Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

Caroline Diorio; Kevin O. McNerney; Michele Lambert; Michele Paessler; Elizabeth M. Anderson; Sarah E. Henrickson; Julie Chase; Emily J. Liebling; Chakkapong Burudpakdee; Jessica H. Lee; Frances B. Balamuth; Allison M. Blatz; Kathleen Chiotos; Julie C. Fitzgerald; Therese M. Giglia; Kandace Gollomp; Audrey R.Odom John; Cristina Jasen; Tomas Leng; Whitney Petrosa; Laura A. Vella; Char Witmer; Kathleen E. Sullivan; Benjamin L. Laskin; Scott E. Hensley; Hamid Bassiri; Edward M. Behrens; David T. Teachey

doi:10.1182/bloodadvances.2020003471

Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

Caroline Diorio, Kevin O. McNerney, Michele Lambert, Michele Paessler, Elizabeth M. Anderson, Sarah E. Henrickson, Julie Chase, Emily J. Liebling, Chakkapong Burudpakdee, Jessica H. Lee, Frances B. Balamuth, Allison M. Blatz, Kathleen Chiotos, Julie C. Fitzgerald, Therese M. Giglia, Kandace Gollomp, Audrey R.Odom John, Cristina Jasen, Tomas Leng, Whitney PetrosaLaura A. Vella, Char Witmer, Kathleen E. Sullivan, Benjamin L. Laskin, Scott E. Hensley, Hamid Bassiri^*, Edward M. Behrens, David T. Teachey

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

Abstract

Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.We enrolled 50 hospitalized pediatric patientswith acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized childrenwith SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

Original language	English (US)
Pages (from-to)	6051-6063
Number of pages	13
Journal	Blood Advances
Volume	4
Issue number	23
DOIs	https://doi.org/10.1182/bloodadvances.2020003471
State	Published - Dec 8 2020

Funding

Acknowledgments Financial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team (D.T.T., E.M.B., and H.B.), National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (R01AI121250 [E.M.B.]; R01AI103280, R01AI123433, and R21AI144472 [A.R.O.J.]; K08 AI136660 [L.A.V.]; and K08AI135091 [S. E. Henrickson]), NIH/National Cancer Institute (R01CA193776, X01HD100702-01, 5UG1CA233249, and R01A1123538) (D.T.T.), the Leukemia and Lymphoma Society (D.T.T.), Cookies for Kids Cancer (D.T.T.), Alex’s Lemonade Stand Foundation for Childhood Cancer (D.T.T.), Children’s Oncology Group (D.T.T.), Stand UP 2 Cancer (D.T.T.), Team Connor Childhood Cancer Foundation (H.B.), Burroughs Wellcome Fund CAMS (S. E. Henrickson and A.R.O.J.), Clinical Immunology Society (S. E. Henrickson), the American Academy of Allergy, Asthma, and Immunology (S. E. Henrickson), and the Agency for Healthcare Research and Quality (K12HS026393) (K.C.). C.D. is supported by an Institute for Translation Medicine and Therapheu-tics (ITMAT) scholarship and by the CHOP Gail Slap Fellowship Award. A.M.B. is supported by NIH/National Institute of General Medical Sciences (T32-GM075766). J.C.F. is supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463). E.M.A. was supported by the NIH Training in Virology T32 Program (T32-AI-007324). Financial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team (D.T.T., E.M.B., and H.B.), National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (R01AI121250 [E.M.B.]; R01AI103280, R01AI123433, and R21AI144472 [A.R.O.J.]; K08 AI136660 [L.A.V.]; and K08AI135091 [S. E. Henrickson]), NIH/National Cancer Institute (R01CA193776, X01HD100702-01, 5UG1CA233249, and R01A1123538) (D.T.T.), the Leukemia and Lymphoma Society (D.T.T.), Cookies for Kids Cancer (D.T.T.), Alex's Lemonade Stand Foundation for Childhood Cancer (D.T.T.), Children's Oncology Group (D.T.T.), Stand UP 2 Cancer (D.T.T.), Team Connor Childhood Cancer Foundation (H.B.), Burroughs Wellcome Fund CAMS (S. E. Henrickson and A.R.O.J.), Clinical Immunology Society (S. E. Henrickson), the American Academy of Allergy, Asthma, and Immunology (S. E. Henrickson), and the Agency for Healthcare Research and Quality (K12HS026393) (K.C.). C.D. is supported by an Institute for Translation Medicine and Therapheutics (ITMAT) scholarship and by the CHOP Gail Slap Fellowship Award. A.M.B. is supported by NIH/National Institute of General Medical Sciences (T32-GM075766). J.C.F. is supported by NIH/National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463). E.M.A. was supported by the NIH Training in Virology T32 Program (T32-AI-007324).

ASJC Scopus subject areas

Hematology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1182/bloodadvances.2020003471

Cite this

Diorio, C., McNerney, K. O., Lambert, M., Paessler, M., Anderson, E. M., Henrickson, S. E., Chase, J., Liebling, E. J., Burudpakdee, C., Lee, J. H., Balamuth, F. B., Blatz, A. M., Chiotos, K., Fitzgerald, J. C., Giglia, T. M., Gollomp, K., John, A. R. O., Jasen, C., Leng, T., ... Teachey, D. T. (2020). Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations. Blood Advances, 4(23), 6051-6063. https://doi.org/10.1182/bloodadvances.2020003471

@article{02b8e223c394445f8d7a5f5382d38383,

title = "Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations",

abstract = "Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.We enrolled 50 hospitalized pediatric patientswith acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized childrenwith SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.",

author = "Caroline Diorio and McNerney, {Kevin O.} and Michele Lambert and Michele Paessler and Anderson, {Elizabeth M.} and Henrickson, {Sarah E.} and Julie Chase and Liebling, {Emily J.} and Chakkapong Burudpakdee and Lee, {Jessica H.} and Balamuth, {Frances B.} and Blatz, {Allison M.} and Kathleen Chiotos and Fitzgerald, {Julie C.} and Giglia, {Therese M.} and Kandace Gollomp and John, {Audrey R.Odom} and Cristina Jasen and Tomas Leng and Whitney Petrosa and Vella, {Laura A.} and Char Witmer and Sullivan, {Kathleen E.} and Laskin, {Benjamin L.} and Hensley, {Scott E.} and Hamid Bassiri and Behrens, {Edward M.} and Teachey, {David T.}",

note = "Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology.",

year = "2020",

month = dec,

day = "8",

doi = "10.1182/bloodadvances.2020003471",

language = "English (US)",

volume = "4",

pages = "6051--6063",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

number = "23",

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Diorio, C, McNerney, KO, Lambert, M, Paessler, M, Anderson, EM, Henrickson, SE, Chase, J, Liebling, EJ, Burudpakdee, C, Lee, JH, Balamuth, FB, Blatz, AM, Chiotos, K, Fitzgerald, JC, Giglia, TM, Gollomp, K, John, ARO, Jasen, C, Leng, T, Petrosa, W, Vella, LA, Witmer, C, Sullivan, KE, Laskin, BL, Hensley, SE, Bassiri, H, Behrens, EM & Teachey, DT 2020, 'Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations', Blood Advances, vol. 4, no. 23, pp. 6051-6063. https://doi.org/10.1182/bloodadvances.2020003471

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T1 - Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

AU - Diorio, Caroline

AU - McNerney, Kevin O.

AU - Lambert, Michele

AU - Paessler, Michele

AU - Anderson, Elizabeth M.

AU - Henrickson, Sarah E.

AU - Chase, Julie

AU - Liebling, Emily J.

AU - Burudpakdee, Chakkapong

AU - Lee, Jessica H.

AU - Balamuth, Frances B.

AU - Blatz, Allison M.

AU - Chiotos, Kathleen

AU - Fitzgerald, Julie C.

AU - Giglia, Therese M.

AU - Gollomp, Kandace

AU - John, Audrey R.Odom

AU - Jasen, Cristina

AU - Leng, Tomas

AU - Petrosa, Whitney

AU - Vella, Laura A.

AU - Witmer, Char

AU - Sullivan, Kathleen E.

AU - Laskin, Benjamin L.

AU - Hensley, Scott E.

AU - Bassiri, Hamid

AU - Behrens, Edward M.

AU - Teachey, David T.

PY - 2020/12/8

Y1 - 2020/12/8

N2 - Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.We enrolled 50 hospitalized pediatric patientswith acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized childrenwith SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

AB - Most children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have mild or minimal disease, with a small proportion developing severe disease or multisystem inflammatory syndrome in children (MIS-C). Complement-mediated thrombotic microangiopathy (TMA) has been associated with SARS-CoV-2 infection in adults but has not been studied in the pediatric population. We hypothesized that complement activation plays an important role in SARS-CoV-2 infection in children and sought to understand if TMA was present in these patients.We enrolled 50 hospitalized pediatric patientswith acute SARS-CoV-2 infection (n = 21, minimal coronavirus disease 2019 [COVID-19]; n = 11, severe COVID-19) or MIS-C (n = 18). As a biomarker of complement activation and TMA, soluble C5b9 (sC5b9, normal 247 ng/mL) was measured in plasma, and elevations were found in patients with minimal disease (median, 392 ng/mL; interquartile range [IQR], 244-622 ng/mL), severe disease (median, 646 ng/mL; IQR, 203-728 ng/mL), and MIS-C (median, 630 ng/mL; IQR, 359-932 ng/mL) compared with 26 healthy control subjects (median, 57 ng/mL; IQR, 9-163 ng/mL; P < .001). Higher sC5b9 levels were associated with higher serum creatinine (P = .01) but not age. Of the 19 patients for whom complete clinical criteria were available, 17 (89%) met criteria for TMA. A high proportion of tested children with SARS-CoV-2 infection had evidence of complement activation and met clinical and diagnostic criteria for TMA. Future studies are needed to determine if hospitalized childrenwith SARS-CoV-2 should be screened for TMA, if TMA-directed management is helpful, and if there are any short- or long-term clinical consequences of complement activation and endothelial damage in children with COVID-19 or MIS-C.

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Evidence of thrombotic microangiopathy in children with SARS-CoV-2 across the spectrum of clinical presentations

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