Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 Associated Encephalopathy/Encephalitis and Multi-systemic Inflammatory Syndrome in Children
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 300
- 试验地点
- 1
- 主要终点
- clinical and laboratory characteristics of COVID-19 associated encephalitis/encephalopathy
研究概览
简要总结
Background and objective From this April, there was a COVID-19 outbreak in Taiwan. The first fatal case of pediatric COVID-19 encephalitis was reported on April 19, 2022 and fatal fulminant cerebral edema in other 4 children with COVID-19 encephalitis was reported within 1 month from Taiwan CDC registry. To date, around 700,000 children got COVID-19 recently. Several children developed MIS-C (multi-system inflammatory syndrome in children)-related shock about 2-6 weeks after COVID-19. Since both COVID-19 associated encephalopathy/ encephalitis and MIS-C are life-threatening, it is urgent to delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis.
Methods Pediatricians will enroll cases of both COVID-19 associated encephalopathy/ encephalitis and MIS-C from several hospitals and medical centers. Their clinical manifestations, lab findings, severity and outcomes will be collected. Clinical assessment of all the systems will be performed. Blood, nasopharyngeal swab and stool will be collected at acute, subacute and convalescent stages for whole exome sequencing, immunopathogenesis including chemokine/cytokine, T/B lymphocyte subset, SARS-CoV2 specific Ab/T/B cell, T and B cell repertoire, viral pathogenesis including multiple viral detection, persistence of fecal SARS-COVID-2 as well as respiratory and gut microbiota. We will establish the animal models for COVID-19 associated encephalopathy/encephalitis and MIS-C, based on the K18-hACE2 or R26R-AGP mouse models established in NTU animal center. Moreover, specific viral or host factors involved in regulating the pathogenesis and immune responses can be investigated, to optimize the protocol for further improvement of the animal models and also to help identify the putative therapeutic targets.
Expected results We will delineate the clinical and laboratory characteristics of COVID-19 associated encephalopathy and encephalitis, the role of immune, virology, genetics mechanism in pathophysiology, and will optimize the treatment algorithm based on the result of this study. We also expect that the important biomarkers and risk factors associated with clinical outcome and severity, the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.
详细描述
Background for COVID-19 associated encephalopathy/encephalitis in children The COVID-19 primarily cause the respiratory diseases, such as croup, bronchiolitis, or pneumonia, but it also can affect the nervous system. According to the data of 1,695 children and adolescents, from March 15, 2020, to December 15, 2020, hospitalized for COVID-19 in 61 hospitals in the United States, 365 (22%) were found to have neurological symptoms. The majority children (322 children, 88%) had transient neurological symptoms. Unfortunately, 43 of them (12%) developed severe life-threatening conditions, including severe encephalopathy (15 children), ischemia or hemorrhagic stroke (12 children), acute central nervous system infection or acute disseminated encephalomyelitis (ADEM) (8 children), acute fulminant cerebral edema (4 children), and Guillain-Barré syndrome (GBS) (4 children). Of the 43 children, 11 patients (26%) died, and another 40% were discharged from the hospital with new neurological sequelae. In Asia, Hong Kong also experienced the Omicron pandemic in March. 171 (14.9%) of 1147 children hospitalized for Omicron were found to have neurological manifestations. The most common was the febrile seizure (11.60%), but there were also 5 children (0.44%) who developed coronavirus-related encephalopathy or encephalitis. Finally, two of them died of neurological causes: one with encephalopathy and the other with fulminant cerebral oedema.
Although the clinical course of acute encephalitis caused by COVID-19 in children is relatively mild in United States and European, the clinical course seemed to be more severe and fulminant in Taiwan. There are five cases of COVID-19 associated encephalopathy and encephalitis in Hong Kong, but the data available for reference is limited. Besides, the clinical course and pathophysiology of children with COVID-19 associated encephalopathy and encephalitis in Taiwan were unknown, it urgently need a clinically oriented, integrated research project.
Clinical research projects for COVID-19 associated encephalopathy/encephalitis in children The aim of this project is
- To analyze the clinical course and classify the stage of COVID-19 associated encephalopathy and encephalitis in children 2. To find the clinical predictor, biomarker, and imaging characteristic in critical case of COVID-19 associated encephalopathy and encephalitis in children 3. To explore the immune mechanism of COVID-19 associated encephalopathy and encephalitis in children 4. To explore the role of genetics in COVID-19 associated encephalopathy and encephalitis in children 5.To Explore the role of viral variants and co-infection in COVID-19 associated encephalopathy and encephalitis in children 6. To establish proper animal models for studying the pathogenesis and therapeutics for COVID-19 associated encephalopathy/encephalitis
Method: case planning for COVID-19 associated encephalopathy/encephalitis in children Active surveillance will be performed nationally to identify children and adolescents (age≤18 years) with COVID-19 related illness hospitalized from July 01, 2022, to February 28, 2023. The data will registry to the public database hold by NTUH and CGMH.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Prospective
入排标准
- 年龄范围
- — 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Age less than 18 years old.
- •A positive SARS-CoV-2 test result (reverse transcriptase-polymerase chain reaction and/or antibody)。
- •Hospitalized children.
- •Clinical diagnostic criteria for encephalitis.
- •Major criteria:
- •. Altered mental status greater than 24 hours without alternative cause identified Minor criteria: need at least 2 minor criteria for encephalitis
- •Focal neurologic signs
- •CSF: pleocytosis
- •EEG: abnormal slow background or epileptiform discharge
- •Neuroimaging: abnormal brain inflammation on MRI *****Major+2 minor: possible encephalitis; Major+3 minor: probable encephalitis; Brain biopsy: confirmed encephalitis
- •The following 6 criteria for MIS-C have to be met: age 0 to 19 years, fever for ≥3 days, clinical signs of multisystem involvement (at least 2 systems), elevated markers of inflammation (e.g., CRP, procalcitonin or ferritin), evidence of SARS-CoV-2 infection and no other obvious microbial cause of inflammation.
排除标准
- •Age more than 18 years old
- •Previous history of encephalopathy, acute encephalopathy caused by other etiology, not COVID-19, development delay, autism, ADHD, epilepsy and febrile seizure
- •Non-hospitalized children
结局指标
主要结局
clinical and laboratory characteristics of COVID-19 associated encephalitis/encephalopathy
时间窗: 2 year
for example: fever, poor consciousness, persistent lethargy, persistent headache, persistent vomiting, muscle twitching, convulsions, unsteady gait, etc.
biomarkers and risk factors of MIS-C
时间窗: 2 year
the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.
次要结局
未报告次要终点