The primary objective was to describe infectious complications in children with acute myeloid leukemia from presentation to the healthcare system to initiation of chemotherapy and to describe how these infections differ depending on neutropenia.
We conducted a retrospective, population-based cohort study that included children and adolescents with acute myeloid leukemia diagnosed and treated at 15 Canadian centers. We evaluated infections that occurred between presentation to the healthcare system (for symptoms that led to the diagnosis of acute myeloid leukemia) until initiation of chemotherapy.
Among 328 children, 92 (28.0%) were neutropenic at presentation. Eleven (3.4%) had sterile-site microbiologically documented infection and four had bacteremia (only one Gram negative). Infection rate was not influenced by neutropenia. No child died from an infectious cause prior to chemotherapy initiation.
It may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed acute myeloid leukemia until initiation of chemotherapy as long as they appear well without a clinical focus of infection. Future work could examine biomarkers or a clinical score to identify children presenting with leukemia and fever who are more likely to have an invasive infection.
Citation: Portwine C, Mitchell D, Johnston D, Gillmeister B, Ethier M-C, Yanofsky R, et al. (2013) Infectious Events Prior to Chemotherapy Initiation in Children with Acute Myeloid Leukemia. PLoS ONE 8(4): e61899. https://doi.org/10.1371/journal.pone.0061899
Editor: Ray Borrow, Health Protection Agency, United Kingdom
Received: November 12, 2012; Accepted: March 14, 2013; Published: April 26, 2013
Copyright: © 2013 Portwine et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Canadian Cancer Society (grant number 019468) and the C17 Research Network. LS is supported by a New Investigator Award from the Canadian Institutes of Health Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Children with acute myeloid leukemia (AML) receive intensive chemotherapy and during treatment, they are at substantial risk of morbidity and mortality from invasive infections. The management of fever with neutropenia is relatively straightforward in these children after they begin chemotherapy. However, when children with acute leukemia initially enter the healthcare system, fever is a common presentation and neutropenia may also be present. The optimal management of children with newly diagnosed leukemia with fever in the period preceding initiation of chemotherapy is uncertain, both for those with and without neutropenia. Cancer-specific fever and neutropenia guidelines do not provide recommendations for this scenario since the setting for guidelines is usually restricted to patients who are receiving treatments for cancer.,  Furthermore, it would be useful to know if infection outcomes differed depending on the presence or absence of neutropenia in this setting since the presence of neutropenia is a major criterion that influences the decision to start antibiotics in febrile children receiving treatment for cancer.
Consequently, we conducted a population-based study of pediatric AML using a retrospective cohort design. The primary objective was to describe infectious complications in children with AML from presentation to the healthcare system to initiation of chemotherapy and to describe how these infections differ depending on neutropenia.
Materials and Methods
This study was approved by the Research Ethics Board at The Hospital for Sick Children and local Research Ethics Boards of the 14 other participating sites (McMaster University-Hamilton Health Sciences/Faculty of Health Sciences Research Ethics Board, Montreal Children's Hospital Research Ethics Board, Children's Hospital of Eastern Ontario Research Ethics Board, University of Winnipeg Research Ethics Board, University of British Columbia/Children's and Women's Health Centre of British Columbia Research Ethics Board, Centre Hospitalier Universitaire Sainte-Justine Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, IWK Research Ethics Board, Queen's University-Health Sciences Research Ethics Board, University of Western Ontario Research Ethics Board for Health Science Research Involving Human Subjects, Memorial University Human Investigation Committee, Centre Hospitalier Universitaire de Quebec Research Ethics Board, University of Alberta Health Research Ethics Board-Biomedical Panel, and Centre Hospitalier Universitaire de Sherbrooke Research Ethics Board). As this was a retrospective review study, the Research Ethics Board at The Hospital for Sick Children and those at the 14 other participating sites waived the need for written informed consent. All demographic information and information about the child's diagnosis and treatment were abstracted from the child's chart.
This manuscript is related to a large retrospective, population-based cohort study in which we included children and adolescents with AML diagnosed and treated in each Canadian province except Saskatchewan. We included children and adolescents ≤18 years with de novo AML diagnosed between January 1, 1995 and December 31, 2004. Children with Down syndrome were also included. We excluded those with acute promyelocytic leukemia, secondary AML, and previous diagnosis of immunodeficiency.
We evaluated infections that occurred between presentation to the healthcare system (for symptoms that led to the diagnosis of AML) until initiation of chemotherapy. Data abstraction was conducted by trained clinical research associates who travelled to each site to abstract and code all data.
We described the occurrence of sterile site invasive infection, clinically documented infection and fever of unknown origin. Fever was defined as a single oral temperature of 38.3° C or a temperature of 38.0° C for 1 hour. In this study, we did not distinguish between infections present at the time of admission and those acquired after admission but prior to initiation of treatment. Positive cultures with common contaminants such as coagulase negative Staphylococcus were only considered true infection if there were two or more positive cultures in the same episode or if the infection was associated with sepsis. In this study, sepsis was defined as systemic inflammatory response syndrome in the presence of suspected or proven infection and organ dysfunction. Clinically documented infections were classified based upon the Centers for Disease Control and Prevention (CDC) definitions of nosocomial infections. However, for our study, we did not require that clinically documented infections be not present or incubating at the time of admission to hospital. Fever of unknown origin was fever occurring in the absence of a positive microbiology result or clinical site of infection.
We compared baseline characteristics and infection outcomes depending upon if the patient was neutropenic (absolute neutrophil count (ANC)<0.5×109/L) at presentation.
Characteristics evaluated were: gender, age, Down syndrome, body mass index percentile at diagnosis, peripheral blood counts at diagnosis and AML morphology. Obesity was defined as body mass index (BMI) ≥95th percentile and underweight was defined as BMI ≤10th percentile for age and gender according to the CDC for those at least 2 years of age. BMI was evaluated as obesity previously has been associated with treatment-related mortality and infections in pediatric AML, .
Characteristics and infection outcomes were compared between those who were and were not neutropenic at presentation using the Wilcoxon rank sum test for continuous variables and Chi square or Fisher's exact test for categorical variables. All tests of significance were two-sided, and statistical significance was defined as P<0.05. Statistical analysis was performed using the SAS statistical program (SAS-PC, version 9·3; SAS Institute Inc., Cary, NC).
There were 343 children with de novo AML who met eligibility criteria in the study time frame. Of these children, 15 began chemotherapy on the same day as presentation to the healthcare center and thus, there were 328 children with pre-chemotherapy information available. The median time between presentation and initiation of chemotherapy was 2 (range 0 to 274) days. There were two patients who had very lengthy delays between presentation and initiation of chemotherapy of 59 and 274 days.
Table S1 illustrates that 92 (28.0%) children were neutropenic at presentation. Gender and age were not significantly associated with neutropenia at presentation whereas children with Down syndrome were significantly less likely to present with neutropenia. Children with neutropenia had a significantly lower initial peripheral blast count and hemoglobin level compared to non-neutropenic children although the initial platelet count was similar between the two groups.
Table 1 and Table S2 illustrate the infection outcomes. Overall, there were 11/328 (3.4%) children who experienced 12 sterile site microbiologically documented infections; the risk did not significantly differ by the presence or absence of neutropenia. There were four episodes of bacteremia with viridans group streptococci (n = 3) and Pseudomonas aeruginosa (n = 1), all occurring in non-neutropenic children. Among the six episodes of urinary tract infection, the causative agents were: Enterococcus species (n = 2), Escherichia coli (n = 2), P. aeruginosa (n = 1) and Candida albicans (n = 1). The two other sterile site infections were Staphylococcus aureus from a peritoneal drain (see below) and a lymph node biopsy. Other than for the one C. albicans urinary tract infection, no other fungi from sterile or non-sterile sites were observed (data not shown). One child experienced sepsis with concurrent pneumonia.
Three children died before initiation of chemotherapy. Two children died of hyperleukocytosis and pulmonary leukostasis. A third child presented with a 10 day history of fever and was found to have pneumonia on chest radiograph; the absolute neutrophil count was 0.2×109/L at presentation. The child was treated with broad-spectrum antibiotics and after 10 days of persistent fever, she was found to have C. albicans from urine and therefore, amphotericin B was initiated. Over the next four days, she developed acute respiratory distress and multi-organ failure; a peritoneal drain grew S. aureus. Autopsy failed to reveal an infectious cause of death and death was attributed to progressive AML.
We conducted a comprehensive assessment of infections occurring before chemotherapy initiation in newly diagnosed pediatric AML. We found that sterile site infections were rare, Gram negative bacteremia occurred in only one child, and many infections were from a urinary site. Infection outcomes were similar between neutropenic and non-neutropenic children. Our findings suggest that it may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed AML until initiation of chemotherapy as long as they appear well without a clinical focus of infection. Reducing antibiotic exposure is important given the relationship between greater antibiotic use and antibiotic resistance,  and invasive fungal infection. However, the safety of this approach has not yet been tested.
Although our analysis did not show a difference in outcomes by neutropenia at presentation, limited power for this comparison is an important consideration since only 28% of children were neutropenic. Patients with non-cancer related neutropenia may be at risk of invasive infection if the neutropenia is associated with profound immunosuppression. Thus, we do not suggest withholding empiric antibiotics in this situation and suggest empiric antibiotics be initiated in a febrile neutropenic child with newly diagnosed AML. Our data also suggest that if empiric antibiotics are initiated (for example, because of neutropenia, unwell appearance or a clinical site of infection), broad-spectrum antibiotics with activity against P.aeruginosa are important.
Future work could examine biomarkers or a clinical score to identify children presenting with leukemia and fever who are more likely to have an invasive infection. This approach may allow antibiotic therapy to be tailored to children at higher risk of infection.
The strengths of our report are the multi-center nature of the study which allowed capture of a large number of children with AML. Further, the data are highly generalizable. However, there are important limitations to our study. Centers had different approaches to supportive care and urgency of chemotherapy initiation. Second, the retrospective design made it more difficult to appreciate the clinical status of the child at presentation.
In conclusion, we found that in children with AML, 28% will present with neutropenia. Sterile site infections were rare. It may be reasonable to withhold empiric antibiotics in febrile non-neutropenic children with newly diagnosed AML until initiation of chemotherapy as long as they appear well without a clinical focus of infection.
Characteristics of children with acute myeloid leukemia with pre-chemotherapy information available by neutropenia at presentation.
All authors contributed to data collection and manuscript writing. All authors have approved the final version of the manuscript.
CANADIAN INFECTIONS IN AML RESEARCH GROUP: David Dix (PI) and Nita Takeuchi (CRA) from British Columbia Children's Hospital; Kent Stobart (PI), Brenda Ennis (CRA) and Linda Churcher (CRA) from Stollery Children's Hospital; Victor Lewis (PI), Janice Hamilton (CRA) and Karen Mazil (CRA) from Alberta Children's Hospital; Sonia Cellot (PI), Dominique Lafreniere (CRA) and Catherine Desjean (CRA) from Hospital Sainte-Justine; Victoria Price (PI), Tina Bocking (CRA), Lynn Russell (CRA) and Emily Murray (CRA) from IWK Health Centre; Lynette Bowes (PI) and Gale Roberts (CRA) from Janeway Child Health Centre; Carol Portwine (PI) and Sabrina Siciliano (CRA) from McMaster Children's Hospital at Hamilton Health Sciences; Joseph Beyene (Collaborator) from McMaster University; Mariana Silva (PI) from Kingston General Hospital; Rochelle Yanofsky (PI), Rebekah Hiebert (CRA) and Krista Mueller (CRA) from CancerCare Manitoba; Shayna Zelcer (PI), Martha Rolland (CRA) and Julie Nichols (CRA) from London Health Sciences; Donna Johnston (PI) and Elaine Dollard (CRA) from Children's Hospital of Eastern Ontario; David Mitchell (PI), Martine Nagy (CRA) and Margaret Hin Chan (CRA) from Montreal Children's Hospital; Bruno Michon (PI), Josee Legris (CRA) and Marie-Christine Gagnon (CRA) from Hospitalier Universitaire de Quebec; Josee Brossard (PI) and Lise Bilodeau (CRA) from Centre Hospitalier Universitaire de Sherbrooke; Lillian Sung (PI), Biljana Gillmeister (CRA), Marie-Chantal Ethier (CRA), Renee Freeman (Collaborator), Jeffrey Traubici (Collaborator), and Upton Allen (Collaborator) from The Hospital for Sick Children.
Conceived and designed the experiments: BG MCE LS. Performed the experiments: CP DM DJ BG MCE RY DD SC VL VP MS SZ LB BM KS J. Brossard J. Beyene LS. Analyzed the data: J. Beyene LS. Contributed reagents/materials/analysis tools: LS. Wrote the paper: CP DM DJ BG MCE RY DD SC VL VP MS SZ LB BM KS J. Brossard J. Beyene LS.
- 1. Hann I, Viscoli C, Paesmans M, Gaya H, Glauser M (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: 580–588.
- 2. Lehrnbecher T, Phillilps R, Alexander S, Alvaro F, Carlesse F, et al. (2012) Guidelines for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem cell transplantation. J Clin Oncol In Press.
- 3. Fadoo Z, Mushtaq N, Alvi S, Ali M (2012) Acute myeloid leukaemia in children: experience at a tertiary care facility of Pakistan. J Pak Med Assoc 62: 125–128.
- 4. Freifeld AG, Bow EJ, Sepkowitz KA, Boeckh MJ, Ito JI, 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: e56–93.
- 5. Dix D, Cellot S, Price V, Gillmeister B, Ethier MC, et al.. (2012) Association between Corticosteroids and Infection, Sepsis and Infectious Death in Pediatric Acute Myeloid Leukemia: from the Canadian Infections in AML Research Group. Clin Infect Dis. In press.
- 6. Santolaya ME, Alvarez AM, Becker A, Cofre J, Enriquez N, et al. (2001) Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol 19: 3415–3421.
- 7. Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, et al. (2002) 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34: 730–751.
- 8. Goldstein B, Giroir B, Randolph A (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6: 2–8.
- 9. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM (1996) CDC definitions for nosocomial infections. In: Olmsted RN, ed,: APIC Infection Control and Applied Epidemiology: Principles and Practice. St. Louis: Mosby.
- 10. Ogden CL, Kuczmarski RJ, Flegal KM, Mei Z, Guo S, et al. (2002) Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109: 45–60.
- 11. Lange BJ, Gerbing RB, Feusner J, Skolnik J, Sacks N, et al. (2005) Mortality in overweight and underweight children with acute myeloid leukemia. JAMA 293: 203–211.
- 12. Sung L, Lange BJ, Gerbing RB, Alonzo TA, Feusner J (2007) Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia. Blood 110: 3532–3539.
- 13. Almyroudis NG, Lesse AJ, Hahn T, Samonis G, Hazamy PA, et al. (2011) Molecular epidemiology and risk factors for colonization by vancomycin-resistant Enterococcus in patients with hematologic malignancies. Infect Control Hosp Epidemiol 32: 490–496.
- 14. Rangaraj G, Granwehr BP, Jiang Y, Hachem R, Raad I (2010) Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer 116: 967–973.
- 15. Hu R, Jiang X, Wu Y (2012) Risk factors for invasive pulmonary fungal infection in patients with hematological malignancies not receiving hematopoietic stem cell transplant. Neoplasma 59: 669–675.
- 16. Sung L, Johnston DL (2007) Approach to febrile neutropenia in the general paediatric setting. Paediatr Child Health 12: 19–21.