Fever Etiology and Prognostic Point-of-Care Biomarkers in African Children with Severe Febrile Illness

非洲严重发热性疾病儿童的发热病因和预后护理点生物标志物

• 批准号: 10656210
• 负责人: Teresa Kortz
• 金额: $ 19.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656210
• 关键词: Acute; Affect; Africa; Africa South of the Sahara; African; Algorithms; Antibiotics; Bacteremia; Bacterial DNA; Bacterial Infections; Bioinformatics; Biological Markers; Biometry; Blood; Blood Glucose; C-reactive protein; Cessation of life; Child; Childhood; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Complex; Data; Data Analyses; Decision Trees; Dehydration; Detection; Deterioration; Development; Diagnostic; Diagnostic Procedure; Early treatment; Etiology; Evidence based intervention; Ferritin; Fever; Funding; Future; Goals; Hemoglobin; Hospitals; Impairment; Infection; Infectious Agent; Intensive Care; Intervention; Knowledge; Laboratories; Learning; Life; Malaria; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Modification; Outcome; Parasitic infection; Pathogen detection; Patients; Perfusion; Physicians; Population; Positioning Attribute; Prevalence; Probability; Process; Prospective, cohort study; Provider; Research Infrastructure; Research Personnel; Resource Allocation; Resource-limited setting; Respiratory distress; Risk; Risk Factors; Sampling; San Francisco; Science; Scientist; Serum; Severities; Source; Tanzania; Technology; Testing; Time; Time Management; Training; Virus Diseases; career; clinical risk; clinically relevant; design; detection method; diagnosis standard; evidence base; global health; health training; high risk; improved; improved outcome; infection risk; innovation; malaria infection; member; mental state; microbial; mortality; next generation sequencing; novel; pathogen; pathogenic bacteria; point of care; point of care testing; predictive marker; procalcitonin; prognostic; prospective; rapid diagnosis; recruit; risk stratification; skills; urgent care

ABSTRACT Severe pediatric febrile illness has high global mortality and disproportionately affects children in resource- limited settings in sub-Saharan Africa (SSA). Though rapid, appropriate treatment can improve outcomes in severe febrile illness, we lack a robust understanding of how to rapidly identify children in need of urgent and specific management. My central hypotheses are that next generation sequencing can improve detection of a serious bacterial infection compared to culture and that biomarker point-of-care tests can predict a serious bacterial infection and clinical deterioration in children presenting with severe febrile illness. With the Pediatric Severe Infection Collaboration (UCSF, Muhimbili Hospital in Tanzania, and the Chan Zuckerberg Biohub in San Francisco), this proposal leverages expertise that uses clinical data, cutting-edge pathogen detection methods, an innovative bioinformatics platform (Global IDSeq), and biomarkers to develop a treatment algorithm for severe febrile illness in Africa. In this prospective cohort study of Tanzanian children with severe febrile illness, we will determine risk factors associated with poor clinical outcomes (Aim 1) and employ both locally available diagnostic techniques (Aim 1) and state-of-the-art next generation sequencing to determine the etiology of severe febrile illness (Aim 2). Using data from Aims 1 & 2, we will determine which POCTs for host serum biomarkers (procalcitonin, C-reactive protein, ferritin, lactate, blood sugar, and hemoglobin) best predict serious bacterial infection and clinical deterioration (Aim 3) and develop a treatment algorithm incorporating clinical signs and biomarkers that will guide management and resource allocation. My long-term career objective is to improve clinical outcomes for children with severe febrile illness through the development and implementation of evidence-based interventions that are appropriate and context-relevant for resource-limited settings. This Mentored Patient-Oriented Research Career Development Award offers me the opportunity to: (1) develop skills and expertise necessary to become an independent physician-scientist in the field of pediatric severe febrile illness; (2) integrate population-specific clinical data, locally available diagnostic data, cutting-edge next generation sequencing science, and host biomarkers to better identify serious bacterial infections and high-risk children; (3) build further clinical research infrastructure and processes in Tanzania for future clinical studies; and (4) learn and apply next-generation sequencing data analysis using a bioinformatics approach and advanced biostatistical analyses of complex observational data. I have assembled a mentoring, collaborative team with diverse expertise who are committed to helping me achieve these goals. After completion of this proposal that employs local clinical data, a highly sensitive method of pathogen detection, an innovative bioinformatics platform, and a unique approach to risk stratification with point-of-care biomarkers, we will be uniquely positioned to create an evidence-based, context–specific treatment algorithm to improve outcomes in children with severe febrile illness in SSA, which will be tested in an R01-funded study.

抽象的 严重的儿科发热性疾病在全球范围内死亡率很高，并且对资源匮乏地区的儿童造成不成比例的影响。 撒哈拉以南非洲 (SSA) 的环境有限。虽然快速，但适当的治疗可以改善结果 严重的发热性疾病，我们对如何快速识别需要紧急和治疗的儿童缺乏深入的了解 具体管理。我的中心假设是下一代测序可以改善对 与培养相比，严重的细菌感染，并且生物标志物即时检测可以预测严重的细菌感染 患有严重发热性疾病的儿童的细菌感染和临床恶化。与儿科 严重感染合作（UCSF、坦桑尼亚 Muhimbili 医院和陈·扎克伯格生物中心） 旧金山），该提案利用了临床数据和尖端病原体检测的专业知识 方法、创新的生物信息学平台（Global IDSeq）和生物标志物来开发治疗方法 非洲严重发热性疾病的算法。在这项针对坦桑尼亚重症儿童的前瞻性队列研究中 发热性疾病，我们将确定与不良临床结果相关的风险因素（目标 1）并同时采用 本地可用的诊断技术（目标 1）和最先进的下一代测序来确定 严重发热性疾病的病因（目标 2）。使用目标 1 和 2 的数据，我们将确定哪些 POCT 宿主血清生物标志物（降钙素原、C反应蛋白、铁蛋白、乳酸、血糖和血红蛋白）最佳 预测严重细菌感染和临床恶化（目标 3）并开发治疗算法 结合临床体征和生物标志物来指导管理和资源分配。 我的长期职业目标是通过以下方法改善患有严重发热性疾病的儿童的临床结果 制定和实施适当且与具体情况相关的循证干预措施 资源有限的设置。这个以患者为导向的研究职业发展奖为我提供了 机会：（1）发展成为独立医师科学家所需的技能和专业知识 小儿发热性疾病领域； (2) 整合特定人群的临床数据、本地可用的诊断 数据、尖端的下一代测序科学和宿主生物标志物，以更好地识别严重细菌 感染和高危儿童； (3) 在坦桑尼亚建立进一步的临床研究基础设施和流程 未来的临床研究； (4) 学习并应用生物信息学的下一代测序数据分析 复杂观测数据的方法和高级生物统计分析。我已经组建了一个指导， 具有不同专业知识的协作团队致力于帮助我实现这些目标。后 完成这项提案，采用当地临床数据，一种高度敏感的病原体检测方法， 创新的生物信息学平台，以及利用即时生物标志物进行风险分层的独特方法， 我们将拥有独特的优势来创建基于证据的、针对具体情况的治疗算法，以改善 SSA 患有严重发热性疾病的儿童的结果，将在 R01 资助的研究中进行测试。

项目成果

Global PARITY: Study Design for a Multi-Centered, International Point Prevalence Study to Estimate the Burden of Pediatric Acute Critical Illness in Resource-Limited Settings.

• DOI: 10.3389/fped.2021.793326
• 发表时间: 2021
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Abbas Q;Holloway A;Caporal P;López-Barón E;Agulnik A;Remy KE;Appiah JA;Attebery J;Fink EL;Lee JH;Hooli S;Kissoon N;Miller E;Murthy S;Muttalib F;Nielsen K;Puerto-Torres M;Rodrigues K;Sakaan F;Rodrigues AT;Tabor EA;von Saint Andre-von Arnim A;Wiens MO;Blackwelder W;He D;Kortz TB;Bhutta AT
• 通讯作者: Bhutta AT

Delayed Presentation and Mortality in Children With Sepsis in a Public Tertiary Care Hospital in Tanzania.

• DOI: 10.3389/fped.2021.764163
• 发表时间: 2021
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Smith AM;Sawe HR;Matthay MA;Murray BL;Reynolds T;Kortz TB
• 通讯作者: Kortz TB

Functional Outcomes and Morbidity in Pediatric Sepsis Survivors: A Tanzanian Experience.

• DOI: 10.3389/fped.2021.805518
• 发表时间: 2021
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Lau-Braunhut SA;Smith AM;Steurer MA;Murray BL;Sawe H;Matthay MA;Reynolds T;Kortz TB
• 通讯作者: Kortz TB

The Burden of Critical Illness in Hospitalized Children in Low- and Middle-Income Countries: Protocol for a Systematic Review and Meta-Analysis.

• DOI: 10.3389/fped.2022.756643
• 发表时间: 2022
• 期刊: Frontiers in pediatrics
• 影响因子: 2.6
• 作者: Kortz TB;Nielsen KR;Mediratta RP;Reeves H;O'Brien NF;Lee JH;Attebery JE;Bhutta EG;Biewen C;Coronado Munoz A;deAlmeida ML;Fonseca Y;Hooli S;Johnson H;Kissoon N;Leimanis-Laurens ML;McCarthy AM;Pineda C;Remy KE;Sanders SC;Takwoingi Y;Wiens MO;Bhutta AT
• 通讯作者: Bhutta AT

Common data elements for predictors of pediatric sepsis: A framework to standardize data collection.

• DOI: 10.1371/journal.pone.0253051
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Mawji A;Li E;Chandna A;Kortz T;Akech S;Wiens MO;Kissoon N;Ansermino M
• 通讯作者: Ansermino M