamm Res 60(2):203–207CrossRefPubMed Liappis AP, Gibbs KW, Nylen ES, Yoon B, Snider RH, Gao B, Becker KL (2011) Exogenous procalcitonin evokes a pro-inflammatory cytokine response. Inflamm Res 60(2):203–207CrossRefPubMed
37.
go back to reference Hoffmann G, Czechowski M, Schloesser M, Schobersberger W (2002) Procalcitonin amplifies inducible nitric oxide synthase gene expression and nitric oxide production in vascular smooth muscle cells. Crit Care Med 30(9):2091–2095CrossRefPubMed Hoffmann G, Czechowski M, Schloesser M, Schobersberger W (2002) Procalcitonin amplifies inducible nitric oxide synthase gene expression and nitric oxide production in vascular smooth muscle cells. Crit Care Med 30(9):2091–2095CrossRefPubMed
38.
go back to reference Becker KL, Nylén ES, Snider RH, Müller B, White JC (2003) Immunoneutralization of procalcitonin as therapy of sepsis. J Endotoxin Res 9(6):367–374PubMed Becker KL, Nylén ES, Snider RH, Müller B, White JC (2003) Immunoneutralization of procalcitonin as therapy of sepsis. J Endotoxin Res 9(6):367–374PubMed
Metadata
Title
Substantially elevated C-reactive protein (CRP), together with low levels of procalcitonin (PCT), contributes to diagnosis of fungal infection in immunocompromised patients
Authors
Markéta Marková
Helena Brodská
Karin Malíčková
Veronika Válková
Petr Cetkovský
Michal Kolář
Martin Haluzík
Publication date
01-10-2013
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 10/2013
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-013-1844-1

Other articles of this Issue 10/2013

Supportive Care in Cancer 10/2013 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine