Fever in infants younger than 2 months of age causes a significant number of emergency department visits and is particularly worrisome because of the potential for serious infection. Management of febrile infants is problematic because clinical observation is not a reliable indicator of serious bacterial illness (SBI), such as bacteremia, meningitis, and urinary tract infection (UTI). Numerous investigators have proposed methods of screening laboratory tests to ascertain the risk of SBI in febrile infants. These screening tests could potentially avoid the invasive and costly sepsis work-up, which usually includes complete blood count (CBC), blood culture, urinalysis, urine culture, and lumbar puncture. We conducted a prospective, cross-sectional study that examined the prevalence of rhinovirus (RV) and coronavirus (CoV), which are two of the most common causes of upper respiratory infections in the first year of life, and human metapneumovirus (hMPV), which is a common cause of bronchiolitis, in infants younger than 2 months of age. This study also examined whether febrile infants with RV were more or less likely to also have a SBI than infants without a viral respiratory infection. Methodology: Fever was defined as rectal temperatures greater than 37.9C or a historical fever greater than 100.3F. Nasal swabs were tested with reverse transcriptase polymerase chain reaction (rt-PCR) techniques for rhinoviruses (RV), human metapneumovirus (hMPV) and coronaviruses (CoV). Nasal samples were also tested for RSV, influenza A and B, parainfluenza types 1, 2 and 3, and adenovirus via direct fluorescent antibody (DFA). Conclusion: Rhinovirus (RV) was the most commonly detected respiratory viral pathogen in our cohort (14% out of 98 total enrolled patients). Coronovirus (CoV) and human metapneumovirus (hMPV) were both detected but in only one patient (1%) each. RV occurred predominantly in the summer (79%). This cohort of patients showed no difference between the incidence of serious bacterial illness (SBI) with and without RV infection (p=0.84).

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]

Respiratory viral testing in hospitalized patients is thought to improve quality of care by reducing the use of diagnostic tests, guiding infection control precautions, and rationalizing antimicrobial therapies. Few small published studies have tested these assumptions, and have demonstrated conflicting results. We conducted a retrospective cohort study of 24,567 hospitalizations using administrative data to determine the associations between viral testing, patient outcomes, and process of care. Viral testing was not associated with improved mortality or length of stay in hospital, and resulted in more resource utilization. The test result did not influence the duration of isolation precautions. This implies that health care providers may not use the results of testing in making management decisions, or in guiding the use of isolation precautions. This study provides the foundation for further scientific evaluation and reform of our current respiratory infection control policy.

Respiratory infection remains a leading cause of morbidity and death in severely immunocompromised febrile neutropenic haematology patients, despite the introduction of numerous prophylactic strategies and advances in diagnosis and treatment. Prognosis is improved if an organism can be isolated and specific therapy commenced as soon as possible. Current practice in this population group is to commence empirical antibiotics and perform flexible bronchoscopy (FB) if temperature does not settle or after patients develop clinical or radiological features suggesting a respiratory source. This delay may result in a lower procedural diagnostic yield due to prior or prolonged anti-microbial treatment, and increased risk of respiratory compromise and procedural complications due to advanced respiratory infections. We hypothesised that proceeding to FB as early as possible after developing febrile neutropenia would improve treatment outcomes. With this randomised, prospective trial, we aim to further define the role of FB with reference to optimal timing of the procedure and its impact on diagnostic yield, future management and complication rate. We also aim to analyse the impact of proven infection on the cytokine profile of immunocompromised patients. Methods: Patients with acute leukaemia, allogeneic bone marrow transplantation or chronic lymphocytic leukaemia (CLL) being treated with Fludarabine/ Mabthera without an obvious non-respiratory source of infection were prospectively randomised into early bronchoscopy or conventional management groups at onset of febrile neutropenia. Bronchoalveolar lavage (BAL) fluid chemokine levels (IP-10, RANTES, MIG, IL-8, MCP-1) were measured using a human Chemokine cytometric bead array (CBA) kit. Results: Thirty-one episodes of febrile neutropenia in 29 patients were analysed; 17 conventional and 14 early. There was an increased yield in fungal growth in the early bronchoscopy group, which was not predicted by prior clinical or radiological changes. However, this had no impact on clinical management in the short-term due to the delayed growth. Overall diagnostic yield was not significantly different between the two groups. Procedural complication rate was negligible overall and there was no difference associated with either group. IP-10 and MIG were significantly lower in those patients who had a fungal pathogen isolated, compared with those study patients who did not (175.17 vs 1157.8, p=0.03, 30.33 vs 247.8, p=0.03 respectively). IP-10 levels were higher in the conventional than early group (1253.0 vs 261.14, p = 0.035) and the study population had higher MCP-1 (734 vs 2.83, p=0.006) and IL-8 levels (606.9 vs 14.25, p=0.00655) than normal controls. Those cases with fungal infection had higher mean MCP-1, RANTES and IL-8 levels than in normal controls (844.0 vs 2.83, p=0.007; 17.5 vs 2.1, p=0.03; 156.0 vs 14.25, p=0.004). Conclusions: Early bronchoscopy as a component of the septic screen in febrile neutropenic patients was feasible and safe. A significant difference in fungal yield was seen in the early bronchoscopy group compared to conventional methods, with a negligible complication rate, but this did not result in a change in immediate clinical management or outcomes. / Thesis (M.Clin.Sc.) - University of Adelaide, School of Medicine, 2009

Respiratory viral testing in hospitalized patients is thought to improve quality of care by reducing the use of diagnostic tests, guiding infection control precautions, and rationalizing antimicrobial therapies. Few small published studies have tested these assumptions, and have demonstrated conflicting results. We conducted a retrospective cohort study of 24,567 hospitalizations using administrative data to determine the associations between viral testing, patient outcomes, and process of care. Viral testing was not associated with improved mortality or length of stay in hospital, and resulted in more resource utilization. The test result did not influence the duration of isolation precautions. This implies that health care providers may not use the results of testing in making management decisions, or in guiding the use of isolation precautions. This study provides the foundation for further scientific evaluation and reform of our current respiratory infection control policy.

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

No description available.

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.