Febrile Neutropenia

  • Blanca E. Gonzalez
  • Linda S. Cabral
  • Jeffery J. AulettaEmail author
Part of the Pediatric Oncology book series (PEDIATRICO)


Febrile neutropenia (FN) is a common, potentially life-threatening complication in pediatric oncology patients due to deficiencies in both innate and adaptive immunity usually secondary to treatment of the underlying malignancy. Although a majority of oncology patients experience FN, large randomized controlled trials to determine appropriate management strategies in pediatric FN are lacking and much of the decision-making process is based on extrapolation of adult guidelines, consensus pediatric guidelines, and institutional protocols. Here we review the relevant literature focusing on available models for risk stratification, appropriate diagnostic evaluations, applicable empiric therapies as well as proper location, timing, and duration of such therapies.


Febrile Neutropenia Absolute Neutrophil Count Invasive Fungal Infection Peripherally Insert Central Catheter Empiric Antimicrobial Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Advani S, Reich NG, Sengupta A et al (2011) Central line-associated bloodstream infection in hospitalized children with peripherally inserted central venous catheters: extending risk analyses outside the intensive care unit. Clin Infect Dis 52:1108–1115PubMedCentralPubMedGoogle Scholar
  2. Agrawal AK, Saini N, Gildengorin G et al (2011) Is routine computed tomographic scanning justified in the first week of persistent febrile neutropenia in children with malignancies? Pediatr Blood Cancer 57:620–624PubMedGoogle Scholar
  3. Aledo A, Heller G, Ren L et al (1998) Septicemia and septic shock in pediatric patients: 140 consecutive cases on a pediatric hematology-oncology service. J Pediatr Hematol Oncol 20:215–221PubMedGoogle Scholar
  4. Ammann RA, Bodner N, Hirt A et al (2010) Predicting adverse events in children with fever and chemotherapy-induced neutropenia: the prospective multicenter SPOG 2003 FN study. J Clin Oncol 28:2008–2014PubMedGoogle Scholar
  5. Aquino VM, Tkaczewski I, Buchanan GR (1997) Early discharge of low-risk febrile neutropenic children and adolescents with cancer. Clin Infect Dis 25:74–78PubMedGoogle Scholar
  6. Aquino VM, Herrera L, Sandler ES et al (2000) Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer. Cancer 88:1710–1714PubMedGoogle Scholar
  7. Archibald S, Park J, Geyer JR et al (2001) Computed tomography in the evaluation of febrile neutropenic pediatric oncology patients. Pediatr Infect Dis J 20:5–10PubMedGoogle Scholar
  8. Ariffin H, Navaratnam P, Mohamed M et al (2000) Ceftazidime-resistant Klebsiella pneumoniae bloodstream infection in children with febrile neutropenia. Int J Infect Dis 4:21–25PubMedGoogle Scholar
  9. Auletta JJ, O’Riordan MA, Nieder ML (1999) Infections in children with cancer: a continued need for the comprehensive physical examination. J Pediatr Hematol Oncol 21:501–508PubMedGoogle Scholar
  10. Azoulay E, Schlemmer B (2006) Diagnostic strategy in cancer patients with acute respiratory failure. Intensive Care Med 32:808–822PubMedGoogle Scholar
  11. Badiei Z, Khalesi M, Alami MH et al (2011) Risk factors associated with life-threatening infections in children with febrile neutropenia: a data mining approach. J Pediatr Hematol Oncol 33:e9–e12PubMedGoogle Scholar
  12. Bakhshi S, Padmanjali KS, Arya LS (2008) Infections in childhood acute lymphoblastic leukemia: an analysis of 222 febrile neutropenic episodes. Pediatr Hematol Oncol 25:385–392PubMedGoogle Scholar
  13. Baorto EP, Aquino VM, Mullen CA et al (2001) Clinical parameters associated with low bacteremia risk in 1100 pediatric oncology patients with fever and neutropenia. Cancer 92:909–913PubMedGoogle Scholar
  14. Blyth CC (2011) Antifungal azoles: old and new. Pediatr Infect Dis J 30:506–507PubMedGoogle Scholar
  15. Boragina M, Patel H, Reiter S et al (2007) Management of febrile neutropenia in pediatric oncology patients: a Canadian survey. Pediatr Blood Cancer 48:521–526PubMedGoogle Scholar
  16. Brack E, Bodmer N, Simon A et al (2012) First-day step-down to oral outpatient treatment versus continued standard treatment in children with cancer and low-risk fever in neutropenia. A randomized controlled trial within the multicenter SPOG 2003 FN study. Pediatr Blood Cancer 59:423–430PubMedGoogle Scholar
  17. Burgos A, Zaoutis TE, Dvorak CC et al (2008) Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics 121:e1286–e1294PubMedGoogle Scholar
  18. Burry E, Punnett A, Mehta A et al (2012) Identification of educational and infrastructural barriers to prompt antibiotic delivery in febrile neutropenia: a quality improvement initiative. Pediatr Blood Cancer 59:431–435PubMedGoogle Scholar
  19. Carraro F, Cicalese MP, Cesaro S et al (2013) Guidelines for the use of long-term central venous catheter in children with hemato-oncological disorders. On behalf of supportive therapy working group of Italian Association of Pediatric Hematology and Oncology (AIEOP). Ann Hematol 92:1405–1412PubMedGoogle Scholar
  20. Caselli D, Cesaro S, Ziino O et al (2012) A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children. Br J Haematol 148:249–255Google Scholar
  21. Castagnola E, Cesaro S, Giacchino M et al (2006) Fungal infections in children with cancer: a prospective, multicenter surveillance study. Pediatr Infect Dis J 25:634–639PubMedGoogle Scholar
  22. Castagnola E, Fontana V, Caviglia I et al (2007) A prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hemopoietic stem cell transplantation. Clin Infect Dis 45:1296–1304PubMedGoogle Scholar
  23. Castagnola E, Furfaro E, Caviglia I et al (2010) Performance of the galactomannan antigen detection test in the diagnosis of invasive aspergillosis in children with cancer or undergoing haemopoietic stem cell transplantation. Clin Microbiol Infect 16:1197–1203PubMedGoogle Scholar
  24. Cheng S, Teuffel O, Ethier MC et al (2011) Health-related quality of life anticipated with different management strategies for paediatric febrile neutropaenia. Br J Cancer 105:606–611PubMedCentralPubMedGoogle Scholar
  25. Chisholm JC, Dommett R (2006) The evolution towards ambulatory and day-case management of febrile neutropenia. Br J Haematol 135:3–16PubMedGoogle Scholar
  26. Connell TG, Rele M, Cowley D et al (2007) How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children’s hospital. Pediatrics 119:891–896PubMedGoogle Scholar
  27. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV et al (2004) Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 114:e111–e118PubMedGoogle Scholar
  28. Cordonnier C, Pautas C, Maury S et al (2009) Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 48:1042–1051PubMedGoogle Scholar
  29. Del Bono V, Mularoni A, Furfaro E et al (2009) Clinical evaluation of a (1,3)-beta-D-glucan assay for presumptive diagnosis of Pneumocystis jiroveci pneumonia in immunocompromised patients. Clin Vaccine Immunol 16:1524–1526PubMedCentralPubMedGoogle Scholar
  30. Dommett R, Geary J, Freeman S et al (2009) Successful introduction and audit of a step-down oral antibiotic strategy for low risk paediatric febrile neutropaenia in a UK, multicentre, shared care setting. Eur J Cancer 45:2843–2849PubMedGoogle Scholar
  31. Duncan C, Chisholm JC, Freeman S et al (2007) A prospective study of admissions for febrile neutropenia in secondary paediatric units in South East England. Pediatr Blood Cancer 49:678–681PubMedGoogle Scholar
  32. Efrati O, Gonik U, Bielorai B et al (2007) Fiberoptic bronchoscopy and bronchoalveolar lavage for the evaluation of pulmonary disease in children with primary immunodeficiency and cancer. Pediatr Blood Cancer 48:324–329PubMedGoogle Scholar
  33. El-Mahallawy HA, El-Wakil M, Moneer MM et al (2011) Antibiotic resistance is associated with longer bacteremic episodes and worse outcome in febrile neutropenic children with cancer. Pediatr Blood Cancer 57:283–288PubMedGoogle Scholar
  34. Everett ED, Pearson S, Rogers W (1979) Rhizopus surgical wound infection with elasticized adhesive tape dressings. Arch Surg 114:738–739PubMedGoogle Scholar
  35. Feusner J, Cohen R, O’Leary M et al (1988) Use of routine chest radiography in the evaluation of fever in neutropenic pediatric oncology patients. J Clin Oncol 6:1699–1702PubMedGoogle Scholar
  36. Fisher BT, Zaoutis TE, Leckerman KH et al (2010) Risk factors for renal failure in pediatric patients with acute myeloid leukemia: a retrospective cohort study. Pediatr Blood Cancer 55:655–661PubMedCentralPubMedGoogle Scholar
  37. Fisher BT, Zaoutis TE, Park JR et al (2012) Galactomannan antigen testing for diagnosis of invasive Aspergillosis in pediatric hematology patients. J Pediatr Infect Dis 1:116–124Google Scholar
  38. Flynn PM (2009) Diagnosis and management of central venous catheter-related bloodstream infections in pediatric patients. Pediatr Infect Dis J 28:1016–1017PubMedGoogle Scholar
  39. Fortun J, Grill F, Martin-Davila P et al (2006) Treatment of long-term intravascular catheter-related bacteraemia with antibiotic-lock therapy. J Antimicrob Chemother 58:816–821PubMedGoogle Scholar
  40. Freifeld AG, Bow EJ, Sepkowitz KA et al (2011) 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 52:e56–e93PubMedGoogle Scholar
  41. Furno P, Bucaneve G, Del Favero A (2002) Monotherapy or aminoglycoside-containing combinations for empirical antibiotic treatment of febrile neutropenic patients: a meta-analysis. Lancet Infect Dis 2:231–242PubMedGoogle Scholar
  42. Gassas A, Grant R, Richardson S et al (2004) Predictors of viridans streptococcal shock syndrome in bacteremic children with cancer and stem-cell transplant recipients. J Clin Oncol 22:1222–1227PubMedGoogle Scholar
  43. Gaur AH, Flynn PM, Giannini MA et al (2003) Difference in time to detection: a simple method to differentiate catheter-related from non-catheter-related bloodstream infection in immunocompromised pediatric patients. Clin Infect Dis 37:469–475PubMedGoogle Scholar
  44. Gaur AH, Flynn PM, Heine DJ (2005) Diagnosis of catheter-related bloodstream infections among pediatric oncology patients lacking a peripheral culture, using differential time to detection. Pediatr Infect Dis J 24:445–449PubMedGoogle Scholar
  45. Gibson F, Chisholm J, Blandford E et al (2013) Developing a national ‘low-risk’ febrile neutropenia framework for use in children and young people’s cancer care. Support Care Cancer 21:1241–1251PubMedGoogle Scholar
  46. Ginocchio F, Verrina E, Furfaro E et al (2012) Case report of the reliability 1,3-beta-D-glucan monitoring during treatment of peritoneal candidiasis in a child receiving continuous peritoneal dialysis. Clin Vaccine Immunol 19:626–627PubMedCentralPubMedGoogle Scholar
  47. Glotzbecker B, Duncan C, Alyea E 3rd et al (2012) Important drug interactions in hematopoietic stem cell transplantation: what every physician should know. Biol Blood Marrow Transplant 18:989–1006PubMedGoogle Scholar
  48. Goldberg E, Gafter-Gvili A, Robenshtok E et al (2008) Empirical antifungal therapy for patients with neutropenia and persistent fever: systematic review and meta-analysis. Eur J Cancer 44:2192–2203PubMedGoogle Scholar
  49. Gonzalez BE, Faverio LA, Marty FM et al (2011) Elevated serum beta-D-glucan levels in immunocompromised children with clinical suspicion for Pneumocystis jirovecii pneumonia. Clin Vaccine Immunol 18:1202–1203PubMedCentralPubMedGoogle Scholar
  50. Gøtzsche PC, Johansen HK (2002) Routine versus selective antifungal administration for control of fungal infections in patients with cancer. Cochrane Database Syst Rev (2):CD000026Google Scholar
  51. Greenberg D, Moser A, Yagupsky P et al (2005) Microbiological spectrum and susceptibility patterns of pathogens causing bacteraemia in paediatric febrile neutropenic oncology patients: comparison between two consecutive time periods with use of different antibiotic treatment protocols. Int J Antimicrob Agents 25:469–473PubMedGoogle Scholar
  52. Groll AH, Kurz M, Schneider W et al (1999) Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses 42:431–442PubMedGoogle Scholar
  53. Groll AH, Castagnola E, Cesaro S et al (2014) Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation. Lancet Oncol 15:e327–e340Google Scholar
  54. Guy SD, Tramontana AR, Worth LJ et al (2012) Use of FDG PET/CT for investigation of febrile neutropenia: evaluation in high-risk cancer patients. Eur J Nucl Med Mol Imaging 39:1348–1355PubMedGoogle Scholar
  55. Guyatt G, Gutterman D, Baumann MH et al (2006) Grading strength of recommendations and quality of evidence in clinical guidelines: report from an American College of Chest Physicians task force. Chest 129:174–181PubMedGoogle Scholar
  56. Hann I, Viscoli C, Paesmans M et al (1997) A comparison of outcome from febrile neutropenic episodes in children compared with adults: results from four EORTC studies. International Antimicrobial Therapy Cooperative Group (IATCG) of the European Organization for Research and Treatment of Cancer (EORTC). Br J Haematol 99:580–588PubMedGoogle Scholar
  57. Haroon A, Zumla A, Bomanji J (2012) Role of fluorine 18 fluorodeoxyglucose positron emission tomography-computed tomography in focal and generalized infectious and inflammatory disorders. Clin Infect Dis 54:1333–1341PubMedGoogle Scholar
  58. Härtel C, Deuster M, Lehrnbecher T et al (2007) Current approaches for risk stratification of infectious complications in pediatric oncology. Pediatr Blood Cancer 49:767–773PubMedGoogle Scholar
  59. Hennequin C, Ranaivoarimalala C, Chouaki T et al (2002) Comparison of aerobic standard medium with specific fungal medium for detecting fusarium spp in blood cultures. Eur J Clin Microbiol Infect Dis 21:748–750PubMedGoogle Scholar
  60. Heussel CP (2011) Importance of pulmonary imaging diagnostics in the management of febrile neutropenic patients. Mycoses 54(Suppl 1):17–26PubMedGoogle Scholar
  61. Ho DY, Lin M, Schaenman J et al (2011) Yield of diagnostic procedures for invasive fungal infections in neutropenic febrile patients with chest computed tomography abnormalities. Mycoses 54:59–70PubMedCentralPubMedGoogle Scholar
  62. Hodgson-Viden H, Grundy PE, Robinson JL (2005) Early discontinuation of intravenous antimicrobial therapy in pediatric oncology patients with febrile neutropenia. BMC Pediatr 5:10PubMedCentralPubMedGoogle Scholar
  63. Jaijakul S, Vazquez JA, Swanson RN et al (2012) (1,3)-beta-D-Glucan as a prognostic marker of treatment response in invasive candidiasis. Clin Infect Dis 55:521–526PubMedGoogle Scholar
  64. Jain P, Sandur S, Meli Y et al (2004) Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates. Chest 125:712–722PubMedGoogle Scholar
  65. Jiancheng W, Minjun H, Yi-jun A et al (2009) Screening Pneumocystis carinii pneumonia in non-HIV-infected immunocompromised patients using polymerase chain reaction. Diagn Microbiol Infect Dis 64:396–401PubMedGoogle Scholar
  66. Johansen HK, Gøtzsche PC (2000) Amphotericin B lipid soluble formulations versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev (3):CD000969Google Scholar
  67. Jørgensen KJ, Gøtzsche PC, Johansen HK (2006) Voriconazole versus amphotericin B in cancer patients with neutropenia. Cochrane Database Syst Rev (1):CD004704Google Scholar
  68. Kalil AC (2011) Is cefepime safe for clinical use? A Bayesian viewpoint. J Antimicrob Chemother 66:1207–1209PubMedGoogle Scholar
  69. Karageorgopoulos DE, Vouloumanou EK, Ntziora F et al (2011) Beta-D-glucan assay for the diagnosis of invasive fungal infections: a meta-analysis. Clin Infect Dis 52:750–770PubMedGoogle Scholar
  70. Kim PW, Wu YT, Cooper C et al (2010) Meta-analysis of a possible signal of increased mortality associated with cefepime use. Clin Infect Dis 51:381–389PubMedGoogle Scholar
  71. Kim A, Nicolau DP, Kuti JL (2011) Hospital costs and outcomes among intravenous antifungal therapies for patients with invasive aspergillosis in the United States. Mycoses 54:e301–e312PubMedGoogle Scholar
  72. Klaassen RJ, Goodman TR, Pham B et al (2000) “Low-risk” prediction rule for pediatric oncology patients presenting with fever and neutropenia. J Clin Oncol 18:1012–1019PubMedGoogle Scholar
  73. Klaassen IL, de Haas V, van Wijk JA et al (2011) Pyuria is absent during urinary tract infections in neutropenic patients. Pediatr Blood Cancer 56:868–870PubMedGoogle Scholar
  74. Klastersky J, Paesmans M, Rubenstein EB et al (2000) 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 18:3038–3051PubMedGoogle Scholar
  75. Klont RR, Mennink-Kersten MA, Verweij PE (2004) Utility of Aspergillus antigen detection in specimens other than serum specimens. Clin Infect Dis 39:1467–1474PubMedGoogle Scholar
  76. Koo S, Bryar JM, Page JH et al (2009) Diagnostic performance of the (1 >3)-beta-D-glucan assay for invasive fungal disease. Clin Infect Dis 49:1650–1659PubMedGoogle Scholar
  77. Kosmin AR, Fekete T (2008) Use of fungal blood cultures in an academic medical center. J Clin Microbiol 46:3800–3801PubMedCentralPubMedGoogle Scholar
  78. Kourkoumpetis TK, Fuchs BB, Coleman JJ et al (2012) Polymerase chain reaction-based assays for the diagnosis of invasive fungal infections. Clin Infect Dis 54:1322–1331PubMedCentralPubMedGoogle Scholar
  79. Lahoti A, Kantarjian H, Salahudeen AK et al (2010) Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome. Cancer 116:4063–4068PubMedCentralPubMedGoogle Scholar
  80. Lalayanni C, Baliakas P, Xochelli A et al (2012) Outbreak of cutaneous zygomycosis associated with the use of adhesive tape in haematology patients. J Hosp Infect 81:213–215PubMedGoogle Scholar
  81. Lee DH, Vielemeyer O (2011) Analysis of overall level of evidence behind Infectious Diseases Society of America practice guidelines. Arch Intern Med 171:18–22PubMedGoogle Scholar
  82. Lehrnbecher T, Foster C, Vazquez N et al (1997) Therapy-induced alterations in host defense in children receiving therapy for cancer. J Pediatr Hematol Oncol 19:399–417PubMedGoogle Scholar
  83. Lehrnbecher T, Venzon D, de Haas M et al (1999) Assessment of measuring circulating levels of interleukin-6, interleukin-8, C-reactive protein, soluble Fcγ receptor type III, and mannose-binding protein in febrile children with cancer and neutropenia. Clin Infect Dis 29:414–419PubMedGoogle Scholar
  84. Lehrnbecher T, Stanescu A, Kuhl J (2002) Short courses of intravenous empirical antibiotic treatment in selected febrile neutropenic children with cancer. Infection 30:17–21PubMedGoogle Scholar
  85. Lehrnbecher T, Phillips R, Alexander S et al (2012) Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol 30:4427–4438PubMedGoogle Scholar
  86. Levine SJ, Kennedy D, Shelhamer JH et al (1992) Diagnosis of Pneumocystis carinii pneumonia by multiple lobe, site-directed bronchoalveolar lavage with immunofluorescent monoclonal antibody staining in human immunodeficiency virus-infected patients receiving aerosolized pentamidine chemoprophylaxis. Am Rev Respir Dis 146:838–843PubMedGoogle Scholar
  87. Lindblom A, Bhadri V, Soderhall S et al (2010) Respiratory viruses, a common microbiological finding in neutropenic children with fever. J Clin Virol 47:234–237PubMedGoogle Scholar
  88. Liu C, Bayer A, Cosgrove SE et al (2011) Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis 52:285–292PubMedGoogle Scholar
  89. Luna A, Ribes R, Caro P et al (2006) MRI of focal splenic lesions without and with dynamic gadolinium enhancement. AJR Am J Roentgenol 186:1533–1547PubMedGoogle Scholar
  90. Luthi F, Leibundgut K, Niggli FK et al (2012) Serious medical complications in children with cancer and fever in chemotherapy-induced neutropenia: results of the prospective multicenter SPOG 2003 FN study. Pediatr Blood Cancer 59:90–95PubMedGoogle Scholar
  91. Maertens JA, Madero L, Reilly AF et al (2010) A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J 29:415–420PubMedGoogle Scholar
  92. Manji A, Beyene J, Dupuis LL et al (2012a) Outpatient and oral antibiotic management of low-risk febrile neutropenia are effective in children – a systematic review of prospective trials. Support Care Cancer 20:1135–1145PubMedGoogle Scholar
  93. Manji A, Lehrnbecher T, Dupuis LL et al (2012b) A meta-analysis of antipseudomonal penicillins and cephalosporins in pediatric patients with fever and neutropenia. Pediatr Infect Dis J 31:353–358PubMedGoogle Scholar
  94. Manji A, Lehrnbecher T, Dupuis LL et al (2012c) A systematic review and meta-analysis of anti-pseudomonal penicillins and carbapenems in pediatric febrile neutropenia. Support Care Cancer 20:2295–2304PubMedGoogle Scholar
  95. Marty FM, Koo S (2009) Role of (1–>3)-beta-D-glucan in the diagnosis of invasive aspergillosis. Med Mycol 47:S233–S240PubMedGoogle Scholar
  96. Masood A, Sallah S (2005) Chronic disseminated candidiasis in patients with acute leukemia: emphasis on diagnostic definition and treatment. Leuk Res 29:493–501PubMedGoogle Scholar
  97. Mays SR, Bogle MA, Bodey GP (2006) Cutaneous fungal infections in the oncology patient: recognition and management. Am J Clin Dermatol 7:31–43PubMedGoogle Scholar
  98. Mebis J, Goossens H, Bruyneel P et al (1998) Decreasing antibiotic resistance of Enterobacteriaceae by introducing a new antibiotic combination therapy for neutropenic fever patients. Leukemia 12:1627–1629PubMedGoogle Scholar
  99. Meckler G, Lindemulder S (2009) Fever and neutropenia in pediatric patients with cancer. Emerg Med Clin North Am 27:525–544PubMedGoogle Scholar
  100. Mermel LA, Allon M, Bouza E et al (2009) Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 49:1–45PubMedCentralPubMedGoogle Scholar
  101. Metan G, Agkus C, Buldu H et al (2010) The interaction between piperacillin/tazobactam and assays for Aspergillus galactomannan and 1,3-beta-D-glucan in patients without risk factors for invasive fungal infections. Infection 38:217–221PubMedGoogle Scholar
  102. Mikulska M, Furfaro E, Del Bono V et al (2012) Piperacillin/tazobactam (TazocinTM) seems to be no longer responsible for false-positive results of the galactomannan assay. J Antimicrob Chemother 67:1746–1748PubMedGoogle Scholar
  103. Mor M, Gilad G, Kornreich L et al (2011) Invasive fungal infections in pediatric oncology. Pediatr Blood Cancer 56:1092–1097PubMedGoogle Scholar
  104. Moyer CD, Sykes PA, Rayner JM (1977) Aeromonas hydrophila septicaemia producing ecthyma gangrenosum in a child with leukaemia. Scand J Infect Dis 9:151–153PubMedGoogle Scholar
  105. Mularoni A, Furfaro E, Faraci M et al (2010) High Levels of beta-D-glucan in immunocompromised children with proven invasive fungal disease. Clin Vaccine Immunol 17:882–883PubMedCentralPubMedGoogle Scholar
  106. Mullen CA (2012) “Good Enough” medicine: noninferiority clinical trials and the management of fever and neutropenia. Pediatr Blood Cancer 59:415–416PubMedGoogle Scholar
  107. Mullen CA, Buchanan GR (1990) Early hospital discharge of children with cancer treated for fever and neutropenia: identification and management of the low-risk patient. J Clin Oncol 8:1998–2004PubMedGoogle Scholar
  108. Mullen CA, Petropoulos D, Roberts WM et al (1999) Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Cancer 86:126–134PubMedGoogle Scholar
  109. Nucci M, Anaissie EJ, Queiroz-Telles F et al (2003) Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer 98:315–319PubMedGoogle Scholar
  110. Orudjev E, Lange BJ (2002) Evolving concepts of management of febrile neutropenia in children with cancer. Med Pediatr Oncol 39:77–85PubMedGoogle Scholar
  111. Ozdemir N, Celkan T, Midilli K et al (2011) Novel influenza A (H1N1) infection in a pediatric hematology oncology clinic during the 2009–2010 pandemia. Pediatr Hematol Oncol 28:288–293PubMedGoogle Scholar
  112. Paganini HR, Sarkis CM, De Martino MG et al (2000) Oral administration of cefixime to lower risk febrile neutropenic children with cancer. Cancer 88:2848–2852PubMedGoogle Scholar
  113. Paganini H, Rodriguez-Brieschcke T, Zubizarreta P et al (2001) Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia. Cancer 91:1563–1567PubMedGoogle Scholar
  114. Paganini HR, Aguirre C, Puppa G et al (2007) A prospective, multicentric scoring system to predict mortality in febrile neutropenic children with cancer. Cancer 109:2572–2579PubMedGoogle Scholar
  115. Pappas PG, Kauffman CA, Andes D et al (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535PubMedGoogle Scholar
  116. Park JR, Coughlin J, Hawkins D et al (2003) Ciprofloxacin and amoxicillin as continuation treatment of febrile neutropenia in pediatric cancer patients. Med Pediatr Oncol 40:93–98PubMedGoogle Scholar
  117. Pattishall EN, Noyes BE, Orenstein DM (1988) Use of bronchoalveolar lavage in immunocompromised children with pneumonia. Pediatr Pulmonol 5:1–5PubMedGoogle Scholar
  118. Paul M, Borok S, Fraser A et al (2005) Additional anti-Gram-positive antibiotic treatment for febrile neutropenic cancer patients. Cochrane Database Syst Rev (3):CD003914Google Scholar
  119. Paul M, Yahav D, Bivas A et al (2010) Anti-pseudomonal beta-lactams for the initial, empirical, treatment of febrile neutropenia: comparison of beta-lactams. Cochrane Database Syst Rev (11):CD005197Google Scholar
  120. Paul M, Dickstein Y, Schlesinger A et al (2013) Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst Rev (6):CD003038Google Scholar
  121. Perfect JR, Dismukes WE, Dromer F et al (2010) Clinical practice guidelines for the management of cryptococcal disease: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis 50:291–322PubMedGoogle Scholar
  122. Petrilli AS, Carlesse FA, Pereira CA (2007) Oral gatifloxacin in the outpatient treatment of children with cancer fever and neutropenia. Pediatr Blood Cancer 49:682–686PubMedGoogle Scholar
  123. Pfeiffer CD, Fine JP, Safdar N (2006) Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 42:1417–1427PubMedGoogle Scholar
  124. Phillips B, Wade R, Stewart LA et al (2010) Systematic review and meta-analysis of the discriminatory performance of risk prediction rules in febrile neutropaenic episodes in children and young people. Eur J Cancer 46:2950–2964PubMedCentralPubMedGoogle Scholar
  125. Phillips RS, Wade R, Lehrnbecher T et al (2012) Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer. BMC Med 10:6PubMedCentralPubMedGoogle Scholar
  126. Pizzo PA, Robichaud KJ, Gill FA et al (1982) Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 72:101–111PubMedGoogle Scholar
  127. Pizzo PA, Hathorn JW, Hiemenz J et al (1986) A randomized trial comparing ceftazidime alone with combination antibiotic therapy in cancer patients with fever and neutropenia. N Engl J Med 315:552–558PubMedGoogle Scholar
  128. Powers JH (2012) Editorial commentary: asking the right questions: morbidity, mortality, and measuring what’s important in unbiased evaluations of antimicrobials. Clin Infect Dis 54:1710–1713PubMedCentralPubMedGoogle Scholar
  129. Prasad P, Sun J, Danner RL et al (2012) Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 54:1699–1709PubMedCentralPubMedGoogle Scholar
  130. Raad I, Hanna HA, Alakech B et al (2004) Differential time to positivity: a useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med 140:18–25PubMedGoogle Scholar
  131. Raad I, Kassar R, Ghannam D et al (2009) Management of the catheter in documented catheter-related coagulase-negative staphylococcal bacteremia: remove or retain? Clin Infect Dis 49:1187–1194PubMedGoogle Scholar
  132. Rackoff WR, Gonin R, Robinson C et al (1996) Predicting the risk of bacteremia in children with fever and neutropenia. J Clin Oncol 14:919–924PubMedGoogle Scholar
  133. Reich HL, Williams Fadeyi D et al (2004) Nonpseudomonal ecthyma gangrenosum. J Am Acad Dermatol 50:S114–S117PubMedGoogle Scholar
  134. Roberts SD, Wells GM, Gandhi NM et al (2012) Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections. Support Care Cancer 20:2589–2594PubMedGoogle Scholar
  135. Rodriguez L, Ethier MC, Phillips B et al (2012) Utility of peripheral blood cultures in patients with cancer and suspected blood stream infections: a systematic review. Support Care Cancer 20:3261–3267PubMedGoogle Scholar
  136. Rolston KV (2005) Challenges in the treatment of infections caused by gram-positive and gram-negative bacteria in patients with cancer and neutropenia. Clin Infect Dis 40:S246–S252PubMedGoogle Scholar
  137. Rosen GP, Nielsen K, Glenn S et al (2005) Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol Oncol 27:135–140PubMedGoogle Scholar
  138. Rosenblum J, Lin J, Kim M et al (2013) Repeating blood cultures in neutropenic children with persistent fevers when the initial blood culture is negative. Pediatr Blood Cancer 60:923–927PubMedCentralPubMedGoogle Scholar
  139. Rybak MJ, Lomaestro BM, Rotschafer JC et al (2009) Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 49:325–327PubMedGoogle Scholar
  140. Sahani DV, Kalva SP (2004) Imaging the liver. Oncologist 9:385–397PubMedGoogle Scholar
  141. Sandoval C, Sinaki B, Weiss R et al (2012) Urinary tract infections in pediatric oncology patients with fever and neutropenia. Pediatr Hematol Oncol 29:68–72PubMedGoogle Scholar
  142. Santolaya ME, Cofre J, Beresi V (1994) C-reactive protein: a valuable aid for the management of febrile children with cancer and neutropenia. Clin Infect Dis 18:589–595PubMedGoogle Scholar
  143. Santolaya ME, Villarroel M, Avendaño LF (1997) Discontinuation of antimicrobial therapy for febrile, neutropenic children with cancer: a prospective study. Clin Infect Dis 25:92–97PubMedGoogle Scholar
  144. Santolaya ME, Alvarez AM, Avilés CL et al (2002) Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis 35:678–683PubMedGoogle Scholar
  145. Santolaya ME, Farfan MJ, De La Maza V et al (2011) Diagnosis of bacteremia in febrile neutropenic episodes in children with cancer: microbiologic and molecular approach. Pediatr Infect Dis J 30:957–961PubMedGoogle Scholar
  146. Scheinemann K, Ethier MC, Dupuis LL et al (2010) Utility of peripheral blood cultures in bacteremic pediatric cancer patients with a central line. Support Care Cancer 18:913–919PubMedGoogle Scholar
  147. Sekine L, Humbwavali J, Wolff FH et al (2010) Caspofungin versus liposomal amphotericin B: are they really comparable? Pediatr Infect Dis J 29:985–986PubMedGoogle Scholar
  148. Semeraro M, Thomée C, Rolland E et al (2010) A predictor of unfavourable outcome in neutropenic paediatric patients presenting with fever of unknown origin. Pediatr Blood Cancer 54:284–290PubMedGoogle Scholar
  149. Shenep JL, Flynn PM, Baker DK et al (2001) Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer. Clin Infect Dis 32:36–43PubMedGoogle Scholar
  150. Simon A, Fleischhack G, Hasan C et al (2000) Surveillance for nosocomial and central line related infections among pediatric hematology-oncology patients. Infect Control Hosp Epidemiol 21:592–596PubMedGoogle Scholar
  151. Smith PB, Benjamin DK Jr, Alexander BD et al (2007) Quantification of 1,3-beta-D-glucan levels in children: preliminary data for diagnostic use of the beta-glucan assay in a pediatric setting. Clin Vaccine Immunol 14:924–925PubMedCentralPubMedGoogle Scholar
  152. Son YM, Na SY, Lee HY et al (2009) Ecthyma gangrenosum: a rare cutaneous manifestation caused by Stenotrophomonas maltophilia in a leukemic patient. Ann Dermatol 21:389–392PubMedCentralPubMedGoogle Scholar
  153. Spellberg B, Ibrahim A, Roilides E et al (2012) Combination therapy for mucormycosis: why, what, and how? Clin Infect Dis 54:S73–S78PubMedGoogle Scholar
  154. Stabell N, Nordal E, Stensvold E et al (2008) Febrile neutropenia in children with cancer: a retrospective Norwegian multicentre study of clinical and microbiological outcome. Scand J Infect Dis 40:301–307PubMedGoogle Scholar
  155. Steinbach WJ (2011) Rational approach to pediatric antifungal therapy. Adv Exp Med Biol 697:231–242PubMedGoogle Scholar
  156. Steinbach WJ, Addison RM, McLaughlin L et al (2007) Prospective Aspergillus galactomannan antigen testing in pediatric hematopoietic stem cell transplant recipients. Pediatr Infect Dis J 26:558–564PubMedGoogle Scholar
  157. Sulahian A, Boutboul F, Ribaud P et al (2001) Value of antigen detection using an enzyme immunoassay in the diagnosis and prediction of invasive aspergillosis in two adult and pediatric hematology units during a 4-year prospective study. Cancer 91:311–318PubMedGoogle Scholar
  158. Sung L, Dupuis LL, Bliss B et al (2003) Randomized controlled trial of once- versus thrice-daily tobramycin in febrile neutropenic children undergoing stem cell transplantation. J Natl Cancer Inst 95:1869–1877PubMedGoogle Scholar
  159. Sung L, Feldman BM, Schwamborn G et al (2004) Inpatient versus outpatient management of low-risk pediatric febrile neutropenia: measuring parents’ and healthcare professionals’ preferences. J Clin Oncol 22:3922–3929PubMedGoogle Scholar
  160. Sung L, Phillips R, Lehrnbecher T (2011) Time for paediatric febrile neutropenia guidelines – children are not little adults. Eur J Cancer 47:811–813PubMedGoogle Scholar
  161. Sung L, Manji A, Beyene J et al (2012) Fluoroquinolones in children With fever and neutropenia: a systematic review of prospective trials. Pediatr Infect Dis J 31:431–435PubMedGoogle Scholar
  162. te Poele EM, Tissing WJ, Kamps WA et al (2009) Risk assessment in fever and neutropenia in children with cancer: what did we learn? Crit Rev Oncol Hematol 72:45–55Google Scholar
  163. Teuffel O, Amir E, Alibhai SM et al (2011a) Cost-effectiveness of outpatient management for febrile neutropenia in children with cancer. Pediatrics 127:e279–e286PubMedGoogle Scholar
  164. Teuffel O, Ethier MC, Alibhai SM et al (2011b) Outpatient management of cancer patients with febrile neutropenia: a systematic review and meta-analysis. Ann Oncol 22:2358–2365PubMedGoogle Scholar
  165. Theuretzbacher U (2012) Pharmacokinetic and pharmacodynamic issues for antimicrobial therapy in patients with cancer. Clin Infect Dis 54:1785–1792PubMedGoogle Scholar
  166. Thomas KE, Owens CM, Veys PA et al (2003) The radiological spectrum of invasive aspergillosis in children: a 10-year review. Pediatr Radiol 33:453–460PubMedGoogle Scholar
  167. Uhlenbrock S, Zimmermann M, Fegeler W et al (2001) Liposomal amphotericin B for prophylaxis of invasive fungal infections in high-risk paediatric patients with chemotherapy-related neutropenia: interim analysis of a prospective study. Mycoses 44:455–463PubMedGoogle Scholar
  168. Uys A, Rapoport BL, Anderson R (2004) Febrile neutropenia: a prospective study to validate the Multinational Association of Supportive Care of Cancer (MASCC) risk-index score. Support Care Cancer 12:555–560PubMedGoogle Scholar
  169. Uys A, Rapoport BL, Fickl H et al (2007) Prediction of outcome in cancer patients with febrile neutropenia: comparison of the Multinational Association of Supportive Care in Cancer risk-index score with procalcitonin, C-reactive protein, serum amyloid A, and interleukins-1β, -6, -8 and -10. Eur J Cancer Care 16:475–483Google Scholar
  170. Vazquez JA (2008) Clinical practice: combination antifungal therapy for mold infections: much ado about nothing? Clin Infect Dis 46:1889–1901PubMedGoogle Scholar
  171. Vidal L, Ben dor I, Paul M et al (2013) Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients. Cochrane Database Syst Rev (10):CD003992Google Scholar
  172. Wacker P, Halperin DS, Wyss M et al (1997) Early hospital discharge of children with fever and neutropenia: a prospective study. J Pediatr Hematol Oncol 19:208–211PubMedGoogle Scholar
  173. Walsh TJ, Pappas P, Winston DJ et al (2002) Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 346:225–234PubMedGoogle Scholar
  174. Walsh TJ, Anaissie EJ, Denning DW et al (2008) Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327–360PubMedGoogle Scholar
  175. Watt K, Benjamin DK Jr, Cohen-Wolkowiez M (2011) Pharmacokinetics of antifungal agents in children. Early Hum Dev 87:S61–S65PubMedCentralPubMedGoogle Scholar
  176. Wicki S, Keisker A, Aebi C et al (2008) Risk prediction of fever in neutropenia in children with cancer: a step towards individually tailored supportive therapy? Pediatr Blood Cancer 51:778–783PubMedGoogle Scholar
  177. Wingard JR, Hiemenz JW, Jantz MA (2012) How I manage pulmonary nodular lesions and nodular infiltrates in patients with hematologic malignancies or undergoing hematopoietic cell transplantation. Blood 120:1791–1800PubMedGoogle Scholar
  178. Xu B, Shi P, Wu H et al (2010) Utility of FDG PET/CT in guiding antifungal therapy in acute leukemia patients with chronic disseminated candidiasis. Clin Nucl Med 35:567–570PubMedGoogle Scholar
  179. Yahav D, Paul M, Fraser A et al (2007) Efficacy and safety of cefepime: a systematic review and meta-analysis. Lancet Infect Dis 7:338–348PubMedGoogle Scholar
  180. Zandijk E, Mewis A, Magerman K et al (2008) False-positive results by the platelia Aspergillus galactomannan antigen test for patients treated with amoxicillin-clavulanate. Clin Vaccine Immunol 15:1132–1133PubMedCentralPubMedGoogle Scholar
  181. Zaoutis TE, Heydon K, Chu JH et al (2006) Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000. Pediatrics 117:e711–e716PubMedGoogle Scholar
  182. Zinner SH (1999) Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis 29:490–494PubMedGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2015

Authors and Affiliations

  • Blanca E. Gonzalez
    • 1
  • Linda S. Cabral
    • 2
  • Jeffery J. Auletta
    • 3
    Email author
  1. 1.Center for Pediatric Infectious DiseasesCleveland ClinicClevelandUSA
  2. 2.Pediatric Blood and Marrow Transplant ProgramRainbow Babies and Children’s HospitalClevelandUSA
  3. 3.Host Defense Program, Hematology/Oncology/BMT and Infectious DiseasesNationwide Children’s HospitalColumbusUSA

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