Prospective cohort study of procalcitonin levels in children with cancer presenting with febrile neutropenia

BACKGROUND: Febrile neutropenia (FNP) causes significant morbidity and mortality in children undergoing treatment for cancer. The development of clinical decision rules to help stratify risks in paediatric FNP patients and the use of inflammatory biomarkers to identify high risk patients is an area of recent research. This study aimed to assess if procalcitonin (PCT) levels could be used to help diagnose or exclude severe infection in children with cancer who present with febrile neutropenia, both as a single measurement and in addition to previously developed clinical decision rules. METHODS: This prospective cohort study of a diagnostic test included patients between birth and 18 years old admitted with febrile neutropenia to the Paediatric Oncology and Haematology Ward in Leeds between 1(st) October 2012 and 30(th) September 2013. Each admission with FNP was treated as a separate episode. Blood was taken for a procalcitonin level at admission with routine investigations. 'R' was used for statistical analysis. Likelihood ratios were calculated and multivariable logistic regression. RESULTS: Forty-eight episodes from 27 patients were included. PCT >2 ng/dL was strongly associated with increased risk of severe infection (likelihood ratio of 26 [95% CI 3.5, 190]). The data suggests that the clinical decision rules are largely ineffective at risk stratification, frequently over-stating the risk of individual episodes. High procalcitonin levels on admission are correlated with a greatly increased risk of severe infection. CONCLUSIONS: This study does not show a definitive benefit in using PCT in FNP though it supports further research on its use. The benefit of novel biomarkers has not been proven and before introducing new tests for patients it is important their benefit above existing features is proven, particularly due to the increasing importance of health economics

Updated Systematic Review and Meta-Analysis of the Performance of Risk Prediction Rules in Children and Young People with Febrile Neutropenia

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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

Taurolidine-citrate lock solution (TauroLock) significantly reduces CVAD-associated grampositive infections in pediatric cancer patients

<p>Abstract</p> <p>Background</p> <p>Taurolidin/Citrate (TauroLock™), a lock solution with broad spectrum antimicrobial activity, may prevent bloodstream infection (BSI) due to coagulase-negative staphylococci (CoNS or 'MRSE' in case of methicillin-resistant isolates) in pediatric cancer patients with a long term central venous access device (CVAD, Port- or/Broviac-/Hickman-catheter type).</p> <p>Methods</p> <p>In a single center prospective 48-months cohort study we compared all patients receiving anticancer chemotherapy from April 2003 to March 2005 (group 1, heparin lock with 200 IU/ml sterile normal saline 0.9%; Canusal^®Wockhardt UK Ltd, Wrexham, Wales) and all patients from April 2005 to March 2007 (group 2; taurolidine 1.35%/Sodium Citrate 4%; TauroLock™, Tauropharm, Waldbüttelbrunn, Germany).</p> <p>Results</p> <p>In group 1 (heparin), 90 patients had 98 CVAD in use during the surveillance period. 14 of 30 (47%) BSI were 'primary Gram positive BSI due to CoNS (n = 4) or MRSE (n = 10)' [incidence density (ID); 2.30 per 1000 inpatient CVAD-utilization days].</p> <p>In group 2 (TauroLock™), 89 patients had 95 CVAD in use during the surveillance period. 3 of 25 (12%) BSI were caused by CoNS. (ID, 0.45). The difference in the ID between the two groups was statistically significant (P = 0.004).</p> <p>Conclusion</p> <p>The use of Taurolidin/Citrate (TauroLock™) significantly reduced the number and incidence density of primary catheter-associated BSI due to CoNS and MRSE in pediatric cancer patients.</p

Predicting microbiologically defined infection in febrile neutropenic episodes in children : global individual participant data multivariable meta-analysis

BACKGROUND: Risk-stratified management of fever with neutropenia (FN), allows intensive management of high-risk cases and early discharge of low-risk cases. No single, internationally validated, prediction model of the risk of adverse outcomes exists for children and young people. An individual patient data (IPD) meta-analysis was undertaken to devise one. METHODS: The 'Predicting Infectious Complications in Children with Cancer' (PICNICC) collaboration was formed by parent representatives, international clinical and methodological experts. Univariable and multivariable analyses, using random effects logistic regression, were undertaken to derive and internally validate a risk-prediction model for outcomes of episodes of FN based on clinical and laboratory data at presentation. RESULTS: Data came from 22 different study groups from 15 countries, of 5127 episodes of FN in 3504 patients. There were 1070 episodes in 616 patients from seven studies available for multivariable analysis. Univariable analyses showed associations with microbiologically defined infection (MDI) in many items, including higher temperature, lower white cell counts and acute myeloid leukaemia, but not age. Patients with osteosarcoma/Ewings sarcoma and those with more severe mucositis were associated with a decreased risk of MDI. The predictive model included: malignancy type, temperature, clinically 'severely unwell', haemoglobin, white cell count and absolute monocyte count. It showed moderate discrimination (AUROC 0.723, 95% confidence interval 0.711-0.759) and good calibration (calibration slope 0.95). The model was robust to bootstrap and cross-validation sensitivity analyses. CONCLUSIONS: This new prediction model for risk of MDI appears accurate. It requires prospective studies assessing implementation to assist clinicians and parents/patients in individualised decision making

Predicting infectious complications in neutropenic children and young people with cancer (IPD protocol)

<p>Abstract</p> <p>Background</p> <p>A common and potentially life-threatening complication of the treatment of childhood cancer is infection, which frequently presents as fever with neutropenia. The standard management of such episodes is the extensive use of intravenous antibiotics, and though it produces excellent survival rates of over 95%, it greatly inconveniences the three-fourths of patients who do not require such aggressive treatment. There have been a number of studies which have aimed to develop risk prediction models to stratify treatment. Individual participant data (IPD) meta-analysis in therapeutic studies has been developed to improve the precision and reliability of answers to questions of treatment effect and recently have been suggested to be used to answer questions regarding prognosis and diagnosis to gain greater power from the frequently small individual studies.</p> <p>Design</p> <p>In the IPD protocol, we will collect and synthesise IPD from multiple studies and examine the outcomes of episodes of febrile neutropenia as a consequence of their treatment for malignant disease. We will develop and evaluate a risk stratification model using hierarchical regression models to stratify patients by their risk of experiencing adverse outcomes during an episode. We will also explore specific practical and methodological issues regarding adaptation of established techniques of IPD meta-analysis of interventions for use in synthesising evidence derived from IPD from multiple studies for use in predictive modelling contexts.</p> <p>Discussion</p> <p>Our aim in using this model is to define a group of individuals at low risk for febrile neutropenia who might be treated with reduced intensity or duration of antibiotic therapy and so reduce the inconvenience and cost of these episodes, as well as to define a group of patients at very high risk of complications who could be subject to more intensive therapies. The project will also help develop methods of IPD predictive modelling for use in future studies of risk prediction.</p