Investigation of Prognostic Biomarkers, Host Factors and Viral Factors for COVID-19 in Children

NCT05576714 | Unknown

• 1 other identifier: 202207201RIND
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

COVID-19-Associated Encephalitis; Multisystem Inflammatory Syndrome in Children

Keywords

COVID-19; encephalitis; MIS-C

Outcome Measures

Primary Outcomes (2)

• clinical and laboratory characteristics of COVID-19 associated encephalitis/encephalopathy

  for example: fever, poor consciousness, persistent lethargy, persistent headache, persistent vomiting, muscle twitching, convulsions, unsteady gait, etc.

  2 year

• biomarkers and risk factors of MIS-C

  the immunopathogenesis of MIS-C, host genetic factors and the viral pathogenesis and microbiota associated with MIS-C will be found.

  2 year

Study Arms (3)

encephalopathy/encephalitis

Children will be classified as the following four diagnoses: 1. Encephalopathy (MERS, ANEC, ASED); 2. Acute encephalitis; 3. ADEM; 4. Fulminant cerebral edema. The classification will be adjudicated and discussed by neurology and critical care experts on the NTUH and CGMH study team (W.T.L, J.J.L, and K.L.L.)

Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis

MIS-C

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.

Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis

control group

Age and gender matched healthy control children or mild COVID-19 cases without MIS-C will be also included for further comparison

Other: delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis

Interventions

delineate its prognostic biomarker, host genetic factors, immunopathogenesis and viral pathogenesis OTHER

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.

MIS-C; control group; encephalopathy/encephalitis

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• 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
• Fever
• Seizures
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Taiwan University Hospital: lead
• Chang Gung Medical Foundation: collaborator
• National Cheng-Kung University Hospital: collaborator
• Chi Mei Medical Hospital: collaborator
• Mackay Memorial Hospital: collaborator
• Tri-Service General Hospital: collaborator
• National Health Research Institutes, Taiwan: collaborator
• National Science and Technology Council: collaborator

Study Sites (1)

National Taiwan University Hospital

Taipei, Chung Cheng District, 100, Taiwan

RECRUITING

Related Publications (29)

• Nygaard U, Holm M, Hartling UB, Glenthoj J, Schmidt LS, Nordly SB, Matthesen AT, von Linstow ML, Espenhain L. Incidence and clinical phenotype of multisystem inflammatory syndrome in children after infection with the SARS-CoV-2 delta variant by vaccination status: a Danish nationwide prospective cohort study. Lancet Child Adolesc Health. 2022 Jul;6(7):459-465. doi: 10.1016/S2352-4642(22)00100-6. Epub 2022 May 6.

  PMID: 35526537 BACKGROUND

• Payne AB, Gilani Z, Godfred-Cato S, Belay ED, Feldstein LR, Patel MM, Randolph AG, Newhams M, Thomas D, Magleby R, Hsu K, Burns M, Dufort E, Maxted A, Pietrowski M, Longenberger A, Bidol S, Henderson J, Sosa L, Edmundson A, Tobin-D'Angelo M, Edison L, Heidemann S, Singh AR, Giuliano JS Jr, Kleinman LC, Tarquinio KM, Walsh RF, Fitzgerald JC, Clouser KN, Gertz SJ, Carroll RW, Carroll CL, Hoots BE, Reed C, Dahlgren FS, Oster ME, Pierce TJ, Curns AT, Langley GE, Campbell AP; MIS-C Incidence Authorship Group; Balachandran N, Murray TS, Burkholder C, Brancard T, Lifshitz J, Leach D, Charpie I, Tice C, Coffin SE, Perella D, Jones K, Marohn KL, Yager PH, Fernandes ND, Flori HR, Koncicki ML, Walker KS, Di Pentima MC, Li S, Horwitz SM, Gaur S, Coffey DC, Harwayne-Gidansky I, Hymes SR, Thomas NJ, Ackerman KG, Cholette JM. Incidence of Multisystem Inflammatory Syndrome in Children Among US Persons Infected With SARS-CoV-2. JAMA Netw Open. 2021 Jun 1;4(6):e2116420. doi: 10.1001/jamanetworkopen.2021.16420.

  PMID: 34110391 BACKGROUND

• Ghosh P, Katkar GD, Shimizu C, Kim J, Khandelwal S, Tremoulet AH, Kanegaye JT; Pediatric Emergency Medicine Kawasaki Disease Research Group; Bocchini J, Das S, Burns JC, Sahoo D. An Artificial Intelligence-guided signature reveals the shared host immune response in MIS-C and Kawasaki disease. Nat Commun. 2022 May 16;13(1):2687. doi: 10.1038/s41467-022-30357-w.

  PMID: 35577777 BACKGROUND

• Chou J, Platt CD, Habiballah S, Nguyen AA, Elkins M, Weeks S, Peters Z, Day-Lewis M, Novak T, Armant M, Williams L, Rockowitz S, Sliz P, Williams DA, Randolph AG, Geha RS; Taking on COVID-19 Together Study Investigators. Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C). J Allergy Clin Immunol. 2021 Sep;148(3):732-738.e1. doi: 10.1016/j.jaci.2021.06.024. Epub 2021 Jul 2.

  PMID: 34224783 BACKGROUND

• Sacco K, Castagnoli R, Vakkilainen S, Liu C, Delmonte OM, Oguz C, Kaplan IM, Alehashemi S, Burbelo PD, Bhuyan F, de Jesus AA, Dobbs K, Rosen LB, Cheng A, Shaw E, Vakkilainen MS, Pala F, Lack J, Zhang Y, Fink DL, Oikonomou V, Snow AL, Dalgard CL, Chen J, Sellers BA, Montealegre Sanchez GA, Barron K, Rey-Jurado E, Vial C, Poli MC, Licari A, Montagna D, Marseglia GL, Licciardi F, Ramenghi U, Discepolo V, Lo Vecchio A, Guarino A, Eisenstein EM, Imberti L, Sottini A, Biondi A, Mato S, Gerstbacher D, Truong M, Stack MA, Magliocco M, Bosticardo M, Kawai T, Danielson JJ, Hulett T, Askenazi M, Hu S; NIAID Immune Response to COVID Group; Chile MIS-C Group; Pavia Pediatric COVID-19 Group; Cohen JI, Su HC, Kuhns DB, Lionakis MS, Snyder TM, Holland SM, Goldbach-Mansky R, Tsang JS, Notarangelo LD. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med. 2022 May;28(5):1050-1062. doi: 10.1038/s41591-022-01724-3. Epub 2022 Feb 17.

  PMID: 35177862 BACKGROUND

• Kumar D, Rostad CA, Jaggi P, Villacis Nunez DS, Prince C, Lu A, Hussaini L, Nguyen TH, Malik S, Ponder LA, Shenoy SPV, Anderson EJ, Briones M, Sanz I, Prahalad S, Chandrakasan S. Distinguishing immune activation and inflammatory signatures of multisystem inflammatory syndrome in children (MIS-C) versus hemophagocytic lymphohistiocytosis (HLH). J Allergy Clin Immunol. 2022 May;149(5):1592-1606.e16. doi: 10.1016/j.jaci.2022.02.028. Epub 2022 Mar 15.

  PMID: 35304157 BACKGROUND

• Sharma C, Ganigara M, Galeotti C, Burns J, Berganza FM, Hayes DA, Singh-Grewal D, Bharath S, Sajjan S, Bayry J. Multisystem inflammatory syndrome in children and Kawasaki disease: a critical comparison. Nat Rev Rheumatol. 2021 Dec;17(12):731-748. doi: 10.1038/s41584-021-00709-9. Epub 2021 Oct 29.

  PMID: 34716418 BACKGROUND

• Natarajan A, Zlitni S, Brooks EF, Vance SE, Dahlen A, Hedlin H, Park RM, Han A, Schmidtke DT, Verma R, Jacobson KB, Parsonnet J, Bonilla HF, Singh U, Pinsky BA, Andrews JR, Jagannathan P, Bhatt AS. Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection. Med. 2022 Jun 10;3(6):371-387.e9. doi: 10.1016/j.medj.2022.04.001. Epub 2022 Apr 13.

  PMID: 35434682 BACKGROUND

• Yonker LM, Gilboa T, Ogata AF, Senussi Y, Lazarovits R, Boribong BP, Bartsch YC, Loiselle M, Rivas MN, Porritt RA, Lima R, Davis JP, Farkas EJ, Burns MD, Young N, Mahajan VS, Hajizadeh S, Lopez XIH, Kreuzer J, Morris R, Martinez EE, Han I, Griswold K Jr, Barry NC, Thompson DB, Church G, Edlow AG, Haas W, Pillai S, Arditi M, Alter G, Walt DR, Fasano A. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier. J Clin Invest. 2021 Jul 15;131(14):e149633. doi: 10.1172/JCI149633.

  PMID: 34032635 BACKGROUND

• Diorio C, Shraim R, Vella LA, Giles JR, Baxter AE, Oldridge DA, Canna SW, Henrickson SE, McNerney KO, Balamuth F, Burudpakdee C, Lee J, Leng T, Farrel A, Lambert MP, Sullivan KE, Wherry EJ, Teachey DT, Bassiri H, Behrens EM. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun. 2021 Dec 10;12(1):7222. doi: 10.1038/s41467-021-27544-6.

  PMID: 34893640 BACKGROUND

• Qian Y, Lei T, Patel PS, Lee CH, Monaghan-Nichols P, Xin HB, Qiu J, Fu M. Direct Activation of Endothelial Cells by SARS-CoV-2 Nucleocapsid Protein Is Blocked by Simvastatin. J Virol. 2021 Nov 9;95(23):e0139621. doi: 10.1128/JVI.01396-21. Epub 2021 Sep 22.

  PMID: 34549987 BACKGROUND

• Oladunni FS, Park JG, Pino PA, Gonzalez O, Akhter A, Allue-Guardia A, Olmo-Fontanez A, Gautam S, Garcia-Vilanova A, Ye C, Chiem K, Headley C, Dwivedi V, Parodi LM, Alfson KJ, Staples HM, Schami A, Garcia JI, Whigham A, Platt RN 2nd, Gazi M, Martinez J, Chuba C, Earley S, Rodriguez OH, Mdaki SD, Kavelish KN, Escalona R, Hallam CRA, Christie C, Patterson JL, Anderson TJC, Carrion R Jr, Dick EJ Jr, Hall-Ursone S, Schlesinger LS, Alvarez X, Kaushal D, Giavedoni LD, Turner J, Martinez-Sobrido L, Torrelles JB. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nat Commun. 2020 Nov 30;11(1):6122. doi: 10.1038/s41467-020-19891-7.

  PMID: 33257679 BACKGROUND

• Winkler ES, Bailey AL, Kafai NM, Nair S, McCune BT, Yu J, Fox JM, Chen RE, Earnest JT, Keeler SP, Ritter JH, Kang LI, Dort S, Robichaud A, Head R, Holtzman MJ, Diamond MS. SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Nat Immunol. 2020 Nov;21(11):1327-1335. doi: 10.1038/s41590-020-0778-2. Epub 2020 Aug 24.

  PMID: 32839612 BACKGROUND

• Vidal E, Lopez-Figueroa C, Rodon J, Perez M, Brustolin M, Cantero G, Guallar V, Izquierdo-Useros N, Carrillo J, Blanco J, Clotet B, Vergara-Alert J, Segales J. Chronological brain lesions after SARS-CoV-2 infection in hACE2-transgenic mice. Vet Pathol. 2022 Jul;59(4):613-626. doi: 10.1177/03009858211066841. Epub 2021 Dec 27.

  PMID: 34955064 BACKGROUND

• Kumari P, Rothan HA, Natekar JP, Stone S, Pathak H, Strate PG, Arora K, Brinton MA, Kumar M. Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice. Viruses. 2021 Jan 19;13(1):132. doi: 10.3390/v13010132.

  PMID: 33477869 BACKGROUND

• Seehusen F, Clark JJ, Sharma P, Bentley EG, Kirby A, Subramaniam K, Wunderlin-Giuliani S, Hughes GL, Patterson EI, Michael BD, Owen A, Hiscox JA, Stewart JP, Kipar A. Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse. Viruses. 2022 May 11;14(5):1020. doi: 10.3390/v14051020.

  PMID: 35632761 BACKGROUND

• Chen YT, Tsai MS, Yang TL, Ku AT, Huang KH, Huang CY, Chou FJ, Fan HH, Hong JB, Yen ST, Wang WL, Lin CC, Hsu YC, Su KY, Su IC, Jang CW, Behringer RR, Favaro R, Nicolis SK, Chien CL, Lin SW, Yu IS. R26R-GR: a Cre-activable dual fluorescent protein reporter mouse. PLoS One. 2012;7(9):e46171. doi: 10.1371/journal.pone.0046171. Epub 2012 Sep 25.

  PMID: 23049968 BACKGROUND

• Leung TF, Wong GW, Hon KL, Fok TF. Severe acute respiratory syndrome (SARS) in children: epidemiology, presentation and management. Paediatr Respir Rev. 2003 Dec;4(4):334-9. doi: 10.1016/s1526-0542(03)00088-5.

  PMID: 14629957 BACKGROUND

• Dhochak N, Singhal T, Kabra SK, Lodha R. Pathophysiology of COVID-19: Why Children Fare Better than Adults? Indian J Pediatr. 2020 Jul;87(7):537-546. doi: 10.1007/s12098-020-03322-y. Epub 2020 May 14.

  PMID: 32410003 BACKGROUND

• Xie X, Chen J, Wang X, Zhang F, Liu Y. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 2006 Apr 4;78(19):2166-71. doi: 10.1016/j.lfs.2005.09.038. Epub 2005 Nov 21.

  PMID: 16303146 BACKGROUND

• Consiglio CR, Cotugno N, Sardh F, Pou C, Amodio D, Rodriguez L, Tan Z, Zicari S, Ruggiero A, Pascucci GR, Santilli V, Campbell T, Bryceson Y, Eriksson D, Wang J, Marchesi A, Lakshmikanth T, Campana A, Villani A, Rossi P; CACTUS Study Team; Landegren N, Palma P, Brodin P. The Immunology of Multisystem Inflammatory Syndrome in Children with COVID-19. Cell. 2020 Nov 12;183(4):968-981.e7. doi: 10.1016/j.cell.2020.09.016. Epub 2020 Sep 6.

  PMID: 32966765 BACKGROUND

• Miller J, Cantor A, Zachariah P, Ahn D, Martinez M, Margolis KG. Gastrointestinal Symptoms as a Major Presentation Component of a Novel Multisystem Inflammatory Syndrome in Children That Is Related to Coronavirus Disease 2019: A Single Center Experience of 44 Cases. Gastroenterology. 2020 Oct;159(4):1571-1574.e2. doi: 10.1053/j.gastro.2020.05.079. Epub 2020 Jun 4. No abstract available.

  PMID: 32505742 BACKGROUND

• Younis JS, Skorecki K, Abassi Z. The Double Edge Sword of Testosterone's Role in the COVID-19 Pandemic. Front Endocrinol (Lausanne). 2021 Mar 16;12:607179. doi: 10.3389/fendo.2021.607179. eCollection 2021.

  PMID: 33796068 BACKGROUND

• Mihalopoulos M, Levine AC, Marayati NF, Chubak BM, Archer M, Badani KK, Tewari AK, Mohamed N, Ferrer F, Kyprianou N. The Resilient Child: Sex-Steroid Hormones and COVID-19 Incidence in Pediatric Patients. J Endocr Soc. 2020 Jul 28;4(9):bvaa106. doi: 10.1210/jendso/bvaa106. eCollection 2020 Sep 1.

  PMID: 32864545 BACKGROUND

• Mjaess G, Karam A, Aoun F, Albisinni S, Roumeguere T. COVID-19 and the male susceptibility: the role of ACE2, TMPRSS2 and the androgen receptor. Prog Urol. 2020 Sep;30(10):484-487. doi: 10.1016/j.purol.2020.05.007. Epub 2020 May 22.

  PMID: 32620366 BACKGROUND

• Cantuti-Castelvetri L, Ojha R, Pedro LD, Djannatian M, Franz J, Kuivanen S, van der Meer F, Kallio K, Kaya T, Anastasina M, Smura T, Levanov L, Szirovicza L, Tobi A, Kallio-Kokko H, Osterlund P, Joensuu M, Meunier FA, Butcher SJ, Winkler MS, Mollenhauer B, Helenius A, Gokce O, Teesalu T, Hepojoki J, Vapalahti O, Stadelmann C, Balistreri G, Simons M. Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020 Nov 13;370(6518):856-860. doi: 10.1126/science.abd2985. Epub 2020 Oct 20.

  PMID: 33082293 BACKGROUND

• Mayi BS, Leibowitz JA, Woods AT, Ammon KA, Liu AE, Raja A. The role of Neuropilin-1 in COVID-19. PLoS Pathog. 2021 Jan 4;17(1):e1009153. doi: 10.1371/journal.ppat.1009153. eCollection 2021 Jan.

  PMID: 33395426 BACKGROUND

• Bunyavanich S, Do A, Vicencio A. Nasal Gene Expression of Angiotensin-Converting Enzyme 2 in Children and Adults. JAMA. 2020 Jun 16;323(23):2427-2429. doi: 10.1001/jama.2020.8707.

  PMID: 32432657 BACKGROUND

• Yang LT, Li WY, Kaartinen V. Tissue-specific expression of Cre recombinase from the Tgfb3 locus. Genesis. 2008 Feb;46(2):112-8. doi: 10.1002/dvg.20372.

  PMID: 18257072 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

blood, nasopharyngeal swab, stool

MeSH Terms

Conditions

pediatric multisystem inflammatory disease, COVID-19 related; COVID-19; Encephalitis

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroinflammatory Diseases

Study Officials

• Luna-Yin Chang, professor

  National Taiwan University Hospital

  STUDY CHAIR

Central Study Contacts

Tsui-Yien Fan, RA

CONTACT

+886 2312 3456; twffccy@gmail.com

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Target Duration: 1 Year
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 10, 2022
• First Posted: October 12, 2022
• Study Start: August 1, 2022
• Primary Completion: July 1, 2025
• Study Completion: July 1, 2025
• Last Updated: October 14, 2022

Record last verified: 2022-10

Locations

TW (1)