Guideline for the Management of Fever and Neutropenia in Children With Cancer and Hematopoietic Stem-Cell Transplantation Recipients: 2017 Update
To update a clinical practice guideline (CPG) for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients.
The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and multinational group of experts in pediatric oncology and infectious diseases that includes a patient advocate. For questions of risk stratification and evaluation, we updated systematic reviews of observational studies. For questions of therapy, we conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. The Grading of Recommendation Assessment, Development and Evaluation approach was used to make strong or weak recommendations and to classify levels of evidence as high, moderate, low, or very low.
Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy. Key differences from our 2012 FN CPG included the listing of a fourth-generation cephalosporin for empirical therapy in high-risk FN, refinement of risk stratification to define patients with high-risk invasive fungal disease (IFD), changes in recommended biomarkers and radiologic investigations for the evaluation of IFD in prolonged FN, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients with prolonged FN.
Changes to the updated FN CPG recommendations will likely influence the care of pediatric patients with cancer and those undergoing hematopoietic stem-cell transplantation. Future work should focus on closing research gaps and on identifying ways to facilitate implementation and adaptation.
Fever and neutropenia (FN) is a common complication of cancer treatment. In 2012, we published a clinical practice guideline (CPG) focused on the management of FN in children with cancer and in recipients of hematopoietic stem-cell transplantation (HSCT).1 Like all CPGs, it is important that the systematic reviews that inform the recommendations are timely, typically considered every 5 years in the absence of important new studies. Consequently, we updated the systematic reviews and present the 2017 pediatric FN CPG.
The International Pediatric Fever and Neutropenia Guideline Panel includes representation from pediatric oncology, infectious diseases, nursing, and pharmacy, as well as a patient advocate and a guideline methodologist from 10 different countries (Data Supplement).
The methodology applied to our CPG update mirrored our 2012 FN CPG. We followed previously validated procedures for creating evidence-based guidelines2 and used the Appraisal of Guidelines for Research & Evaluation II instrument as a framework.3 Each member completed a conflict of interest form (Data Supplement). The funding agencies had no role to play in the recommendations or editing of the manuscript. The Grading of Recommendation Assessment, Development and Evaluation approach was used to generate recommendations. Details of methodology may be found in the Data Supplement.
Members were divided into working groups that focused on the three major sections addressed in the initial CPG: initial presentation, ongoing management, and empirical antifungal therapy. Given the paucity of pediatric data at the time of initial CPG development, none of the original systematic reviews were restricted to randomized controlled trials (RCTs). For the guideline update, we decided to focus on pediatric RCTs for questions related to therapy because we believed that clinical practice was unlikely to change on the basis of additional observational studies alone. For questions related to risk stratification and evaluation, the original systematic reviews were updated. The Data Supplement contains details of the search strategies, flow diagrams of study identification and selection, and eligibility criteria.
Table 1 presents the 2017 recommendations, highlights changes from the 2012 FN CPG, and provides key remarks. The associated evidence profiles are illustrated in the Data Supplement when data were not published in separate manuscripts. Research gaps are presented in Table 2.
What clinical features and laboratory markers can be used to classify pediatric patients with FN as being at low risk or high risk of poor outcomes?
A1. Adopt a validated risk stratification strategy (Table 3) and incorporate it into routine clinical management (strong recommendation, low-quality evidence).
The 2012 recommendation was derived from a systematic review16 that demonstrated a number of schemas that varied by patients included, definitions of FN, and outcomes measured. Updating the systematic review (Data Supplement) demonstrated further validation of previously published schemas, and more small studies deriving new rules. Six clinically based low-risk stratification schemas that rely on a single assessment at presentation have been validated in different pediatric populations (Table 3). Even with further information, we remain unable to clearly recommend any single prediction rule. There remains evidence of geographical and temporal variation; thus, all schemas require local validation before use. The choice of strategy should be determined by an institution’s ability to implement more complex rules and the timeliness of receipt of required components of the rule, such as C-reactive protein. Two additional risk stratification schemas including repeated measurement of biomarkers have been derived and successfully validated in their originating groups.17,18 These use clinical assessment and IL-8 measurements for all pediatric patients17 or IL8 and C-reactive protein for a high-risk group.18
What clinical, laboratory, and imaging studies are useful at the initial presentation of FN to assess the cause of the episode and guide future treatment?
A2. Obtain blood cultures at the onset of FN from all lumens of central venous catheters (strong recommendation, low-quality evidence).
A3. Consider obtaining peripheral blood cultures concurrent with central venous catheter cultures (weak recommendation, moderate-quality evidence).
A4. Consider urinalysis and urine culture in patients in whom a clean-catch, midstream specimen is readily available (weak recommendation, low-quality evidence).
A5. Obtain chest radiography (CXR) only in patients with respiratory signs or symptoms (strong recommendation, moderate-quality evidence).
The value of peripheral blood cultures has been addressed in nine studies,19-27 two of which were published after 2011.19,20 The updated estimate of the proportion of true bacteremia episodes detected by peripheral blood cultures alone, when central venous catheter cultures are negative, was 12% (95% CI, 8%–17%). Thus, peripheral cultures consistently increase the identification of true bacteremia compared with central cultures alone, which may be related to timing or volume. It is a weak recommendation because the impact of increased yield is unknown and it should be balanced against pain and isolation of contaminants.
In terms of urinalysis and urine culture to detect urinary tract infections in pediatric FN, in one study, all patients with positive urine cultures were asymptomatic,28 strengthening the conclusion that restricting urine culture to those with symptoms is not adequate. The use of abnormal urinalysis to triage culture is also not recommended because pyuria was present in only 4% of urinary tract infection episodes during neutropenia29 and nitrite testing in younger children (without cancer) is less discriminatory than in older patients.30
Two additional studies have been added to the initial systematic review16 of the use of routine CXR during the initial assessment of pediatric FN. One was undertaken in a broad cohort of patients with FN31 and one in children undergoing HSCT.32 Both demonstrated rates of pneumonia of < 3% in an asymptomatic child. Asymptomatic children who did not undergo CXR had no significant adverse clinical consequences.33 Thus, no change was made to the strong recommendation to obtain CXR only in patients with respiratory signs or symptoms.
What empirical antibiotics are appropriate for children with high-risk FN?
A6. In high-risk FN:
A6a. Use monotherapy with an antipseudomonal β-lactam, a fourth-generation cephalosporin, or a carbapenem as empirical therapy in pediatric high-risk FN (strong recommendation, high-quality evidence).
A6b. Reserve the addition of a second gram-negative agent or a glycopeptide for patients who are clinically unstable, when a resistant infection is suspected, or for centers with a high rate of resistant pathogens (strong recommendation, moderate-quality evidence).
In the systematic review of RCTs of pediatric FN, we compared monotherapy with aminoglycoside-containing combination therapy, and the results are presented in Table 4.34 In this comparison, a rate ratio > 1 indicates that monotherapy is better than combination therapy. No significant differences in failure rates, infection-related mortality, or overall mortality were observed. Three studies were conducted solely in patients with high-risk FN,35-37 and among these studies, no difference in treatment failure was observed (rate ratio, 1.14; 95% CI, 0.54 to 2.39; P = .73). However, it is important to note that these three RCTs did not evaluate monotherapy with a β-lactam against the same β-lactam plus an aminoglycoside, thus highlighting the importance of the specific monotherapy β-lactam antibiotic used. This analysis confirmed the efficacy and safety of monotherapy without the addition of aminoglycosides in treatment settings in which resistance rates were low enough to permit random assignment between monotherapy and combination therapy. Consequently, the updated CPG continues to have a strong recommendation to use empirical monotherapy in high-risk FN. However, local epidemiology and resistance patterns should be evaluated regularly.
Table 4 also demonstrates the comparison between antipseudomonal penicillin monotherapy and fourth-generation cephalosporin monotherapy.38-42 Five studies were included; one study42 was identified in the updated search after publication of the FN systematic review.34 No differences in treatment failure, infection-related mortality, or duration of fever were observed, and the point estimate for mortality was in favor of the fourth-generation cephalosporin, thus arguing for its inclusion in the empirical antibiotic recommendation. The 0.81 day increase in duration of antibiotics associated with cephalosporin therapy was not considered clinically meaningful.
In children with low-risk FN, is initial or step-down outpatient management as effective and safe as inpatient management? Is initial or step-down oral antibiotic management as effective and safe as management with parenteral antibiotics?
A7. In low-risk FN:
A7a. Consider initial or step-down outpatient management if the infrastructure is in place to ensure careful monitoring and follow-up (weak recommendation, moderate-quality evidence).
A7b. Consider oral antibiotic administration if the child is able to tolerate this route of administration reliably (weak recommendation, moderate-quality evidence).
In the systematic review of pediatric FN RCTs, treatment setting and route of antibiotic administration were examined34 (Table 4). Four studies randomized patients to inpatient versus outpatient therapy43-46; no differences in outcomes were observed. The point estimates favored outpatient management in the mortality analyses, and no infection-related deaths were reported for the 124 randomly assigned low-risk patients treated as outpatients. It is a weak recommendation because institutions must have the infrastructure in place to safely implement outpatient management. Because clinical outcomes were similar among strategies, resources and preferences are important considerations in strategy choice.
Table 4 also lists the comparison between intravenous and oral therapy among patients treated in the same setting (n = eight studies).47-54 There was no significant difference in treatment failure, and no infection-related mortality was reported among the 470 patients randomly assigned to receive oral empirical therapy. It is a weak recommendation because readmission may be higher among outpatients treated with oral versus parenteral therapy, and other outcomes were similar. Thus, resources and preferences are important considerations.
When and how should the initial empirical antibiotic therapy be modified during the pediatric FN episode?
B1. In patients who are responding to initial empirical antibiotic therapy, discontinue double coverage for gram-negative infection or empirical glycopeptide (if initiated) after 24 to 72 hours if there is no specific microbiologic indication to continue combination therapy (strong recommendation, moderate-quality evidence).
B2. Do not modify the initial empirical antibacterial regimen based solely on persistent fever in children who are clinically stable (strong recommendation, low-quality evidence).
B3. In children with persistent fever who become clinically unstable, escalate the initial empirical antibacterial regimen to include coverage for resistant gram-negative, gram-positive, and anaerobic bacteria (strong recommendation, very low-quality evidence).
In the 2012 FN CPG, early discontinuation of combination therapy was based on the rationale for initial monotherapy without the addition of an aminoglycoside or empirical glycopeptide. As described previously, the recent systematic review confirmed the efficacy and safety of monotherapy without the addition of an aminoglycoside.34 The evidence remains indirect because the RCTs were in the setting of initial therapy and not ongoing therapy and consequently, this reduces the evidence quality to moderate.
There were no pediatric RCTs that evaluated the role of continuing empirical glycopeptides or the appropriate course of action in patients with persistent fever who remain clinically stable or who deteriorate. Thus, there were no changes to the 2012 recommendations.
When can empirical antibiotics be discontinued in patients with low- and high-risk FN?
B4. In all patients, discontinue empirical antibiotics in patients who have negative blood cultures at 48 hours, who have been afebrile for at least 24 hours, and who have evidence of marrow recovery (strong recommendation, low-quality evidence).
B5. In patients with low-risk FN, consider discontinuation of empirical antibiotics at 72 hours in patients who have negative blood cultures and who have been afebrile for at least 24 hours, irrespective of marrow recovery status, as long as careful follow-up is ensured (weak recommendation, moderate-quality evidence).
The 2012 CPG recommendation to discontinue antibiotics in patients with negative blood cultures who have been afebrile for at least 24 hours and who have evidence of count recovery was based on a summary of both randomized and observational trials.55-74 In that analysis, the risk of recurrent fever was low in patients with definitive marrow recovery.
No new RCTs of antibiotic cessation were identified in our recent systematic review,34 and thus, the recommendations have not changed. Two RCTs included in the 2012 CPG compared early cessation with continuation of empirical antibiotics.58,75 Both studies were small and showed no differences in outcomes. However, it is notable that the two patients with bacteremia (viridans group streptococci and Enterobacter aerogenes) were both in the cessation arm. Importantly, a large proportion of patients in one study75 had evidence of marrow recovery at the time of random assignment, whereas this proportion was not stated in the second study.58 Thus, it remains a weak recommendation to discontinue antibiotics in low-risk patients who have been afebrile for at least 24 hours but who have no evidence of count recovery on Day 3, because the specific question of safety of antibiotic discontinuation without marrow recovery has not been directly addressed.
The optimal duration of empirical antibiotics for high-risk patients with sustained bone marrow suppression was not addressed in the systematic review34 and continues to be an important research gap.
What clinical parameters can classify pediatric patients with persistent FN as high risk or low risk of invasive fungal disease (IFD)?
C1. Patients at high risk of IFD are those with acute myeloid leukemia, high-risk acute lymphoblastic leukemia (ALL), or relapsed acute leukemia, and children undergoing allogeneic HSCT. Children with prolonged neutropenia and children receiving high-dose corticosteroids are also at high risk of IFD. All others should be categorized as IFD low risk (strong recommendation, low quality evidence).
The updated CPG was modified based on a systematic review of risk factors for IFD specifically in pediatric oncology and HSCT recipients.75a This review included 22 studies76-97 and confirmed most risk factors for IFD previously described in the 2012 CPG. However, additional factors now specified include high-risk ALL and high-dose corticosteroids. The Panel recognized that high-risk ALL is a heterogeneous group and that the risk of IFD may be explained by prolonged neutropenia and corticosteroid administration. However, data to provide further specification around which patient with ALL is at particular risk of IFD and the treatment phases of elevated risk are not available.
What clinical features, laboratory tests, and imaging studies are useful to identify a fungal cause for persistent or recurrent FN despite broad-spectrum antibiotics?
C2. In terms of biomarkers to guide empirical antifungal management for prolonged (≥ 96 hours) FN in IFD high-risk patients:
C2a. Consider not using serum galactomannan (GM; weak recommendation, moderate-quality evidence).
C2b. Do not use β-d-glucan (BG; strong recommendation, low-quality evidence).
C2c. Do not use fungal polymerase chain reaction (PCR) testing in blood (strong recommendation, moderate-quality evidence).
C3. In terms of imaging for the evaluation of prolonged (≥ 96 hours) FN in IFD high-risk patients:
C3a. Perform computed tomography (CT) of the lungs (strong recommendation, low-quality evidence).
C3b. Consider imaging of abdomen in patients without localizing signs or symptoms (weak recommendation, low-quality evidence).
C3c. Consider not routinely performing CT of sinuses in patients without localizing signs or symptoms (weak recommendation, low-quality evidence).
In the 2012 CPG, we included recommendations related to surveillance and further investigation of identified foci of infection such as lung nodules. In this CPG update, we realized that these areas were outside of the scope of the FN CPG and thus, those recommendations have been removed.
The 2017 FN CPG altered the recommendation related to GM testing based on a recently conducted systematic review of fungal biomarkers in pediatric cancer and HSCT.98 Eight studies assessed GM as a diagnostic tool in children with symptoms potentially suggestive of IFD, such as prolonged FN.99-106 Among these studies, seven showed positive predictive values (PPV) ≤ 75%, and four studies showed PPV < 50%. Table 5 illustrates a clinical vignette of GM testing in a population with a 10% risk of invasive aspergillosis (IA) during FN and illustrates that using the pooled sensitivity and specificity of 89% and 85% from the systematic review, PPV would be 41% and negative predictive value (NPV) would be 97%. Among 100 patients at high risk of IA evaluated, testing would miss one patient with true infection and would erroneously conclude IA in 14 patients without infection. Of the 23 children with a positive test, only nine would actually have IA; in other words, most patients with a positive test in this clinical setting will not have IA. The basis for the weak recommendation against use of GM during FN was the poor PPV, and the limited usefulness of high NPV because GM does not rule out non-Aspergillus molds.
The recommendation related to BG testing remains unchanged. In the systematic review of biomarkers for IFD,98 only one study evaluated BG in an applicable setting,107 and it showed PPV of 49% (95% CI, 32 to 66) and NPV of 96% (95% CI, 89 to 99), precluding clinical usefulness.
The updated CPG includes a new strong recommendation against the use of fungal PCR in blood for evaluation of IFD during prolonged FN based on eight studies99,108-114 that applied PCR in a similar setting.109 Table 5 illustrates a clinical vignette of PCR testing in a population with a 10% risk of IFD during FN and illustrates that using the pooled sensitivity and specificity of 76% and 58% from the systematic review, PPV would be 17% and NPV would be 95%. Among 100 IFD high-risk patients evaluated, testing would miss two patients with true infection and would erroneously conclude IFD in 38 patients without infection. Of the 46 patients with a positive test, only eight would truly have IFD. The basis for the strong recommendation against use of PCR is the poor PPV and NPV, which were not sufficiently high to be clinically useful. The Panel also noted the current lack of standardization for PCR testing, which also makes clinical use challenging.
A limitation of the recommendations related to fungal biomarkers is how we approached them as diagnostic tests and evaluated their usefulness in detecting true disease. Randomized trials comparing utilization with nonutilization of these biomarkers to detect IFD would be a better approach to evaluation, but such trials are unlikely to be feasible. In fact, our current standard to recommend empirical antifungal therapy for IFD high-risk patients with prolonged fever is based on the assumption that prolonged fever is a good predictor of IFD when this factor has never been evaluated as a diagnostic test. Comparative effectiveness studies of fungal biomarker use may be the best way to bridge this knowledge gap.
The data supporting recommendations related to imaging for the evaluation of IFD during prolonged FN are shown in the Data Supplement. A strong recommendation to perform lung CTs remained unchanged in the updated CPG. Of the nine studies evaluating lung CT115-123 for the evaluation of IFD, lungs were usually the most frequent site of infection, and characteristic radiographic signs were often observed. A new weak recommendation for abdominal imaging even in the absence of localizing signs or symptoms was made with this CPG update, based on the systematic review (Data Supplement). Among the four studies included,118,122-124 findings on imaging consistent with IFD were observed in many patients without localizing signs or symptoms. The Panel noted that the ideal imaging modality is not known, but ultrasound is readily available, is not associated with radiation exposure, and usually does not require sedation and thus, is likely preferable over CT or magnetic resonance imaging for abdominal assessment.
In the updated CPG, a revised weak recommendation against routine sinus imaging was made in the absence of localizing signs or symptoms based on the systematic review (Data Supplement). Among the five studies that described sinus findings,118,122,123,125,126 sinus imaging was frequently abnormal in prolonged FN, and abnormalities did not distinguish between those with and without sinus IFD. It is a weak recommendation because studies directly addressing the usefulness of routine sinus CTs were limited.
When should empirical antifungal therapy be initiated, what antifungal agents are appropriate, and when is it appropriate to discontinue empirical therapy?
C4. In IFD high-risk patients with prolonged (≥ 96 hours) FN unresponsive to broad-spectrum antibacterial agents, initiate caspofungin or liposomal amphotericin B (L-AmB) for empirical antifungal therapy (strong recommendation, high-quality evidence).
C5. In IFD low-risk patients with prolonged (≥ 96 hours) FN, consider withholding empirical antifungal therapy (weak recommendation, low-quality evidence).
Recommendations regarding the choice of empirical antifungal agents in IFD high-risk patients remain unchanged from the 2012 FN CPG, but they are changed in IFD low-risk patients. Recommendations in IFD high-risk patients were originally based on three RCTs127-129 demonstrating that caspofungin was as effective as L-AmB,127,128 and that L-AmB was less nephrotoxic than amphotericin B deoxycholate.129 Either caspofungin or L-AmB was strongly recommended as empirical antifungal therapy. One recent study prospectively compared administration of empirical antifungal therapy versus withholding empirical antifungal therapy in neutropenic children with persistent fever who were IFD low-risk. No benefit relative to fever resolution or IFD was detected from empirical antifungal therapy.127
No RCTs addressed empirical antifungal therapy cessation or a pre-emptive antifungal therapy approach and thus, original recommendations were unchanged. Both of these areas remain important knowledge gaps in pediatric FN.
We updated the 2012 FN CPG for children with cancer and HSCT recipients. Although most recommendations remained unchanged, some key differences emerged. Changes included the listing of a fourth-generation cephalosporin for empirical therapy, refinement of IFD risk stratification, changes in recommended biomarkers and radiologic investigations for the evaluation of IFD, and a weak recommendation to withhold empirical antifungal therapy in IFD low-risk patients.
Implementation is an important issue, and national and international guidance will be important to effect change. Adaptation will be required at the institutional level to delineate specific rather than generic antibiotic choices and to decide whether to implement or not implement weak recommendations. Decision making for weak recommendations could also be made at the specific provider or patient level. Cost-effectiveness studies may be relevant when deciding whether to implement weak recommendations.
Changes to the updated FN CPG recommendations will likely influence the care of children with cancer and pediatric patients undergoing HSCT. Future work should focus on closing research gaps and identifying ways to facilitate implementation.
Supported by meeting grants from the Canadian Institutes of Health Research and the Garron Comprehensive Cancer Centre.
Conception and design: Thomas Lehrnbecher, Paula Robinson, Robert Phillips, Brian Fisher, Lillian Sung
Financial support: Lillian Sung
Administrative support: Paula Robinson, Lillian Sung
Collection and assembly of data: Thomas Lehrnbecher, Paula Robinson, Robert Phillips, Brian Fisher, Lillian Sung
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Consulting or Advisory Role: Gilead Sciences, Merck/Merck Sharp & Dohme, Astellas Pharma
Speakers’ Bureau: Astellas Pharma, Gilead Sciences
Research Funding: Gilead Sciences
Travel, Accommodations, Expenses: Astellas Pharma
No relationship to disclose
Research Funding: Pfizer (Inst), Merck (Inst), Ansun BioPharma (Inst)
No relationship to disclose
Travel, Accommodations, Expenses: EUSA Pharma
No relationship to disclose
Speakers' Bureau: Astellas, United Medical, Pfizer
Consulting or Advisory Role: Astellas Pharma, Basilea, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Zeneus/Cephalon
Speakers' Bureau: Astellas Pharma, Basilea, Gilead Sciences, Merck Sharp & Dohme, Schering-Plough, Zeneus/Cephalon, Pfizer
Research Funding: Gilead Sciences, Merck Sharp & Dohme, Pfizer, Schering-Plough
No relationship to disclose
No relationship to disclose
Consulting or Advisory Role: Gilead Sciences, Merck
Research Funding: Astellas Pharma
Consulting or Advisory Role: Basilea, Astellas Pharma, Pharmaceutica, Gilead Sciences, Pfizer
Travel, Accommodations, Expenses: Pfizer
No relationship to disclose
Consulting or Advisory Role: Jazz Pharmaceuticals
Research Funding: Jazz Pharmaceuticals
Research Funding: Gilead Sciences (Inst)
No relationship to disclose
Consulting or Advisory Role: Napriva
Research Funding: Merck (Inst)
No relationship to disclose
No relationship to disclose
We thank Sandra Cabral and Erin Plenert for administrative support.
|1.||Lehrnbecher T, Phillips R, Alexander S, et al: Guideline for the management of fever and neutropenia in children with cancer and/or undergoing hematopoietic stem-cell transplantation. J Clin Oncol 30:4427-4438, 2012 Link, Google Scholar|
|2.||Oxman AD, Fretheim A, Schünemann HJ: Improving the use of research evidence in guideline development: introduction. Health Res Policy Syst 4:12, 2006 Crossref, Medline, Google Scholar|
|3.||Brouwers MC, Kho ME, Browman GP, et al: Development of the AGREE II, part 1: Performance, usefulness and areas for improvement. CMAJ 182:1045-1052, 2010 Crossref, Medline, Google Scholar|
|4.||Rackoff WR, Gonin R, Robinson C, et al: Predicting the risk of bacteremia in childen with fever and neutropenia. J Clin Oncol 14:919-924, 1996 Link, Google Scholar|
|5.||Alexander SW, Wade KC, Hibberd PL, et al: Evaluation of risk prediction criteria for episodes of febrile neutropenia in children with cancer. J Pediatr Hematol Oncol 24:38-42, 2002 Crossref, Medline, Google Scholar|
|6.||Rondinelli PI, Ribeiro Kde C, de Camargo B: A proposed score for predicting severe infection complications in children with chemotherapy-induced febrile neutropenia. J Pediatr Hematol Oncol 28:665-670, 2006 Crossref, Medline, Google Scholar|
|7.||Santolaya ME, Alvarez AM, Becker A, et al: Prospective, multicenter evaluation of risk factors associated with invasive bacterial infection in children with cancer, neutropenia, and fever. J Clin Oncol 19:3415-3421, 2001 Link, Google Scholar|
|8.||Ammann RA, Hirt A, Lüthy AR, et al: Identification of children presenting with fever in chemotherapy-induced neutropenia at low risk for severe bacterial infection. Med Pediatr Oncol 41:436-443, 2003 Crossref, Medline, Google Scholar|
|9.||Ammann RA, Bodmer N, Hirt A, et al: Predicting adverse events in children with fever and chemotherapy-induced neutropenia: The prospective multicenter SPOG 2003 FN study. J Clin Oncol 28:2008-2014, 2010 Link, Google Scholar|
|10.||Madsen K, Rosenman M, Hui S, et al: Value of electronic data for model validation and refinement: Bacteremia risk in children with fever and neutropenia. J Pediatr Hematol Oncol 24:256-262, 2002 Crossref, Medline, Google Scholar|
|11.||Dommett R, Geary J, Freeman S, et al: 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 45:2843-2849, 2009 Crossref, Medline, Google Scholar|
|12.||Arif T, Sutcliffe R, Hewitt M, et al: G239 validation of two risk stratification guidelines in a one year cohort of febrile admissions in paediatric oncology patients in a UK centre. Arch Dis Child 99:A103, 2014 Crossref, Medline, Google Scholar|
|13.||Santolaya ME, Alvarez AM, Avilés CL, et al: Prospective evaluation of a model of prediction of invasive bacterial infection risk among children with cancer, fever, and neutropenia. Clin Infect Dis 35:678-683, 2002 Crossref, Medline, Google Scholar|
|14.||Macher E, Dubos F, Garnier N, et al: Predicting the risk of severe bacterial infection in children with chemotherapy-induced febrile neutropenia. Pediatr Blood Cancer 55:662-667, 2010 Crossref, Medline, Google Scholar|
|15.||Miedema KG, de Bont ES, Oude Nijhuis CS, et al: Validation of a new risk assessment model for predicting adverse events in children with fever and chemotherapy-induced neutropenia. J Clin Oncol 29:e182-e184; author reply e185, 2011 Google Scholar|
|16.||Phillips RS, Lehrnbecher T, Alexander S, et al: Updated systematic review and meta-analysis of the performance of risk prediction rules in children and young people with febrile neutropenia. PLoS One 7:e38300, 2012 Crossref, Medline, Google Scholar|
|17.||Miedema KG, Tissing WJ, Abbink FC, et al: Risk-adapted approach for fever and neutropenia in paediatric cancer patients--a national multicentre study. Eur J Cancer 53:16-24, 2016 Crossref, Medline, Google Scholar|
|18.||Santolaya ME, Alvarez AM, Avilés CL, et al: Prospective validation of a risk prediction model for severe sepsis in children with cancer and high-risk febrile neutropenia. Pediatr Infect Dis J 32:1318-1323, 2013 Crossref, Medline, Google Scholar|
|19.||Handrup MM, Møller JK, Rutkjaer C, et al: Importance of blood cultures from peripheral veins in pediatric patients with cancer and a central venous line. Pediatr Blood Cancer 62:99-102, 2015 Crossref, Medline, Google Scholar|
|20.||Leblanc D, Bartel N, Velasco-Gonzales C, et al: The utility of peripheral blood cultures in febrile pediatric oncology patients. Pediatr Blood Cancer 61:S56, 2014 Google Scholar|
|21.||Rodríguez L, Ethier M-C, Phillips B, et al: Utility of peripheral blood cultures in patients with cancer and suspected blood stream infections: A systematic review. Support Care Cancer 20:3261-3267, 2012 Crossref, Medline, Google Scholar|
|22.||DesJardin JA, Falagas ME, Ruthazer R, et al: Clinical utility of blood cultures drawn from indwelling central venous catheters in hospitalized patients with cancer. Ann Intern Med 131:641-647, 1999 Crossref, Medline, Google Scholar|
|23.||Chen WT, Liu TM, Wu SH, et al: Improving diagnosis of central venous catheter-related bloodstream infection by using differential time to positivity as a hospital-wide approach at a cancer hospital. J Infect 59:317-323, 2009 Crossref, Medline, Google Scholar|
|24.||Adamkiewicz TV, Lorenzana A, Doyle J, et al: Peripheral vs. central blood cultures in patients admitted to a pediatric oncology ward. Pediatr Infect Dis J 18:556-558, 1999 Crossref, Medline, Google Scholar|
|25.||Raad I, Hanna HA, Alakech B, et al: Differential time to positivity: A useful method for diagnosing catheter-related bloodstream infections. Ann Intern Med 140:18-25, 2004 Crossref, Medline, Google Scholar|
|26.||Handrup MM, Moller JK, Schroder H: Catheter-related bloodstream infections in children with cancer admitted with fever. 42nd Congress of the International Society of Pediatric Oncology (SIOP), Boston, MA, October 21-24, 2010 Google Scholar|
|27.||Barriga FJ, Varas M, Potin M, et al: Efficacy of a vancomycin solution to prevent bacteremia associated with an indwelling central venous catheter in neutropenic and non-neutropenic cancer patients. Med Pediatr Oncol 28:196-200, 1997 Crossref, Medline, Google Scholar|
|28.||Sandoval C, Sinaki B, Weiss R, et al: Urinary tract infections in pediatric oncology patients with fever and neutropenia. Pediatr Hematol Oncol 29:68-72, 2012 Crossref, Medline, Google Scholar|
|29.||Klaassen IL, de Haas V, van Wijk JA, et al: Pyuria is absent during urinary tract infections in neutropenic patients. Pediatr Blood Cancer 56:868-870, 2011 Crossref, Medline, Google Scholar|
|30.||Mori R, Yonemoto N, Fitzgerald A, et al: Diagnostic performance of urine dipstick testing in children with suspected UTI: A systematic review of relationship with age and comparison with microscopy. Acta Paediatr 99:581-584, 2010 Crossref, Medline, Google Scholar|
|31.||Roberts SD, Wells GM, Gandhi NM, et al: Diagnostic value of routine chest radiography in febrile, neutropenic children for early detection of pneumonia and mould infections. Support Care Cancer 20:2589-2594, 2012 Crossref, Medline, Google Scholar|
|32.||Cox JA, DeMasi J, McCollom S, et al: The diagnostic utility of routine chest radiography in the evaluation of the initial fever in patients undergoing hematopoietic stem cell. Pediatr Blood Cancer 57:666-668, 2011 Crossref, Medline, Google Scholar|
|33.||Renoult E, Buteau C, Turgeon N, et al: Is routine chest radiography necessary for the initial evaluation of fever in neutropenic children with cancer? Pediatr Blood Cancer 43:224-228, 2004 Crossref, Medline, Google Scholar|
|34.||Robinson PD, Lehrnbecher T, Phillips R, et al: Strategies for empiric management of pediatric fever and neutropenia in patients with cancer and hematopoietic stem-cell transplantation recipients: A systematic review of randomized trials. J Clin Oncol 34:2054-2060, 2016 Link, Google Scholar|
|35.||Pereira CA, Petrilli AS, Carlesse FA, et al: Cefepime monotherapy is as effective as ceftriaxone plus amikacin in pediatric patients with cancer and high-risk febrile neutropenia in a randomized comparison. J Microbiol Immunol Infect 42:141-147, 2009 Medline, Google Scholar|
|36.||Petrilli AS, Cypriano M, Dantas LS, et al: Evaluation of ticarcillin/clavulanic acid versus ceftriaxone plus amikacin for fever and neutropenia in pediatric patients with leukemia and lymphoma. Braz J Infect Dis 7:111-120, 2003 Crossref, Medline, Google Scholar|
|37.||El Haddad AMA: Comparison of cefoperazone-sulbactam versus piperacillin plus amikacin as empiric therapy in pediatric febrile neutropenic cancer patients. Curr Ther Res Clin Exp 56:1094-1099, 1995 Crossref, Google Scholar|
|38.||Ichikawa M, Suzuki D, Ohshima J, et al: Piperacillin/tazobactam versus cefozopran for the empirical treatment of pediatric cancer patients with febrile neutropenia. Pediatr Blood Cancer 57:1159-1162, 2011 Crossref, Medline, Google Scholar|
|39.||Uygun V, Karasu GT, Ogunc D, et al: Piperacillin/tazobactam versus cefepime for the empirical treatment of pediatric cancer patients with neutropenia and fever: A randomized and open-label study. Pediatr Blood Cancer 53:610-614, 2009 Crossref, Medline, Google Scholar|
|40.||Corapcioglu F, Sarper N, Zengin E: Monotherapy with piperacillin/tazobactam versus cefepime as empirical therapy for febrile neutropenia in pediatric cancer patients: A randomized comparison. Pediatr Hematol Oncol 23:177-186, 2006 Crossref, Medline, Google Scholar|
|41.||Sano H, Kobayashi R, Suzuki D, et al: Comparison between piperacillin/tazobactam and cefepime monotherapies as an empirical therapy for febrile neutropenia in children with hematological and malignant disorders: A prospective, randomized study. Pediatr Blood Cancer 62:356-358, 2015 Crossref, Medline, Google Scholar|
|42.||Aamir M, Abrol P, Sharma D, et al: A clinical evaluation of efficacy and safety of cefepime monotherapy versus piperacillin-tazobactam in patients of paediatric age group with febrile neutropenia in a tertiary care centre of north India. Trop Doct 46:142-148, 2016 Crossref, Medline, Google Scholar|
|43.||Orme LM, Babl FE, Barnes C, et al: Outpatient versus inpatient IV antibiotic management for pediatric oncology patients with low risk febrile neutropenia: A randomised trial. Pediatr Blood Cancer 61:1427-1433, 2014 Crossref, Medline, Google Scholar|
|44.||Brack E, Bodmer N, Simon A, et al: 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 59:423-430, 2012 Crossref, Medline, Google Scholar|
|45.||Ahmed N, El-Mahallawy HA, Ahmed IA, et al: Early hospital discharge versus continued hospitalization in febrile pediatric cancer patients with prolonged neutropenia: A randomized, prospective study. Pediatr Blood Cancer 49:786-792, 2007 Crossref, Medline, Google Scholar|
|46.||Santolaya ME, Alvarez AM, Avilés CL, et al: Early hospital discharge followed by outpatient management versus continued hospitalization of children with cancer, fever, and neutropenia at low risk for invasive bacterial infection. J Clin Oncol 22:3784-3789, 2004 Link, Google Scholar|
|47.||Cagol AR, Castro Junior CG, Martins MC, et al: Oral vs. intravenous empirical antimicrobial therapy in febrile neutropenic patients receiving childhood cancer chemotherapy. J Pediatr (Rio J) 85:531-535, 2009 Medline, Google Scholar|
|48.||Gupta A, Swaroop C, Agarwala S, et al: Randomized controlled trial comparing oral amoxicillin-clavulanate and ofloxacin with intravenous ceftriaxone and amikacin as outpatient therapy in pediatric low-risk febrile neutropenia. J Pediatr Hematol Oncol 31:635-641, 2009 Crossref, Medline, Google Scholar|
|49.||Paganini H, Gómez S, Ruvinsky S, et al: Outpatient, sequential, parenteral-oral antibiotic therapy for lower risk febrile neutropenia in children with malignant disease: A single-center, randomized, controlled trial in Argentina. Cancer 97:1775-1780, 2003 Crossref, Medline, Google Scholar|
|50.||Paganini H, Rodriguez-Brieshcke T, Zubizarreta P, et al: Oral ciprofloxacin in the management of children with cancer with lower risk febrile neutropenia. Cancer 91:1563-1567, 2001 Crossref, Medline, Google Scholar|
|51.||Shenep JL, Flynn PM, Baker DK, et al: Oral cefixime is similar to continued intravenous antibiotics in the empirical treatment of febrile neutropenic children with cancer. Clin Infect Dis 32:36-43, 2001 Crossref, Medline, Google Scholar|
|52.||Paganini HR, Sarkis CM, De Martino MG, et al: Oral administration of cefixime to lower risk febrile neutropenic children with cancer. Cancer 88:2848-2852, 2000 Crossref, Medline, Google Scholar|
|53.||Petrilli AS, Dantas LS, Campos MC, et al: Oral ciprofloxacin vs. intravenous ceftriaxone administered in an outpatient setting for fever and neutropenia in low-risk pediatric oncology patients: Randomized prospective trial. Med Pediatr Oncol 34:87-91, 2000 Crossref, Medline, Google Scholar|
|54.||Mullen CA, Petropoulos D, Roberts WM, et al: Outpatient treatment of fever and neutropenia for low risk pediatric cancer patients. Cancer 86:126-134, 1999 Crossref, Medline, Google Scholar|
|55.||Oude Nijhuis C, Kamps WA, Daenen SM, et al: Feasibility of withholding antibiotics in selected febrile neutropenic cancer patients. J Clin Oncol 23:7437-7444, 2005 Link, Google Scholar|
|56.||Aquino VM, Buchanan GR, Tkaczewski I, et al: Safety of early hospital discharge of selected febrile children and adolescents with cancer with prolonged neutropenia. Med Pediatr Oncol 28:191-195, 1997 Crossref, Medline, Google Scholar|
|57.||Pizzo PA, Robichaud KJ, Gill FA, et al: Duration of empiric antibiotic therapy in granulocytopenic patients with cancer. Am J Med 67:194-200, 1979 Crossref, Medline, Google Scholar|
|58.||Santolaya ME, Villarroel M, Avendaño LF, et al: Discontinuation of antimicrobial therapy for febrile, neutropenic children with cancer: A prospective study. Clin Infect Dis 25:92-97, 1997 Crossref, Medline, Google Scholar|
|59.||Wacker P, Halperin DS, Wyss M, et al: Early hospital discharge of children with fever and neutropenia: A prospective study. J Pediatr Hematol Oncol 19:208-211, 1997 Crossref, Medline, Google Scholar|
|60.||Cohen KJ, Leamer K, Odom L, et al: Cessation of antibiotics regardless of ANC is safe in children with febrile neutropenia. A preliminary prospective trial. J Pediatr Hematol Oncol 17:325-330, 1995 Crossref, Medline, Google Scholar|
|61.||Bash RO, Katz JA, Cash JV, et al: Safety and cost effectiveness of early hospital discharge of lower risk children with cancer admitted for fever and neutropenia. Cancer 74:189-196, 1994 Crossref, Medline, Google Scholar|
|62.||Hodgson-Viden H, Grundy PE, Robinson JL: Early discontinuation of intravenous antimicrobial therapy in pediatric oncology patients with febrile neutropenia. BMC Pediatr 5:10, 2005 Crossref, Medline, Google Scholar|
|63.||Lehrnbecher T, Stanescu A, Kühl J: Short courses of intravenous empirical antibiotic treatment in selected febrile neutropenic children with cancer. Infection 30:17-21, 2002 Crossref, Medline, Google Scholar|
|64.||Griffin TC, Buchanan GR: Hematologic predictors of bone marrow recovery in neutropenic patients hospitalized for fever: Implications for discontinuation of antibiotics and early discharge from the hospital. J Pediatr 121:28-33, 1992 Crossref, Medline, Google Scholar|
|65.||Kaplan AH, Weber DJ, Davis L, et al: Short courses of antibiotics in selected febrile neutropenic patients. Am J Med Sci 302:353-354, 1991 Crossref, Medline, Google Scholar|
|66.||Mullen CA, Buchanan GR: Early hospital discharge of children with cancer treated for fever and neutropenia: Identification and management of the low-risk patient. J Clin Oncol 8:1998-2004, 1990 Link, Google Scholar|
|67.||Aquino VM, Tkaczewski I, Buchanan GR: Early discharge of low-risk febrile neutropenic children and adolescents with cancer. Clin Infect Dis 25:74-78, 1997 Crossref, Medline, Google Scholar|
|68.||Slobbe L, Waal Lv, Jongman LR, et al: Three-day treatment with imipenem for unexplained fever during prolonged neutropaenia in haematology patients receiving fluoroquinolone and fluconazole prophylaxis: a prospective observational safety study. Eur J Cancer 45:2810-2817, 2009 Crossref, Medline, Google Scholar|
|69.||Cornelissen JJ, Rozenberg-Arska M, Dekker AW: Discontinuation of intravenous antibiotic therapy during persistent neutropenia in patients receiving prophylaxis with oral ciprofloxacin. Clin Infect Dis 21:1300-1302, 1995 Crossref, Medline, Google Scholar|
|70.||de Marie S, van den Broek PJ, Willemze R, et al: Strategy for antibiotic therapy in febrile neutropenic patients on selective antibiotic decontamination. Eur J Clin Microbiol Infect Dis 12:897-906, 1993 Crossref, Medline, Google Scholar|
|71.||Joshi JH, Schimpff SC, Tenney JH, et al: Can antibacterial therapy be discontinued in persistently febrile granulocytopenic cancer patients? Am J Med 76:450-457, 1984 Crossref, Medline, Google Scholar|
|72.||Björnsson S, Preisler H, Henderson ES: A study of antibiotic therapy in fever of unknown origin in neutropenic cancer patients. Med Pediatr Oncol 3:379-385, 1977 Crossref, Medline, Google Scholar|
|73.||Mahendra P, Jacobson SK, Ager S, et al: Short-course intravenous antibiotics with oral quinolone prophylaxis in the treatment of neutropenic fever in autologous bone marrow or peripheral blood progenitor cell transplant recipients. Acta Haematol 96:64-67, 1996 Crossref, Medline, Google Scholar|
|74.||Tomiak AT, Yau JC, Huan SD, et al: Duration of intravenous antibiotics for patients with neutropenic fever. Ann Oncol 5:441-445, 1994 Crossref, Medline, Google Scholar|
|75.||Klaassen RJ, Allen U, Doyle JJ: Randomized placebo-controlled trial of oral antibiotics in pediatric oncology patients at low-risk with fever and neutropenia. J Pediatr Hematol Oncol 22:405-411, 2000 Crossref, Medline, Google Scholar|
|75a.||Fisher B, Robinson P, Lehrnbecher T, et al: Risk factors for invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: A systematic review. J Pediatric Infect Dis Soc. In press Google Scholar|
|76.||Johnston DL, Lewis V, Yanofsky R, et al: Invasive fungal infections in paediatric acute myeloid leukaemia. Mycoses 56:482-487, 2013 Crossref, Medline, Google Scholar|
|77.||Castagnola E, Bagnasco F, Bandettini R, et al: Role of acute graft-versus-host disease in the risk of bacteremia and invasive fungal disease after allogeneic hemopoietic stem cell transplantation in children. Results from a single-center observational study. Biol Blood Marrow Transplant 20:1068-1073, 2014 Crossref, Medline, Google Scholar|
|78.||Hol JA, Wolfs TF, Bierings MB, et al: Predictors of invasive fungal infection in pediatric allogeneic hematopoietic SCT recipients. Bone Marrow Transplant 49:95-101, 2014 Crossref, Medline, Google Scholar|
|79.||Srinivasan A, Wang C, Srivastava DK, et al: Timeline, epidemiology, and risk factors for bacterial, fungal, and viral infections in children and adolescents after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 19:94-101, 2013 Crossref, Medline, Google Scholar|
|80.||Satwani P, Baldinger L, Freedman J, et al: Incidence of viral and fungal infections following busulfan-based reduced-intensity versus myeloablative conditioning in pediatric allogeneic stem cell transplantation recipients. Biol Blood Marrow Transplant 15:1587-1595, 2009 Crossref, Medline, Google Scholar|
|81.||Kobayashi R, Kaneda M, Sato T, et al: Evaluation of risk factors for invasive fungal infection after allogeneic stem cell transplantation in pediatric patients. J Pediatr Hematol Oncol 29:786-791, 2007 Crossref, Medline, Google Scholar|
|82.||Dvorak CC, Steinbach WJ, Brown JM, et al: Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 36:621-629, 2005 Crossref, Medline, Google Scholar|
|83.||Benjamin DK, Jr., Miller WC, Bayliff S, et al: Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J 21:227-234, 2002 Crossref, Medline, Google Scholar|
|84.||Hovi L, Saarinen-Pihkala UM, Vettenranta K, et al: Invasive fungal infections in pediatric bone marrow transplant recipients: Single center experience of 10 years. Bone Marrow Transplant 26:999-1004, 2000 Crossref, Medline, Google Scholar|
|85.||Jain S, Kapoor G: Invasive aspergillosis in children with acute leukemia at a resource-limited oncology center. J Pediatr Hematol Oncol 37:e1-e5, 2015 Crossref, Medline, Google Scholar|
|86.||Castagnola E, Rossi MR, Cesaro S, et al: Incidence of bacteremias and invasive mycoses in children with acute non-lymphoblastic leukemia: Results from a multi-center Italian study. Pediatr Blood Cancer 55:1103-1107, 2010 Crossref, Medline, Google Scholar|
|87.||Sung L, Gamis A, Alonzo TA, et al: Infections and association with different intensity of chemotherapy in children with acute myeloid leukemia. Cancer 115:1100-1108, 2009 Crossref, Medline, Google Scholar|
|88.||Castagnola E, Caviglia I, Pistorio A, et al: Bloodstream infections and invasive mycoses in children undergoing acute leukaemia treatment: a 13-year experience at a single Italian institution. Eur J Cancer 41:1439-1445, 2005 Crossref, Medline, Google Scholar|
|89.||Rosen GP, Nielsen K, Glenn S, et al: Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol Oncol 27:135-140, 2005 Crossref, Medline, Google Scholar|
|90.||McCullers JA, Vargas SL, Flynn PM, et al: Candidal meningitis in children with cancer. Clin Infect Dis 31:451-457, 2000 Crossref, Medline, Google Scholar|
|91.||Villarroel M, Avilés CL, Silva P, et al: Risk factors associated with invasive fungal disease in children with cancer and febrile neutropenia: A prospective multicenter evaluation. Pediatr Infect Dis J 29:816-821, 2010 Crossref, Medline, Google Scholar|
|92.||Lucero Y, Brücher R, Alvarez AM, et al: Invasive fungal infections in children with cancer, neutropenia and fever, in Chile [in Spansh]. Rev Med Chil 130:1139-1146, 2002 Medline, Google Scholar|
|93.||Wiley JM, Smith N, Leventhal BG, et al: Invasive fungal disease in pediatric acute leukemia patients with fever and neutropenia during induction chemotherapy: A multivariate analysis of risk factors. J Clin Oncol 8:280-286, 1990 Link, Google Scholar|
|94.||Styczynski J, Czyzewski K, Wysocki M, et al: Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study. Clin Microbiol Infect 22:179.e1-179 e10, 2016 Google Scholar|
|95.||Babor F, Schuster F, Mackenzie C, et al: Invasive aspergillosis in pediatric oncology patients: A rare event with poor prognosis--case analysis to plan better targeted prophylactic or therapeutic measurement. Klin Padiatr 224:160-165, 2012 Crossref, Medline, Google Scholar|
|96.||Hale KA, Shaw PJ, Dalla-Pozza L, et al: Epidemiology of paediatric invasive fungal infections and a case-control study of risk factors in acute leukaemia or post stem cell transplant. Br J Haematol 149:263-272, 2010 Crossref, Medline, Google Scholar|
|97.||Lai HP, Chen YC, Chang LY, et al: Invasive fungal infection in children with persistent febrile neutropenia. J Formos Med Assoc 104:174-179, 2005 Medline, Google Scholar|
|98.||Lehrnbecher T, Robinson PD, Fisher BT, et al: Galactomannan, β-D-glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: A systematic review and meta-analysis. Clin Infect Dis 63:1340-1348, 2016 Crossref, Medline, Google Scholar|
|99.||El-Mahallawy HA, Shaker HH, Ali Helmy H, et al: Evaluation of pan-fungal PCR assay and Aspergillus antigen detection in the diagnosis of invasive fungal infections in high risk paediatric cancer patients. Med Mycol 44:733-739, 2006 Crossref, Medline, Google Scholar|
|100.||Choi SH, Kang ES, Eo H, et al: Aspergillus galactomannan antigen assay and invasive aspergillosis in pediatric cancer patients and hematopoietic stem cell transplant recipients. Pediatr Blood Cancer 60:316-322, 2013 Crossref, Medline, Google Scholar|
|101.||Dinand V, Anjan M, Oberoi JK, et al: Threshold of galactomannan antigenemia positivity for early diagnosis of invasive aspergillosis in neutropenic children. J Microbiol Immunol Infect 49:66-73, 2016 Crossref, Medline, Google Scholar|
|102.||de Mol M, de Jongste JC, van Westreenen M, et al: Diagnosis of invasive pulmonary aspergillosis in children with bronchoalveolar lavage galactomannan. Pediatr Pulmonol 48:789-796, 2013 Crossref, Medline, Google Scholar|
|103.||Armenian SH, Nash KA, Kapoor N, et al: Prospective monitoring for invasive aspergillosis using galactomannan and polymerase chain reaction in high risk pediatric patients. J Pediatr Hematol Oncol 31:920-926, 2009 Crossref, Medline, Google Scholar|
|104.||Castagnola E, Furfaro E, Caviglia I, et al: 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 16:1197-1203, 2010 Crossref, Medline, Google Scholar|
|105.||Jha AK, Bansal D, Chakrabarti A, et al: Serum galactomannan assay for the diagnosis of invasive aspergillosis in children with haematological malignancies. Mycoses 56:442-448, 2013 Crossref, Medline, Google Scholar|
|106.||Reinwald M, Konietzka CA, Kolve H, et al: Assessment of Aspergillus-specific PCR as a screening method for invasive aspergillosis in paediatric cancer patients and allogeneic haematopoietic stem cell recipients with suspected infections. Mycoses 57:537-543, 2014 Crossref, Medline, Google Scholar|
|107.||Zhao L, Tang JY, Wang Y, et al: Value of plasma beta-Glucan in early diagnosis of invasive fungal infection in children [in Chinese]. Zhongguo Dang Dai Er Ke Za Zhi 11:905-908, 2009 Medline, Google Scholar|
|108.||Lin MT, Lu HC, Chen WL: Improving efficacy of antifungal therapy by polymerase chain reaction-based strategy among febrile patients with neutropenia and cancer. Clin Infect Dis 33:1621-1627, 2001 Crossref, Medline, Google Scholar|
|109.||Lehrnbecher T, Robinson PD, Fisher BT, et al: Galactomannan, beta-D-glucan, and polymerase chain reaction-based assays for the diagnosis of invasive fungal disease in pediatric cancer and hematopoietic stem cell transplantation: A systematic review and meta-analysis. Clin Infect Dis 63:1340-1348, 2016 Crossref, Medline, Google Scholar|
|110.||Cesaro S, Stenghele C, Calore E, et al: Assessment of the lightcycler PCR assay for diagnosis of invasive aspergillosis in paediatric patients with onco-haematological diseases. Mycoses 51:497-504, 2008 Crossref, Medline, Google Scholar|
|111.||Hummel M, Spiess B, Roder J, et al: Detection of Aspergillus DNA by a nested PCR assay is able to improve the diagnosis of invasive aspergillosis in paediatric patients. J Med Microbiol 58:1291-1297, 2009 Crossref, Medline, Google Scholar|
|112.||Landlinger C, Preuner S, Bašková L, et al: Diagnosis of invasive fungal infections by a real-time panfungal PCR assay in immunocompromised pediatric patients. Leukemia 24:2032-2038, 2010 Crossref, Medline, Google Scholar|
|113.||Mandhaniya S, Iqbal S, Sharawat SK, et al: Diagnosis of invasive fungal infections using real-time PCR assay in paediatric acute leukaemia induction. Mycoses 55:372-379, 2012 Crossref, Medline, Google Scholar|
|114.||Reinwald M, Hummel M, Kovalevskaya E, et al: Therapy with antifungals decreases the diagnostic performance of PCR for diagnosing invasive aspergillosis in bronchoalveolar lavage samples of patients with haematological malignancies. J Antimicrob Chemother 67:2260-2267, 2012 Crossref, Medline, Google Scholar|
|115.||Han SB, Kim SK, Bae EY, et al: Clinical features and prognosis of invasive pulmonary aspergillosis in Korean children with hematologic/oncologic siseases. J Korean Med Sci 30:1121-1128, 2015 Crossref, Medline, Google Scholar|
|116.||Batra S, Li B, Underhill N, et al: Clinical utility of bronchoalveolar lavage and respiratory tract biopsies in diagnosis and management of suspected invasive respiratory fungal infections in children. Pediatr Blood Cancer 62:1579-1586, 2015 Crossref, Medline, Google Scholar|
|117.||Gasparetto TD, Escuissato DL, Marchiori E: Pulmonary infections following bone marrow transplantation: High-resolution CT findings in 35 paediatric patients. Eur J Radiol 66:117-121, 2008 Crossref, Medline, Google Scholar|
|118.||Archibald S, Park J, Geyer JR, et al: Computed tomography in the evaluation of febrile neutropenic pediatric oncology patients. Pediatr Infect Dis J 20:5-10, 2001 Crossref, Medline, Google Scholar|
|119.||Winer-Muram HT, Arheart KL, Jennings SG, et al: Pulmonary complications in children with hematologic malignancies: Accuracy of diagnosis with chest radiography and CT. Radiology 204:643-649, 1997 Crossref, Medline, Google Scholar|
|120.||Taccone A, Occhi M, Garaventa A, et al: CT of invasive pulmonary aspergillosis in children with cancer. Pediatr Radiol 23:177-180, 1993 Crossref, Medline, Google Scholar|
|121.||Irga N, Kosiak W, Szalewska M, et al: Invasive fungal infections in children treated for oncohematologic disorders - Selected diagnostic and therapeutic issues [in Polish]. Onkologia Polska 13:185-190, 2010 Google Scholar|
|122.||Ahmad Sarji S, Wan Abdullah W, Wastie M: Imaging features of fungal infection in immuno-suppressed patients in a local ward outbreak. Biomed Imaging Interv J 2:e21, 2006 Google Scholar|
|123.||Cohn SM, Pokala HR, Siegel JD, et al: Application of a standardized screening protocol for diagnosis of invasive mold infections in children with hematologic malignancies. Support Care Cancer 24:5025-5033, 2016 Crossref, Medline, Google Scholar|
|124.||Bartley DL, Hughes WT, Parvey LS, et al: Computed tomography of hepatic and splenic fungal abscesses in leukemic children. Pediatr Infect Dis 1:317-321, 1982 Crossref, Medline, Google Scholar|
|125.||Park AH, Muntz HR, Smith ME, et al: Pediatric invasive fungal rhinosinusitis in immunocompromised children with cancer. Otolaryngol Head Neck Surg 133:411-416, 2005 Crossref, Medline, Google Scholar|
|126.||Kavanagh KT, Hughes WT, Parham DM, et al: Fungal sinusitis in immunocompromised children with neoplasms. Ann Otol Rhinol Laryngol 100:331-336, 1991 Crossref, Medline, Google Scholar|
|127.||Caselli D, Cesaro S, Ziino O, et al: A prospective, randomized study of empirical antifungal therapy for the treatment of chemotherapy-induced febrile neutropenia in children. Br J Haematol 158:249-255, 2012 Crossref, Medline, Google Scholar|
|128.||Maertens JA, Madero L, Reilly AF, et al: 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 29:415-420, 2010 Crossref, Medline, Google Scholar|
|129.||Sandler ES, Mustafa MM, Tkaczewski I, et al: Use of amphotericin B colloidal dispersion in children. J Pediatr Hematol Oncol 22:242-246, 2000 Crossref, Medline, Google Scholar|