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Overview of neutropenic fever syndromes

Eric Bow, MD
John R Wingard, MD
Section Editor
Carol A Kauffman, MD
Deputy Editor
Anna R Thorner, MD


Cancer patients receiving cytotoxic antineoplastic therapy sufficient to adversely affect myelopoiesis and the developmental integrity of the gastrointestinal mucosa are at risk for invasive infection due to colonizing bacteria and/or fungi that translocate across intestinal mucosal surfaces. Since the magnitude of the neutrophil-mediated component of the inflammatory response may be muted in neutropenic patients [1], a fever may be the earliest and only sign of infection. It is critical to recognize neutropenic fever early and to initiate empiric systemic antibacterial therapy promptly in order to avoid progression to a sepsis syndrome and possibly death.

This topic will provide an overview of the concepts related to neutropenic fever, including definitions of fever and neutropenia and categories of risk. The risk assessment and diagnostic approach to patients presenting with neutropenic fever are discussed in detail separately. The management of neutropenic fever syndromes in cancer patients at high and low risk for complications and the prophylaxis of infections in such patients are also discussed in detail separately. Granulocyte transfusions are also reviewed elsewhere. (See "Risk assessment of adults with chemotherapy-induced neutropenia" and "Diagnostic approach to the adult cancer patient with neutropenic fever" and "Treatment of neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)" and "Treatment and prevention of neutropenic fever syndromes in adult cancer patients at low risk for complications" and "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients" and "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation" and "Granulocyte transfusions".)


Guidelines have been developed for the evaluation and management of fever in neutropenic patients with cancer [2,3]. The recommendations below are generally in keeping with the 2010 Infectious Diseases Society of America (IDSA) guidelines [2] and the 2013 American Society of Clinical Oncology (ASCO) guidelines [4]. (See 'Society guideline links' below.)


Fever — The definition of fever as an indicator of infection in neutropenic patients has varied. In 1868, Carl Wunderlich proposed that the mean normal body temperature was 37°C (98.6°F) with an upper limit of normal of 38°C (100.4°F), above which fever was defined [5-7]. Despite the observation that there is a range of normal body temperatures, in one survey, a majority (75 percent) of 270 medical professionals reported the belief that normal body temperature is 37°C (98.6°F) [7,8]. A survey of members of the British Society for Haematology regarding their institutional definitions of fever identified 10 definitions of fever, ranging from a single temperature >37.5°C to either a single temperature >39°C or two successive temperatures >38.4°C [9]. These beliefs notwithstanding, the empirically observed mean oral temperature of 148 healthy adults between ages 18 and 40 years was reported as 36.8±0.4°C (98.2±0.7°F) with a range of 35.6°C (96.0°F) to 38.2°C (100.8°F), the latter defining the upper limit of normal [6].

The Infectious Diseases Society of America defines fever in neutropenic patients as a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period [2]. We agree with using this definition of fever in neutropenic patients. Similar definitions have been provided from South America, Europe, and Asia [10-12].

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Literature review current through: Nov 2017. | This topic last updated: Oct 09, 2017.
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  1. Sickles EA, Greene WH, Wiernik PH. Clinical presentation of infection in granulocytopenic patients. Arch Intern Med 1975; 135:715.
  2. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 2011; 52:e56.
  3. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and treatment of cancer-related infections. Version 2.2014. http://www.nccn.org (Accessed on November 06, 2014).
  4. Flowers CR, Seidenfeld J, Bow EJ, et al. Antimicrobial prophylaxis and outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2013; 31:794.
  5. Wunderlich CA, Seguin E. Medical thermometry and human temperature, William Wood & Co, New York 1871.
  6. Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA 1992; 268:1578.
  7. Davie A, Amoore J. Best practice in the measurement of body temperature. Nurs Stand 2010; 24:42.
  8. Mackowiak PA, Wasserman SS. Physicians' perceptions regarding body temperature in health and disease. South Med J 1995; 88:934.
  9. Clarke RT, Warnick J, Stretton K, Littlewood TJ. Improving the immediate management of neutropenic sepsis in the UK: lessons from a national audit. Br J Haematol 2011; 153:773.
  10. Santolaya ME, Rabagliati R, Bidart T, et al. [Consensus: Rational approach towards the patient with cancer, fever and neutropenia]. Rev Chilena Infectol 2005; 22 Suppl 2:S79.
  11. Link H, Böhme A, Cornely OA, et al. Antimicrobial therapy of unexplained fever in neutropenic patients--guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO), Study Group Interventional Therapy of Unexplained Fever, Arbeitsgemeinschaft Supportivmassnahmen in der Onkologie (ASO) of the Deutsche Krebsgesellschaft (DKG-German Cancer Society). Ann Hematol 2003; 82 Suppl 2:S105.
  12. Jun HX, Zhixiang S, Chun W, et al. Clinical guidelines for the management of cancer patients with neutropenia and unexplained fever. Int J Antimicrob Agents 2005; 26 Suppl 2:S128.
  13. Willies GH, Woolf CJ. The site of action of corticosteroid antipyresis in the rabbit. J Physiol 1980; 300:1.
  14. Egi M, Morita K. Fever in non-neurological critically ill patients: a systematic review of observational studies. J Crit Care 2012; 27:428.
  15. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common terminology criteria for adverse events (CTCAE). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed on February 16, 2012).
  16. From the Immunocompromised Host Society. The design, analysis, and reporting of clinical trials on the empirical antibiotic management of the neutropenic patient. Report of a consensus panel. J Infect Dis 1990; 161:397.
  17. Bow EJ. Neutropenic fever syndromes in patients undergoing cytotoxic therapy for acute leukemia and myelodysplastic syndromes. Semin Hematol 2009; 46:259.
  18. Klastersky J, Paesmans M, Rubenstein EB, et al. The Multinational Association for Supportive Care in Cancer risk index: A multinational scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000; 18:3038.
  19. Dzarr AA, Kamal M, Baba AA. A comparison between infrared tympanic thermometry, oral and axilla with rectal thermometry in neutropenic adults. Eur J Oncol Nurs 2009; 13:250.
  20. Ciuraru NB, Braunstein R, Sulkes A, Stemmer SM. The influence of mucositis on oral thermometry: when fever may not reflect infection. Clin Infect Dis 2008; 46:1859.
  21. Niven DJ, Gaudet JE, Laupland KB, et al. Accuracy of peripheral thermometers for estimating temperature: a systematic review and meta-analysis. Ann Intern Med 2015; 163:768.
  22. Farnell S, Maxwell L, Tan S, et al. Temperature measurement: comparison of non-invasive methods used in adult critical care. J Clin Nurs 2005; 14:632.
  23. Fulbrook P. Core body temperature measurement: a comparison of axilla, tympanic membrane and pulmonary artery blood temperature. Intensive Crit Care Nurs 1997; 13:266.
  24. Doezema D, Lunt M, Tandberg D. Cerumen occlusion lowers infrared tympanic membrane temperature measurement. Acad Emerg Med 1995; 2:17.
  25. O'Toole S. Alternatives to mercury thermometers. Prof Nurse 1997; 12:783.
  26. Fisk J, Arcona S. Tympanic membrane vs. pulmonary artery thermometry. Nurs Manage 2001; 32:42, 45.
  27. Jevon P, Jevon M. Using a tympanic thermometer. Nurs Times 2001; 97:43.
  28. Erickson RS, Meyer LT, Woo TM. Accuracy of chemical dot thermometers in critically ill adults and young children. Image J Nurs Sch 1996; 28:23.
  29. Safdar A, Armstrong D. Infections in patients with hematologic neoplasms and hematopoietic stem cell transplantation: neutropenia, humoral, and splenic defects. Clin Infect Dis 2011; 53:798.
  30. Hübel K, Hegener K, Schnell R, et al. Suppressed neutrophil function as a risk factor for severe infection after cytotoxic chemotherapy in patients with acute nonlymphocytic leukemia. Ann Hematol 1999; 78:73.
  31. Pizzo PA. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 328:1323.
  32. Schimpff SC, Young VM, Greene WH, et al. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens. Ann Intern Med 1972; 77:707.
  33. Bodey GP, Jadeja L, Elting L. Pseudomonas bacteremia. Retrospective analysis of 410 episodes. Arch Intern Med 1985; 145:1621.
  34. Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36:1103.
  35. Holland T, Fowler VG Jr, Shelburne SA 3rd. Invasive gram-positive bacterial infection in cancer patients. Clin Infect Dis 2014; 59 Suppl 5:S331.
  36. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer 2005; 103:1103.
  37. Raad I, Chaftari AM. Advances in prevention and management of central line-associated bloodstream infections in patients with cancer. Clin Infect Dis 2014; 59 Suppl 5:S340.
  38. Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients. Clin Microbiol Infect 2013; 19:474.
  39. Montassier E, Batard E, Gastinne T, et al. Recent changes in bacteremia in patients with cancer: a systematic review of epidemiology and antibiotic resistance. Eur J Clin Microbiol Infect Dis 2013; 32:841.
  40. Trecarichi EM, Tumbarello M. Antimicrobial-resistant Gram-negative bacteria in febrile neutropenic patients with cancer: current epidemiology and clinical impact. Curr Opin Infect Dis 2014; 27:200.
  41. Perez F, Adachi J, Bonomo RA. Antibiotic-resistant gram-negative bacterial infections in patients with cancer. Clin Infect Dis 2014; 59 Suppl 5:S335.
  42. Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias among adult and paediatric haematology and cancer patients. J Infect 2014; 68:321.
  43. Pagano L, Caira M, Nosari A, et al. Etiology of febrile episodes in patients with acute myeloid leukemia: results from the Hema e-Chart Registry. Arch Intern Med 2011; 171:1502.
  44. Morris PG, Hassan T, McNamara M, et al. Emergence of MRSA in positive blood cultures from patients with febrile neutropenia--a cause for concern. Support Care Cancer 2008; 16:1085.
  45. Gardner A, Mattiuzzi G, Faderl S, et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol 2008; 26:5684.
  46. Cho SY, Choi HY. Opportunistic fungal infection among cancer patients. A ten-year autopsy study. Am J Clin Pathol 1979; 72:617.
  47. Bow EJ, Meddings JB. Intestinal mucosal dysfunction and infection during remission-induction therapy for acute myeloid leukaemia. Leukemia 2006; 20:2087.
  48. Saral R, Ambinder RF, Burns WH, et al. Acyclovir prophylaxis against herpes simplex virus infection in patients with leukemia. A randomized, double-blind, placebo-controlled study. Ann Intern Med 1983; 99:773.
  49. Saral R, Burns WH, Laskin OL, et al. Acyclovir prophylaxis of herpes-simplex-virus infections. N Engl J Med 1981; 305:63.
  50. Lee HS, Park JY, Shin SH, et al. Herpesviridae viral infections after chemotherapy without antiviral prophylaxis in patients with malignant lymphoma: incidence and risk factors. Am J Clin Oncol 2012; 35:146.
  51. Bell MS, Scullen P, McParlan D, et al. Neutropenic sepsis guidelines. Northern Ireland Cancer Network, Belfast 2010. p. 1-11.
  52. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296.
  53. Chemotherapy services in England: Ensuring quality and safety. National Chemotherapy Advisory Group, London 2009.
  54. Rosa RG, Goldani LZ. Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother 2014; 58:3799.
  55. Schimpff S, Satterlee W, Young VM, Serpick A. Empiric therapy with carbenicillin and gentamicin for febrile patients with cancer and granulocytopenia. N Engl J Med 1971; 284:1061.
  56. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589.
  57. Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045.
  58. Zuckermann J, Moreira LB, Stoll P, et al. Compliance with a critical pathway for the management of febrile neutropenia and impact on clinical outcomes. Ann Hematol 2008; 87:139.
  59. Lynn JJ, Chen KF, Weng YM, Chiu TF. Risk factors associated with complications in patients with chemotherapy-induced febrile neutropenia in emergency department. Hematol Oncol 2013; 31:189.
  60. Wright JD, Neugut AI, Ananth CV, et al. Deviations from guideline-based therapy for febrile neutropenia in cancer patients and their effect on outcomes. JAMA Intern Med 2013; 173:559.
  61. Ko BS, Ahn S, Lee YS, et al. Impact of time to antibiotics on outcomes of chemotherapy-induced febrile neutropenia. Support Care Cancer 2015; 23:2799.
  62. Cohen MA, Lewis GM. Neurotropenic fever. J Emerg Med 2006; 31:227.
  63. André S, Taboulet P, Elie C, et al. Febrile neutropenia in French emergency departments: results of a prospective multicentre survey. Crit Care 2010; 14:R68.
  64. Courtney DM, Aldeen AZ, Gorman SM, et al. Cancer-associated neutropenic fever: clinical outcome and economic costs of emergency department care. Oncologist 2007; 12:1019.
  65. Schimpff SC, Gaya H, Klastersky J, et al. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. The EORTC international antimicrobial therapy project group. J Infect Dis 1978; 137:14.
  66. Cullen M, Steven N, Billingham L, et al. Antibacterial prophylaxis after chemotherapy for solid tumors and lymphomas. N Engl J Med 2005; 353:988.
  67. Nirenberg A, Mulhearn L, Lin S, Larson E. Emergency department waiting times for patients with cancer with febrile neutropenia: a pilot study. Oncol Nurs Forum 2004; 31:711.
  68. Richardson S, Pallot D, Hughes T, Littlewood T. Improving management of neutropenic sepsis in the emergency department. Br J Haematol 2009; 144:617.
  69. Amado VM, Vilela GP, Queiroz A Jr, Amaral AC. Effect of a quality improvement intervention to decrease delays in antibiotic delivery in pediatric febrile neutropenia: a pilot study. J Crit Care 2011; 26:103.e9.
  70. Okera M, Chan S, Dernede U, et al. A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network. Interpretation of study results in light of NCAG/NCEPOD findings. Br J Cancer 2011; 104:407.
  71. Keng MK, Thallner EA, Elson P, et al. Reducing Time to Antibiotic Administration for Febrile Neutropenia in the Emergency Department. J Oncol Pract 2015; 11:450.
  72. Lim C, Bawden J, Wing A, et al. Febrile neutropenia in EDs: the role of an electronic clinical practice guideline. Am J Emerg Med 2012; 30:5.
  73. McKenzie H, Hayes L, White K, et al. Chemotherapy outpatients' unplanned presentations to hospital: a retrospective study. Support Care Cancer 2011; 19:963.
  74. Sepkowitz KA. Treatment of patients with hematologic neoplasm, fever, and neutropenia. Clin Infect Dis 2005; 40 Suppl 4:S253.