Introduction: There is uncertainty whether low-risk febrile neutropenia (FN) episodes in children with cancer are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four different treatment strategies for low-risk FN in pediatric cancer patients. Outcome measures were quality-adjusted FN episodes (QAFNE), costs (Canadian dollar), and incremental cost-effectiveness ratios (ICER). Results: The most cost-effective strategy was outpatient treatment with intravenous antibiotics. It was cost saving ($2,732 versus $2,757) and more effective (0.66 QAFNE versus 0.55 QAFNE) as compared to outpatient treatment with oral antibiotics. An early discharge strategy after 48 hours in hospital was slightly more effective but significantly more expensive than outpatient treatment with intravenous antibiotics resulting in an unacceptably high ICER of more than $130,000 per QAFNE. Inpatient care was the least cost-effective strategy. Conclusions: Outpatient strategies for treatment of low-risk FN in children are more cost-effective than traditional inpatient care.

Introduction: There is uncertainty whether low-risk febrile neutropenia (FN) episodes in children with cancer are best managed in the inpatient or outpatient setting. Methods: A cost-utility model was created to compare four different treatment strategies for low-risk FN in pediatric cancer patients. Outcome measures were quality-adjusted FN episodes (QAFNE), costs (Canadian dollar), and incremental cost-effectiveness ratios (ICER). Results: The most cost-effective strategy was outpatient treatment with intravenous antibiotics. It was cost saving ($2,732 versus $2,757) and more effective (0.66 QAFNE versus 0.55 QAFNE) as compared to outpatient treatment with oral antibiotics. An early discharge strategy after 48 hours in hospital was slightly more effective but significantly more expensive than outpatient treatment with intravenous antibiotics resulting in an unacceptably high ICER of more than $130,000 per QAFNE. Inpatient care was the least cost-effective strategy. Conclusions: Outpatient strategies for treatment of low-risk FN in children are more cost-effective than traditional inpatient care.

Thesis (M.Med. (Paediatrics and Child Health)) -- University of Limpopo, 2022 / BACKGROUND Febrile neutropenia is a medical emergency that complicates the clinical course and treatment of both hematological and solid malignancies, potentially worsening the overall outcome and increasing the financial burden. The epidemiology of pathogens is varied, and determines the selection of empiric antibiotic therapy for febrile neutropenia. Empirically piperacillin/tazobactam plus amikacin has been recommended as the most suitable antibiotic for management of febrile neutropenia. There is a lack of local studies to provide advice for antibiotic choice in our setting. OBJECTIVE To identify causative organisms of infection and antibiotic susceptibility patterns in childhood cancer patients with chemotherapy related febrile neutropenia in Pietersburg Hospital Oncology Ward Limpopo Province. METHODS This is a retrospective cross-sectional study that reviewed all the febrile neutropenic episodes in children with cancer and with a positive blood culture during the febrile neutropenia episode. Data collected included patient demographics (date of birth, sex, date of diagnosis) diagnosis, organisms cultured and the antibiotic sensitivity profile. RESULTS There were 152 records of positive blood cultures identified of 348 episodes of febrile neutropenia for 413 patients. The median age of study population is 6years (mean age of 6.8years; range 3 to 11years) with male predominance at (61.2%). The most common cancer diagnosis was Acute Lymphoblastic Leukemia (ALL) (33.6%) followed by Nephroblastoma (15.8%), Acute myeloid leukemia (11.2%), Non- Hodgkin’s lymphoma (9.9%), Hodgkin’s lymphoma (5.9%) and other cancers (15.3%). The majority of causative organisms were gram-positive bacteria (45%) followed by gram-negative bacteria (32.4%) and fungi (6.1%). Gram-positive organisms were statistically significant pathogens causing bacteraemia more often in neutropenic patients than gram-negative organisms with a p value=0.016. The majority (n=102; 67.10%) were sensitive organisms with the minority being multidrug resistant organisms (n=23; 15.1%) and 17.8% were contaminants n=27. The most common gram-positive pathogens were Coagulase negative staphylococcus n=37; (21.6%). The most common multidrug resistant organisms were Klebsiella pneumoniae CRE (10.7 %;), followed by Enterococcus faecium VRE (1.9%), Klebsiella oxytoca CRE (1.3%), Enterococcus faecalis VRE (0.6%), and Staphylococcus aureus MRSA (0.6%). No multidrug resistant fungal organisms were cultured. The majority of organisms were sensitive to the first line empiric therapy piperacillin/tazobactam plus Amikacin (67.10%). Thirty patients died during these febrile neutropenic episodes and case fatality rate was 8.6%. CONCLUSION This study confirmed that the causative bacteria of febrile neutropenia in this study were susceptible to the first line empiric therapy piperacillin/tazobactam plus amikacin, and this regimen is therefore appropriate for this paediatric oncology unit.

This article reports the findings of a grounded theory study of the processes involved in adherence and treatment seeking delay for febrile neutropenia in chemotherapy patients. Interviews were conducted with 12 patients. Six theoretical constructs were generated, namely ‘Recall of Treatment Advice’, ‘Impact of Emotions’, ‘Influence of Social Networks’, ‘Symptom Monitoring Behaviour’, ‘Symptom Interpretation’, and ‘Preparation and Journey Time’. A model was developed to reflect the complex interplay between these theoretical constructs. Data extracts are presented to illustrate the grounding of the model in patients’ accounts, and the model is discussed with reference to previous theory and research.

New approaches quantifying the effect of treatment are needed in oncology to improve the drug development process and to enable treatment optimization for existing therapies. This thesis focuses on the development of pharmacometric models for biomarkers, side effects and efficacy in order to identify predictors of clinical response in anti-cancer drug therapy. The variability in myelosuppression was characterized in six different cytotoxic anticancer treatments to evaluate a model-based dose individualization approach utilizing neutrophil counts as a biomarker. The estimated impact of inter-occasion variability was relatively low in relation to the inter-individual variability, indicating that myelosuppression is predictable from one treatment course to another. The approach may thereby be useful for dose optimization within an individual. To further study and to identify predictors for the severe side effect febrile neutropenia (FN), the relationship between the shape of the myelosuppression time-course and the probability of FN was characterized. Patients with a rapid decline in neutrophil counts and high drug sensitivity were identified to have a higher probability of developing FN compared with other patients who experience grade 4 neutropenia. Predictors of clinical response in patients receiving sunitinib for the treatment of gastro-intestinal stromal tumor (GIST) were identified by the development of an integrated modeling framework. Drug exposure, biomarkers, tumor dynamics, side effects and overall survival (OS) were linked in a unified structure, and univariate and multivariate exposure variables were tested for their predictive capacities. The soluble biomarker, sVEGFR-3 and tumor size at start of treatment were found to be promising predictors of overall survival, with decreased sVEGFR-3 levels and smaller baseline tumor size being predictive of longer OS. Also hypertension and neutropenia was identified as predictors of OS. The developed modeling framework may be useful to monitor clinical response, optimize dosing in sunitinib and to facilitate dose individualization.

This study was designed to evaluate the response of innate immunity to acute bacterial inflammation in terms of cytokines and other biomolecules concentration changes in the blood of investigated childhood oncology patients during the beginning of febrile neutropenia (FN) episode and to assess the relevance of these biomarkers for sepsis/bacteremia evaluation. This study was performed at Vilnius University Children Hospital and State Research Institute Centre for Innovative Medicine from 2009 to 2011. Serum samples were collected during 82 fever episodes in a total of 53 oncology patients. The study population consisted of pediatric oncology patients admitted to the hospital with the diagnosis of neutropenia and fever. According to microbiological and clinical findings, patients with episodes of FN were classified into 2 groups: 1) fever of unknown origin (FUO) group – patients with negative blood culture, absence of clinical signs of sepsis and clinically or microbiologically documented local infection, 2) septic/bacteremia (SB) group – patients with positive blood culture (documented Gram-positive or Gram-negative bacteremia) and/or clinically documented sepsis. We measured the levels of cytokines (IL-6, IL-8, IL-10), their receptors (sIL-2R) and other biomarkers (PCT, CRP, sHLA-G) for three consecutive days. We showed that on day 1 the most accurate biomarkers for bacteremia/sepsis discrimination were cytokines (IL-6, IL-10, IL-8), on day 2 – IL-8 and PCT. On day 1 the... [to full text] / Viena iš pagrindinių taikomos šiuolaikinės intensyvios chemoterapijos komplikacijų yra organizmo imuninės sistemos slopinimas ir su tuo susijusi neutropenija, kuri savo ruožtu sąlygoja padidėjusią riziką susirgti bakterinės kilmės infekcinėmis ligomis. Šio darbo tikslas buvo įvertinti ūmaus bakterinio uždegimo bei sepsio patogenezėje dalyvaujančių citokinų (IL-6, IL-8, IL-10), citokinų receptorių (sIL-2R), ūmios fazės baltymų bei kitų imuninio atsako komponentų (CRB, PCT, sHLA-G) tinkamumą bakterinio proceso ankstyvai diagnostikai tarp pacientų su febrline neutropenija (FN), šių biožymenų tinkamumą ir pritaikomumą kasdienėje klinikinėje praktikoje. Tiriamoji medžiaga surinkta 2009–2011 m. Vilniaus universiteto Vaikų ligoninės Onkohematologijos skyriuje. Į tyrimą buvo įtraukta 53 onkohematologinėmis ligomis sergantys vaikai su FN, kurie gydymo eigoje turėjo 82 karščiavimo epizodus. Nuo pirmos karščiavimo dienos tris dienas iš eilės buvo imami kraujo mėginiai bei nustatomos citokinų (IL-6, IL-8, IL-10), CRB, PCT, sHLA-G ir sIL-2R koncentracijos. Remiantis klinikinių bei mikrobiologinių tyrimų duomenimis, FN epizodai buvo suskirstyti į dvi grupes – neaiškios kilmės karščiavimo (NKK), į kurią buvo įtraukti pacientai be sepsio požymių bei su neigiamais mikrobiologiniais pasėliais ir bakteriemijos/sepsio (BS). BS grupę sudarė pacientai su teigiamais mikrobiologiniais pasėliais ir(ar) kliniškai diagnozuotu sepsiu. Mūsų atlikto tyrimo rezultatais bakteriemijos/sepsio vertinimui FN... [toliau žr. visą tekstą]

Viena iš pagrindinių taikomos šiuolaikinės intensyvios chemoterapijos komplikacijų yra organizmo imuninės sistemos slopinimas ir su tuo susijusi neutropenija, kuri savo ruožtu sąlygoja padidėjusią riziką susirgti bakterinės kilmės infekcinėmis ligomis. Šio darbo tikslas buvo įvertinti ūmaus bakterinio uždegimo bei sepsio patogenezėje dalyvaujančių citokinų (IL-6, IL-8, IL-10), citokinų receptorių (sIL-2R), ūmios fazės baltymų bei kitų imuninio atsako komponentų (CRB, PCT, sHLA-G) tinkamumą bakterinio proceso ankstyvai diagnostikai tarp pacientų su febrline neutropenija (FN), šių biožymenų tinkamumą ir pritaikomumą kasdienėje klinikinėje praktikoje. Tiriamoji medžiaga surinkta 2009–2011 m. Vilniaus universiteto Vaikų ligoninės Onkohematologijos skyriuje. Į tyrimą buvo įtraukta 53 onkohematologinėmis ligomis sergantys vaikai su FN, kurie gydymo eigoje turėjo 82 karščiavimo epizodus. Nuo pirmos karščiavimo dienos tris dienas iš eilės buvo imami kraujo mėginiai bei nustatomos citokinų (IL-6, IL-8, IL-10), CRB, PCT, sHLA-G ir sIL-2R koncentracijos. Remiantis klinikinių bei mikrobiologinių tyrimų duomenimis, FN epizodai buvo suskirstyti į dvi grupes – neaiškios kilmės karščiavimo (NKK), į kurią buvo įtraukti pacientai be sepsio požymių bei su neigiamais mikrobiologiniais pasėliais ir bakteriemijos/sepsio (BS). BS grupę sudarė pacientai su teigiamais mikrobiologiniais pasėliais ir(ar) kliniškai diagnozuotu sepsiu. Mūsų atlikto tyrimo rezultatais bakteriemijos/sepsio vertinimui FN... [toliau žr. visą tekstą] / This study was designed to evaluate the response of innate immunity to acute bacterial inflammation in terms of cytokines and other biomolecules concentration changes in the blood of investigated childhood oncology patients during the beginning of febrile neutropenia (FN) episode and to assess the relevance of these biomarkers for sepsis/bacteremia evaluation. This study was performed at Vilnius University Children Hospital and State Research Institute Centre for Innovative Medicine from 2009 to 2011. Serum samples were collected during 82 fever episodes in a total of 53 oncology patients. The study population consisted of pediatric oncology patients admitted to the hospital with the diagnosis of neutropenia and fever. According to microbiological and clinical findings, patients with episodes of FN were classified into 2 groups: 1) fever of unknown origin (FUO) group – patients with negative blood culture, absence of clinical signs of sepsis and clinically or microbiologically documented local infection, 2) septic/bacteremia (SB) group – patients with positive blood culture (documented Gram-positive or Gram-negative bacteremia) and/or clinically documented sepsis. We measured the levels of cytokines (IL-6, IL-8, IL-10), their receptors (sIL-2R) and other biomarkers (PCT, CRP, sHLA-G) for three consecutive days. We showed that on day 1 the most accurate biomarkers for bacteremia/sepsis discrimination were cytokines (IL-6, IL-10, IL-8), on day 2 – IL-8 and PCT. On day 1 the... [to full text]

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13110号 / 論医博第2128号 / 新制||医||1022(附属図書館) / (主査)教授 髙折 晃史, 教授 佐藤 俊哉, 教授 川上 浩司 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introdução: A neutropenia febril (NF) é um evento adverso intrínseco ao transplante de células-tronco hematopoiéticas (TCTH), decorrente da mielossupressão ocasionada pelo procedimento, que impacta de modo importante na morbidade e na mortalidade do paciente. Objetivos: Analisar os pacientes submetidos ao TCTH quanto a ocorrência de NF. Método: Coorte retrospectiva conduzida com 61 pacientes submetidos ao TCTH no Hospital de Clínicas da Universidade Estadual de Campinas. Foram extraídos dados relativos a características basais dos pacientes, procedimento de TCTH, tempo de internação e desfecho clínico para determinar os fatores associados à NF. As variáveis independentes foram idade, sexo, comorbidades, diagnóstico, tipo de transplante, regime de condicionamento, fonte das células, nº de CD34, tempo de enxertia, escore de risco pré-TCTH do EBMT, SAPSII. A NF foi definida de acordo com o Common Terminology Criteria for Adverse Events (CTC/AE) v4.0, considerando o desfecho dicotômico, a duração em dias, a data da ocorrência, o grau e a análise de sobrevida. Os dados foram analisados por meio de testes paramétricos e não paramétricos, dependendo do nível de mensuração das variáveis e utilizaram-se Kaplan-Meier e regressão logística. Para todas as análises considerou-se nível de significância de 5%. Resultados: A incidência de NF nos pacientes submetidos ao TCTH foi de 78,7%, com duração média de 8,3 dias, sem diferença significativa entre os tipos de transplantes (p=0,176). Não foram encontrados fatores de risco para a NF, porém, os pacientes submetidos ao transplante autólogo (p=0,022) e ao regime de condicionamento mieloablativo (p=0,026) apresentaram menor sobrevida para este evento adverso. Os pacientes que utilizaram ventilação mecânica (p=0,052), que necessitaram do uso de drogas vasoativas (p=0,012) e que foram a óbito (OR=9,66; p=0,052), apresentaram NF em sua totalidade. Conclusão: A incidência de NF foi expressiva e, ainda que não tenham sido identificados fatores associados a ela, os pacientes submetidos ao regime NMA e TCTH alogênico apresentaram maior sobrevida para o surgimento de NF. Estes achados relativos a sobrevida podem subsidiar o enfermeiro na proposição de intervenções, visando evitar complicações infecciosas decorrentes da NF. / Introduction: Febrile neutropenia (FN) is an intrinsic adverse event to hematopoietic stem cell transplantation (HSCT), due to the myelosuppression caused by the procedure, which has an important impact on patient morbidity and mortality. Objectives: To analyze the patients submitted to HSCT regarding the occurrence of FN. Method: Retrospective cohort with 61 patients submitted to HSCT at Hospital de Clínicas, State University of Campinas. Data were extracted on the baseline information of patients, HSCT procedure, time of hospitalization and clinical outcome to determine the factors associated with FN. The independent variables were age, gender, comorbidities, diagnosis, type of transplantation, conditioning regime, cell source, CD34 number, grafting time, pre-HSCT risk score of EBMT, SAPSII. The FN was defined according to the Common Terminology Criteria for Adverse Events (CTC / AE) v4.0, considering the dichotomous outcome, duration in days, date of occurrence, degree and survival analysis. Data were analyzed using parametric and non-parametric tests, depending on the level of measurement of the variables and Kaplan-Meier and logistic regression were used. A significance level of 5% was considered for all analyzes. Results: The incidence of FN in patients submitted to HSCT was 78.7%, with an average duration of 8.3 days, with no significant difference between the types of transplants (p = 0.176). No risk factors were found for FN, however, patients submitted to autologous transplantation (p = 0.022) and myeloablative conditioning (p = 0.026) presented lower survival rates for this adverse event. Patients who used mechanical ventilation (p = 0.052), who required the use of vasoactive drugs (p = 0.012) and who died (OR = 9.66, p = 0.052) presented FN in their entirety. In addition, the occurrence of FN had an association with longer hospitalization time (p = 0.003). Conclusion: The incidence of FN was significant. Although no associated factors were identified, patients submitted to NMA and allogeneic HSCT presented a higher survival rate for the onset of FN. These findings regarding survival can subsidize the nurse in proposing interventions, in order to avoid infectious complications due to FN.

Contexte: Le pronostic des neutropénie fébrile (NF) post-chimiothérapie de l’enfant a été amélioré par une antibiothérapie à large spectre systématique. Cependant des infections sévères ne surviennent que dans 15-25% des cas. Il a été recommandé en 2012 de faire évoluer la prise en charge en tenant compte du risque infectieux en utilisant des règles de décision clinique (RDC). Nous avions montré que les outils publiés pour distinguer ce risque étaient peu performants, non validés ou non applicables sur notre population. Une nouvelle RDC (score) permettant de distinguer les épisodes de NF à bas risque d’infection sévère a été construite. Cette RDC a été validée en interne. Compte tenu des différences mises en évidence dans les populations de tumeurs solides et d’hémopathies, il pourrait être pertinent d’utiliser un arbre de décision clinique pour classer le risque infectieux dont la première division serait le type de cancer et de valider cette nouvelle RDC.L’objectif de ce travail était de calibrer cette RDC sous forme d’arbre et de la valider sur un échantillon multicentrique pour distinguer les enfants avec NF à bas risque d’infection sévère. Méthodes: La première étape a été d’évaluer la méthodologie de développement des RDC déjà publiées pour identifier d’éventuelles limites méthodologiques. Ensuite, nous avons décrit les différences entre les hémopathies ou avec les tumeurs solides. Puis, la nouvelle RDC a été calibrée sous forme d’un arbre de décision à l’aide du logiciel Sipina. Sa performance a été évaluée en termes de sensibilité (Se), spécificité (Sp), et rapport de vraisemblance négatif (RVN).En parallèle, un protocole de validation multicentrique prospectif a été monté, avec pour objectif une Se proche de 100% et un RVN inférieur à 0,1. Il a été validé par le CCTIRS et par la CNIL. Il a été financé par la Ligue Contre le Cancer (72 000 euros). Trente et un centres ont été recrutés. La RDC n’a été appliquée qu’a posteriori ; la prise en charge de cette population n’a donc pas été modifiée. La performance de la RDC entre la population de validation et construction a été analysée en termes de Se, Sp, RVN. L’évaluation des pratiques de prise en charge des NF post-chimiothérapie de l’enfant a été faite en parallèle sous la forme d’une enquête nationale, dans la perspective d’une étude d’impact ultérieure.Résultats: L’étude de la méthodologie des RDC déjà publiées a montré que les critères de développement d’une RDC étaient respectés dans 71% des cas (médiane). Une RDC avait atteint le plus haut niveau d’évidence, mais sa population de construction était différente de la nôtre et cette RDC n’était pas reproductible sur notre population. Il existait 2 à 3 fois plus d’infection sévère chez les patients atteints d’une hémopathie maligne. Deux arbres de décision ont donc été construits pour différencier le risque d’infection sévère. Pour les patients avec une tumeur solide il avait des Se de 96%, Sp de 59% et RVN à 0,07, pour ceux avec une hémopathie maligne, il avait des Se de 99%, Sp de 52% et RVN à 0,03. Les inclusions de la validation multicentrique se sont déroulées de janvier 2012 à mai 2016. 1806 épisodes ont été inclus (333 infections sévères, 18,4%). L’application de la RDC a été faite a posteriori(en cours). L’enquête nationale menée en parallèle sur la prise en charge faite en pratique dans les centres français a montré une grande variabilité de prise en charge notamment dans les définitions de la neutropénie et de la fièvre. Un travail doit être initié avec la Société Française des Cancers de l’Enfant pour uniformiser la prise en charge des NF et déterminer le type d’allègement thérapeutique à proposer en vue de l’étude d’impact, en utilisant cette RDC. Conclusion: Les étapes de construction et de validation de cette nouvelle RDC ont été réalisées en respectant les standards méthodologiques. Une étude d’évaluation de l’impact de la RDC devra être mise en place pour atteindre le plus haut niveau d’évidence. / Purpose: Chemotherapy-induced febrile neutropenia (FN) is known to be a risk for severe infection and death in the absence of prompt and appropriate antibiotic therapy. Immediate hospitalization for rapid institution of empirical broad-spectrum intravenous antibiotic therapy has led to reduce the mortality. However, documented or severe infections occur in only 15-25% of cases. In 2012 paediatric guidelines suggested to adapt the management of FN episodes to the infectious risk. In a previous work, none of the published clinical decision rules (CDRs) to rule out severe infections have been validated and have only rarely been tested in an external set of children. The methodological standards used to derive and validate these CDRs were a real concern. A new CDR was previously derived as a scoring system in Lille to classify the patients at high or low risk of severe infection, with a dataset collected in 2 centers in Lille, in following methodological standards. Differences between solid tumours and blood cancers were observed in children with FN for numbers and types of infections. As a result, we considered relevant to build a decision tree model to predict the low risk for severe infection with a first division that could be the type of cancer. This new decision rule was already validated in an internal set of data, but required an external validation.The aim of this project was to calibrate the CDR as a decision tree and validate its performance a posteriori in an external set of patients, using prospectively collected data from multiple centers.Methods: the methodological standards of available CDRs were first analysed. The new CDR derived on a bicentric dataset was reused to calibrate the CDR as a decision tree, using Sipina software. A prospective multicentric observational protocol funded by 72000€ provided by “la Ligue Contre le Cancer” was developed for an external validation of the CDR to expect near 100% sensitivity (Se) and a negative likelihood ratio (LR) below 0.1. The ethical regulation was followed. Thirty-one centers were recruited in France (27/30 referent centers for management of children with cancer, and 4 proximity centers fit to manage children with FN). The CDR was not applied to the included patients, and remained confidential. The data were collected on an e-CRF “capture system”. The data were captured by an assistant of clinical research and controlled by a physician researcher after the monitoring of the data in all centers. The CDR was a posteriori applied on the dataset. The performance of the CDR between validation and derivation sets of patients was analysed in terms of Se, specificity (Sp) and negative LR.Results: the methodological standards of development of a CDR were not always followed for the development of the published CDR predicting infection for FN in children. Only one CDR followed all criteria and reached the highest level of evidence, but this CDR was built in a very different population from our and was not reproducible. A decision tree model of the CDR was built to distinguish children with FN at low risk of severe infection. For children with solid tumours, the CDR had 96% Se, 59% Sp, and a negative LR at 0.07. For children with blood cancers, the CDR had 99% Se, 52% Sp, and a negative LR at 0.03.For external validation, inclusions started in 2012 until May 2016. Of the 31 centers, 23 included 1806 cases (333 severe infections [18.4%]). The retrospective application of the CDR on all included case in ongoing. A national survey was also conducted as the same time to analyse the real management of children with FN in France in order to determine the type of management that could be proposed for low risk patients when the CDR will be tested in an impact study.Conclusion: the different steps for the construction and validation of the new CDR were conducted following standards. This CDR is in progress to reach the highest level of evidence.