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Chimeric antigen receptor (CAR) T-cells directed against CD19 have drastically altered outcomes for children with relapsed and refractory acute lymphoblastic leukemia (r/r ALL). Pediatric patients with r/r ALL treated with CAR-T are at increased risk of both cytokine release syndrome (CRS) and sepsis. We sought to investigate the biologic differences between CRS and sepsis and to develop predictive models which could accurately differentiate CRS from sepsis at the time of critical illness. We identified 23 different cytokines that were significantly different between patients with sepsis and CRS. Using elastic net prediction modeling and tree classification, we identified cytokines that were able to classify subjects as having CRS or sepsis accurately. A markedly elevated interferon γ (IFNγ) or a mildly elevated IFNγ in combination with a low IL1ß were associated with CRS. A normal to mildly elevated IFNγ in combination with an elevated IL1ß was associated with sepsis. This combination of IFNγ and IL1ß was able to categorize subjects as having CRS or sepsis with 97% accuracy. As CAR-T therapies become more common, these data provide important novel information to better manage potential associated toxicities.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Sepse , Criança , Estado Terminal , Síndrome da Liberação de Citocina , Humanos , Receptores de Antígenos de Linfócitos T , Sepse/diagnósticoRESUMO
OBJECTIVES: Duplicative institutional review board/research ethics committee review for multicenter studies may impose administrative burdens and inefficiencies affecting study implementation and quality. Understanding variability in site-specific institutional review board/research ethics committee assessment and barriers to using a single review committee (an increasingly proposed solution) can inform a more efficient process. We provide needed data about the regulatory oversight process for the Sepsis PRevalence, OUtcomes, and Therapies multicenter point prevalence study. DESIGN: Survey. SETTING: Sites invited to participate in Sepsis PRevalence, OUtcomes, and Therapies. SUBJECTS: Investigators at sites that expressed interest and/or participated in Sepsis PRevalence, OUtcomes, and Therapies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Using an electronic survey, we collected data about 1) logistics of protocol submission, 2) institutional review board/research ethics committee requested modifications, and 3) use of a single institutional review board (for U.S. sites). We collected surveys from 104 of 167 sites (62%). Of the 97 sites that submitted the protocol for institutional review board/research ethics committee review, 34% conducted full board review, 54% expedited review, and 4% considered the study exempt. Time to institutional review board/research ethics committee approval required a median of 34 (range 3-186) days, which took longer at sites that required protocol modifications (median [interquartile range] 50 d [35-131 d] vs 32 d [14-54 d)]; p = 0.02). Enrollment was delayed at eight sites due to prolonged (> 50 d) time to approval. Of 49 U.S. sites, 43% considered using a single institutional review board, but only 18% utilized this option. Time to final approval for U.S. sites using the single institutional review board was 62 days (interquartile range, 34-70 d) compared with 34 days (interquartile range, 15-54 d) for nonsingle institutional review board sites (p = 0.16). CONCLUSIONS: Variability in regulatory oversight was evident for this minimal-risk observational research study, most notably in the category of type of review conducted. Duplicative review prolonged time to protocol approval at some sites. Use of a single institutional review board for U.S. sites was rare and did not improve efficiency of protocol approval. Suggestions for minimizing these challenges are provided.
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Revisão Ética , Comitês de Ética em Pesquisa/estatística & dados numéricos , Sepse/epidemiologia , Humanos , Prevalência , Estudos Prospectivos , Projetos de Pesquisa/estatística & dados numéricos , Sepse/terapia , Inquéritos e Questionários , Fatores de TempoRESUMO
OBJECTIVES: To describe the epidemiology, morbidity, and mortality of new or progressive multiple organ dysfunction syndrome in children with severe sepsis. DESIGN: Secondary analysis of a prospective, cross-sectional, point prevalence study. SETTING: International, multicenter PICUs. PATIENTS: Pediatric patients with severe sepsis identified on five separate days over a 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 567 patients from 128 PICUs in 26 countries enrolled, 384 (68%) developed multiple organ dysfunction syndrome within 7 days of severe sepsis recognition. Three hundred twenty-seven had multiple organ dysfunction syndrome on the day of sepsis recognition. Ninety-one of these patients developed progressive multiple organ dysfunction syndrome, whereas an additional 57 patients subsequently developed new multiple organ dysfunction syndrome, yielding a total proportion with severe sepsis-associated new or progressive multiple organ dysfunction syndrome of 26%. Hospital mortality in patients with progressive multiple organ dysfunction syndrome was 51% compared with patients with new multiple organ dysfunction syndrome (28%) and those with single-organ dysfunction without multiple organ dysfunction syndrome (10%) (p < 0.001). Survivors of new or progressive multiple organ dysfunction syndrome also had a higher frequency of moderate to severe disability defined as a Pediatric Overall Performance Category score of greater than or equal to 3 and an increase of greater than or equal to 1 from baseline: 22% versus 29% versus 11% for progressive, new, and no multiple organ dysfunction syndrome, respectively (p < 0.001). CONCLUSIONS: Development of new or progressive multiple organ dysfunction syndrome is common (26%) in severe sepsis and is associated with a higher risk of morbidity and mortality than severe sepsis without new or progressive multiple organ dysfunction syndrome. Our data support the use of new or progressive multiple organ dysfunction syndrome as an important outcome in trials of pediatric severe sepsis although efforts are needed to validate whether reducing new or progressive multiple organ dysfunction syndrome leads to improvements in more definitive morbidity and mortality endpoints.
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Insuficiência de Múltiplos Órgãos/complicações , Sepse/complicações , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Progressão da Doença , Feminino , Saúde Global , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica , Masculino , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/epidemiologia , Fenótipo , Prevalência , Prognóstico , Estudos Prospectivos , Sepse/diagnóstico , Sepse/epidemiologiaRESUMO
OBJECTIVES: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. DESIGN: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. SETTING: European and U.S. PICUs. PATIENTS: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. CONCLUSIONS: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.
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Cuidados Críticos , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Padrões de Prática Médica/estatística & dados numéricos , Sepse , Índice de Gravidade de Doença , Adolescente , Criança , Pré-Escolar , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde/estatística & dados numéricos , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Masculino , Análise Multivariada , Prevalência , Estudos Prospectivos , Sepse/diagnóstico , Sepse/epidemiologia , Sepse/terapia , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
INTRODUCTION: Consensus criteria for pediatric severe sepsis have standardized enrollment for research studies. However, the extent to which critically ill children identified by consensus criteria reflect physician diagnosis of severe sepsis, which underlies external validity for pediatric sepsis research, is not known. We sought to determine the agreement between physician diagnosis and consensus criteria to identify pediatric patients with severe sepsis across a network of international pediatric intensive care units (PICUs). METHODS: We conducted a point prevalence study involving 128 PICUs in 26 countries across 6 continents. Over the course of 5 study days, 6925 PICU patients <18 years of age were screened, and 706 with severe sepsis defined either by physician diagnosis or on the basis of 2005 International Pediatric Sepsis Consensus Conference consensus criteria were enrolled. The primary endpoint was agreement of pediatric severe sepsis between physician diagnosis and consensus criteria as measured using Cohen's κ. Secondary endpoints included characteristics and clinical outcomes for patients identified using physician diagnosis versus consensus criteria. RESULTS: Of the 706 patients, 301 (42.6%) met both definitions. The inter-rater agreement (κ ± SE) between physician diagnosis and consensus criteria was 0.57 ± 0.02. Of the 438 patients with a physician's diagnosis of severe sepsis, only 69% (301 of 438) would have been eligible to participate in a clinical trial of pediatric severe sepsis that enrolled patients based on consensus criteria. Patients with physician-diagnosed severe sepsis who did not meet consensus criteria were younger and had lower severity of illness and lower PICU mortality than those meeting consensus criteria or both definitions. After controlling for age, severity of illness, number of comorbid conditions, and treatment in developed versus resource-limited regions, patients identified with severe sepsis by physician diagnosis alone or by consensus criteria alone did not have PICU mortality significantly different from that of patients identified by both physician diagnosis and consensus criteria. CONCLUSIONS: Physician diagnosis of pediatric severe sepsis achieved only moderate agreement with consensus criteria, with physicians diagnosing severe sepsis more broadly. Consequently, the results of a research study based on consensus criteria may have limited generalizability to nearly one-third of PICU patients diagnosed with severe sepsis.
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Sepse/diagnóstico , Adolescente , Pesquisa Biomédica/normas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Variações Dependentes do Observador , Padrões de Prática Médica , Prevalência , Sepse/epidemiologia , Sepse/mortalidade , Resultado do TratamentoRESUMO
RATIONALE: Limited data exist about the international burden of severe sepsis in critically ill children. OBJECTIVES: To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive care units to better inform interventional trials. METHODS: A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality. MEASUREMENTS AND MAIN RESULTS: Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range [IQR], 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 [corrected] patients per group. CONCLUSIONS: Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.
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Saúde Global/estatística & dados numéricos , Insuficiência de Múltiplos Órgãos/epidemiologia , Sepse/epidemiologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Bases de Dados Factuais , Mortalidade Hospitalar , Humanos , Lactente , Recém-Nascido , Unidades de Terapia Intensiva Pediátrica/estatística & dados numéricos , Insuficiência de Múltiplos Órgãos/microbiologia , Insuficiência de Múltiplos Órgãos/mortalidade , Avaliação de Processos e Resultados em Cuidados de Saúde/estatística & dados numéricos , Prevalência , Estudos Prospectivos , Respiração Artificial/estatística & dados numéricos , Sepse/microbiologia , Sepse/mortalidadeRESUMO
OBJECTIVE: The point prevalence methodology is a valuable epidemiological study design that can optimize patient enrollment, prospectively gather individual-level data, and measure practice variability across a large number of geographic regions and healthcare settings. The objective of this article is to review the design, implementation, and analysis of recent point prevalence studies investigating the global epidemiology of pediatric critical illness. DATA SOURCES: Literature review and primary datasets. STUDY SELECTION: Multicenter, international point prevalence studies performed in PICUs since 2007. DATA EXTRACTION: Study topic, number of sites, number of study days, patients screened, prevalence of disease, use of specified therapies, and outcomes. DATA SYNTHESIS: Since 2007, five-point prevalence studies have been performed on acute lung injury, neurologic disease, thromboprophylaxis, fluid resuscitation, and sepsis in PICUs. These studies were performed in 59-120 sites in 7-28 countries. All studies accounted for seasonal variation in pediatric disease by collecting data over multiple study days. Studies screened up to 6,317 patients and reported data on prevalence and therapeutic variability. Three studies also reported short-term outcomes, a valuable but atypical data element in point prevalence studies. Using these five studies as examples, the advantages and disadvantages and approach to designing, implementing, and analyzing point prevalence studies are reviewed. CONCLUSIONS: Point prevalence studies in pediatric critical care can efficiently provide valuable insight on the global epidemiology of disease and practice patterns for critically ill children.