To develop an evidence-based guideline for the empiric management of pediatric fever and neutropenia (FN).
The International Pediatric Fever and Neutropenia Guideline Panel is a multidisciplinary and ...multinational group composed of experts in pediatric oncology and infectious disease as well as a patient advocate. The Panel was convened for the purpose of creating this guideline. We followed previously validated procedures for creating evidence-based guidelines. Working groups focused on initial presentation, ongoing management, and empiric antifungal therapy. Each working group developed key clinical questions, conducted systematic reviews of the published literature, and compiled evidence summaries. The Grades of Recommendation Assessment, Development, and Evaluation approach was used to generate summaries, and evidence was classified as high, moderate, low, or very low based on methodologic considerations.
Recommendations were made related to initial presentation (risk stratification, initial evaluation, and treatment), ongoing management (modification and cessation of empiric antibiotics), and empiric antifungal treatment (risk stratification, evaluation, and treatment) of pediatric FN. For each recommendation, the strength of the recommendation and level of evidence are presented.
This guideline represents an evidence-based approach to FN specific to children with cancer. Although some recommendations are similar to adult-based guidelines, there are key distinctions in multiple areas. Implementation will require adaptation to the local context.
Despite major improvements in outcome over the past decades, acute myeloid leukemia (AML) remains a life-threatening malignancy in children, with current survival rates of ∼ 70%. State-of-the-art ...recommendations in adult AML have recently been published in this journal by Döhner et al. The primary goal of an international expert panel of the International BFM Study Group AML Committee was to set standards for the management, diagnosis, response assessment, and treatment in childhood AML. This paper aims to discuss differences between childhood and adult AML, and to highlight recommendations that are specific to children. The particular relevance of new diagnostic and prognostic molecular markers in pediatric AML is presented. The general management of pediatric AML, the management of specific pediatric AML cohorts (such as infants) or subtypes of the disease occurring in children (such as Down syndrome related AML), as well as new therapeutic approaches, and the role of supportive care are discussed.
Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. ...Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS).
Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions.
Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio HR, 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387).
Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.
This report illustrates the importance of a detailed history and physical exam and careful analysis of hematologic parameters when diagnosing ITP. This case demonstrates that even with subtle ...deviations from typical ITP findings one must promptly reevaluate the diagnosis. This case also highlights the importance of peripheral smear review by an expert in pediatric hematopathology.
A previously healthy 10 year-old Asian boy presented with 2 months of easy bruising. Review of systems was negative for any constitutional symptoms. On examination, he appeared well but had numerous large ecchymoses. He had no appreciable lymphadenopathy or splenomegaly. The liver was palpable 1.5 cm below the costal margin. A complete blood count (CBC) showed: platelets = 17 × 109/L, hemoglobin = 128 g/L, white blood cell count = 5.43 × 109/L, and neutrophils = 1.63 × 109/L. A blood smear was reported as normal. Urate was 370 umol/L and lactate dehydrogenase (LDH) was 803 U/L. The child was admitted with a presumptive diagnosis of immune thrombocytopenic purpura (ITP) and treated with intravenous immunoglobulin. The following day, the blood smear was reviewed by a hematopathologist who identified blasts. A bone marrow aspiration (BMA) confirmed the diagnosis of precursor B-cell acute lymphoblastic leukemia.
In children presenting with suspected ITP, leukemia should always be considered. A BMA was historically performed on all patients with presumed ITP to rule out leukemia. In 2011, the American Society of Hematology (ASH) stopped recommending routine BMA in patients suspected of having ITP. ASH advises in cases with unusual findings on history, physical examination or CBC, it is reasonable to perform a BMA. Our patient had mild hepatomegaly, which may have qualified him for a BMA. He also had an elevated LDH and urate, which are not listed as criteria for BMA by ASH but were considered atypical for ITP by the clinical team. A literature search did not reveal any primary data assessing these markers. While corticosteroids are a first line treatment in ITP, they must be reserved for when clinicians are confident that the patient does not have leukemia. Steroid administration prior to diagnosing leukemia results in delayed diagnosis and may increase the risk of complications and decrease survival.
This update of the 2013 clinical practice guideline provides clinicians with guidance regarding the use of aprepitant and palonosetron for the prevention of acute chemotherapy‐induced nausea and ...vomiting (CINV) in children. The recommendations were based on three systematic reviews. Substantive changes were made to the guideline recommendations including the inclusion of palonosetron to the 5‐HT3 antagonists recommended for children receiving highly emetogenic chemotherapy (HEC) and the recommendation of aprepitant for children 6 months of age or older receiving HEC. To optimize CINV control in children, future work must focus on closing critical research gaps.
Objective was to describe the effect of antibiotic and granulocyte colony-stimulating factor (G-CSF) prophylaxis and discharge policy on infection risk and nonrelapse-related mortality (NRM) during ...chemotherapy for children with acute myeloid leukemia. Patients were non–Down syndrome children enrolled on Children's Oncology Group (COG) trial AAML0531. We surveyed sites to determine institutional standards for systemic antibacterial, antifungal, and G-CSF prophylaxis, and mandatory hospitalization during neutropenia. COG institution survey response rate was 180 of 216 (83.3%). Of 1024 patients enrolled on AAML0531, 897 were non-Down patients from survey-responding institutions. In multiple regression, antibacterial prophylaxis reduced any sterile-site bacterial infection (incidence rate ratio IRR 0.85; 95% confidence interval CI, 0.72-1.01; P = .058) and Gram-positive sterile-site infection (IRR 0.71; 95% CI, 0.57-0.90; P = .004). Prophylactic G-CSF reduced bacterial (IRR 0.79; 95% CI, 0.67-0.92; P = .004) and Clostridium difficile infections (CDIs; IRR 0.46; 95% CI, 0.25-0.84; P = .012). Mandatory hospitalization did not reduce bacterial/fungal infection or significantly reduce NRM but did increase CDI (IRR 1.96; 95% CI, 1.34-2.87; P < .001). Antibacterial and G-CSF prophylaxis reduced infection rates while mandatory hospitalization did not reduce infection or significantly affect NRM. This trial was registered at www.clinicaltrials.gov as #AAML0531.
•Systemic antibacterial and granulocyte colony-stimulating factor prophylaxis appear to reduce bacterial infection rates.•Mandatory hospitalization during profound neutropenia did not reduce infection or significantly reduce nonrelapse-related mortality.
Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ...ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the International Society of Pediatric Oncology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.
Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk ...stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review.
The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685.
We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this.
The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.
OBJECTIVE:The tumor necrosis factor (TNF)-α promoter −308 A/G polymorphism has been reported to be associated with sepsis with inconsistent results. We conducted a systematic review and meta-analysis ...to determine whether the TNF-α −308 A/G polymorphism TNF2 (G/A or A/A) confers susceptibility to sepsis or is associated with increased risk of death from sepsis.
DATA SOURCES:We performed an electronic search of OVID MEDLINE from 1950 to June 2008 and EMBASE from 1980 to June 2008.
STUDY SELECTION:From 1935 reviewed study articles, 25 were included based on predefined inclusion criteria.
DATA EXTRACTION:Two reviewers independently extracted data onto standardized forms.
DATA SYNTHESIS:An association between development of sepsis and the TNF2 genotype was found in the overall population (odds ratio, 2.15; 95% confidence interval, 1.45–3.19; p < .01). Stratification by ethnicity indicated that the contribution to this observation may be stronger among the Asian population (odds ratio, 3.16; 95% confidence interval, 1.92 to 5.20; p < .01) compared with other ethnicities. There was no association between the TNF2 genotype and mortality from sepsis (odds ratio, 1.48; 95% confidence interval, 0.81 to 2.70; p = .20). However, when stratified for ethnicity, there may be an increased risk for fatal outcomes among Asians (odds ratio, 10.75; 95% confidence interval, 2.98 to 38.78; p < .01).
CONCLUSIONS:Our systematic review and meta-analysis demonstrates that the TNF2 polymorphism is associated with sepsis. However, TNF2 is not associated with sepsis mortality.
While medical records have detailed information, they are limited in reach to the availability and accessibility of those records. On the other hand, administrative data while limited in scope, have ...a much further reach in coverage of an entire population. However, few studies have validated the use of administrative data for identifying infections in pediatric populations. Pediatric patients from Ontario, Canada aged <18 years were randomly sampled from the Electronic Medical Record Administrative data Linked Database (EMRALD). Using physician diagnoses from the electronic medical record (EMR) as the reference standard, we determined the criterion validity of physician billing claims in administrative data for identifying infectious disease syndromes from 2012 to 2014. Diagnosis codes were assessed by infection category (respiratory, skin and soft tissue, gastrointestinal, urinary tract and otitis externa) and for all infections combined. Sensitivity analyses assessed the performance if patients had more than one reason to visit the physician. We analysed 2,139 patients and found 33.3% of all visits were for an infection, and respiratory infections accounted for 67.6% of the infections. When we combined all infection categories, sensitivity was 0.74 (95% CI 0.70-0.77), specificity was 0.95 (95% CI 0.93-0.96), positive predictive value (PPV) was 0.87 (95% CI 0.84-0.90), and negative predictive value (NPV) was 0.88 (95% CI 0.86-0.89). For respiratory infections, sensitivity was 0.77 (95% CI 0.73-0.81), specificity was 0.96 (95% CI 0.95-0.97), PPV was 0.85 (95% CI 0.81-0.88), and NPV was 0.94 (95% CI 0.92-0.95). Similar performance was observed for skin and soft tissue, gastrointestinal, urinary tract, and otitis externa infections, but with lower sensitivity. Performance measures were highest when the patient visited the physician with only one health complaint. We found when using linked EMR data as the reference standard, administrative billing codes are reasonably accurate in identifying infections in a pediatric population.
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