Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Carmelo Carmona-Rivera; Yu Zhang; Kerry Dobbs; Tovah E. Markowitz; Clifton L. Dalgard; Andrew J. Oler; Dillon R. Claybaugh; Deborah Draper; Meng Truong; Ottavia M. Delmonte; Francesco Licciardi; Ugo Ramenghi; Nicoletta Crescenzio; Luisa Imberti; Alessandra Sottini; Virginia Quaresima; Chiara Fiorini; Valentina Discepolo; Andrea Lo Vecchio; Alfredo Guarino; Luca Pierri; Andrea Catzola; Andrea Biondi; Paolo Bonfanti; Maria C.Poli Harlowe; Yasmin Espinosa; Camila Astudillo; Emma Rey-Jurado; Cecilia Vial; Javiera de la Cruz; Ricardo Gonzalez; Cecilia Pinera; Jacqueline W. Mays; Ashley Ng; Andrew Platt; Beth Drolet; John Moon; Edward W. Cowen; Heather Kenney; Sarah E. Weber; Riccardo Castagnoli; Mary Magliocco; Michael A. Stack; Gina Montealegre; Karyl Barron; Danielle L. Fink; Douglas B. Kuhns; Stephen M. Hewitt; Lisa M. Arkin; Daniel S. Chertow; Helen C. Su; Luigi D. Notarangelo; Mariana J. Kaplan

doi:10.1172/jci.insight.160332

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

Carmelo Carmona-Rivera, Yu Zhang, Kerry Dobbs, Tovah E. Markowitz, Clifton L. Dalgard, Andrew J. Oler, Dillon R. Claybaugh, Deborah Draper, Meng Truong, Ottavia M. Delmonte, Francesco Licciardi, Ugo Ramenghi, Nicoletta Crescenzio, Luisa Imberti, Alessandra Sottini, Virginia Quaresima, Chiara Fiorini, Valentina Discepolo, Andrea Lo Vecchio, Alfredo GuarinoLuca Pierri, Andrea Catzola, Andrea Biondi, Paolo Bonfanti, Maria C.Poli Harlowe, Yasmin Espinosa, Camila Astudillo, Emma Rey-Jurado, Cecilia Vial, Javiera de la Cruz, Ricardo Gonzalez, Cecilia Pinera, Jacqueline W. Mays, Ashley Ng, Andrew Platt, Beth Drolet, John Moon, Edward W. Cowen, Heather Kenney, Sarah E. Weber, Riccardo Castagnoli, Mary Magliocco, Michael A. Stack, Gina Montealegre, Karyl Barron, Danielle L. Fink, Douglas B. Kuhns, Stephen M. Hewitt, Lisa M. Arkin, Daniel S. Chertow, Helen C. Su, Luigi D. Notarangelo, Mariana J. Kaplan^*

^*Corresponding author for this work

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

16 Scopus citations

Abstract

Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes,"remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

Original language	English
Article number	e160332
Journal	JCI Insight
Volume	7
Issue number	16
DOIs	https://doi.org/10.1172/jci.insight.160332
State	Published - 22 Aug 2022
Externally published	Yes

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Carmona-Rivera, C., Zhang, Y., Dobbs, K., Markowitz, T. E., Dalgard, C. L., Oler, A. J., Claybaugh, D. R., Draper, D., Truong, M., Delmonte, O. M., Licciardi, F., Ramenghi, U., Crescenzio, N., Imberti, L., Sottini, A., Quaresima, V., Fiorini, C., Discepolo, V., Vecchio, A. L., ... Kaplan, M. J. (2022). Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19. JCI Insight, 7(16), Article e160332. https://doi.org/10.1172/jci.insight.160332

@article{7edbcba6ea294d11a022967ffcabbfe0,

title = "Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19",

abstract = "Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as {"}COVID toes,{"}remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.",

author = "Carmelo Carmona-Rivera and Yu Zhang and Kerry Dobbs and Markowitz, {Tovah E.} and Dalgard, {Clifton L.} and Oler, {Andrew J.} and Claybaugh, {Dillon R.} and Deborah Draper and Meng Truong and Delmonte, {Ottavia M.} and Francesco Licciardi and Ugo Ramenghi and Nicoletta Crescenzio and Luisa Imberti and Alessandra Sottini and Virginia Quaresima and Chiara Fiorini and Valentina Discepolo and Vecchio, {Andrea Lo} and Alfredo Guarino and Luca Pierri and Andrea Catzola and Andrea Biondi and Paolo Bonfanti and Harlowe, {Maria C.Poli} and Yasmin Espinosa and Camila Astudillo and Emma Rey-Jurado and Cecilia Vial and {de la Cruz}, Javiera and Ricardo Gonzalez and Cecilia Pinera and Mays, {Jacqueline W.} and Ashley Ng and Andrew Platt and Beth Drolet and John Moon and Cowen, {Edward W.} and Heather Kenney and Weber, {Sarah E.} and Riccardo Castagnoli and Mary Magliocco and Stack, {Michael A.} and Gina Montealegre and Karyl Barron and Fink, {Danielle L.} and Kuhns, {Douglas B.} and Hewitt, {Stephen M.} and Arkin, {Lisa M.} and Chertow, {Daniel S.} and Su, {Helen C.} and Notarangelo, {Luigi D.} and Kaplan, {Mariana J.}",

note = "Publisher Copyright: {\textcopyright} 2022, Carmona-Rivera et al.",

year = "2022",

month = aug,

day = "22",

doi = "10.1172/jci.insight.160332",

language = "English",

volume = "7",

journal = "JCI Insight",

issn = "2379-3708",

number = "16",

}

Carmona-Rivera, C, Zhang, Y, Dobbs, K, Markowitz, TE, Dalgard, CL, Oler, AJ, Claybaugh, DR, Draper, D, Truong, M, Delmonte, OM, Licciardi, F, Ramenghi, U, Crescenzio, N, Imberti, L, Sottini, A, Quaresima, V, Fiorini, C, Discepolo, V, Vecchio, AL, Guarino, A, Pierri, L, Catzola, A, Biondi, A, Bonfanti, P, Harlowe, MCP, Espinosa, Y, Astudillo, C, Rey-Jurado, E, Vial, C, de la Cruz, J, Gonzalez, R, Pinera, C, Mays, JW, Ng, A, Platt, A, Drolet, B, Moon, J, Cowen, EW, Kenney, H, Weber, SE, Castagnoli, R, Magliocco, M, Stack, MA, Montealegre, G, Barron, K, Fink, DL, Kuhns, DB, Hewitt, SM, Arkin, LM, Chertow, DS, Su, HC, Notarangelo, LD & Kaplan, MJ 2022, 'Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19', JCI Insight, vol. 7, no. 16, e160332. https://doi.org/10.1172/jci.insight.160332

TY - JOUR

T1 - Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

AU - Carmona-Rivera, Carmelo

AU - Zhang, Yu

AU - Dobbs, Kerry

AU - Markowitz, Tovah E.

AU - Dalgard, Clifton L.

AU - Oler, Andrew J.

AU - Claybaugh, Dillon R.

AU - Draper, Deborah

AU - Truong, Meng

AU - Delmonte, Ottavia M.

AU - Licciardi, Francesco

AU - Ramenghi, Ugo

AU - Crescenzio, Nicoletta

AU - Imberti, Luisa

AU - Sottini, Alessandra

AU - Quaresima, Virginia

AU - Fiorini, Chiara

AU - Discepolo, Valentina

AU - Vecchio, Andrea Lo

AU - Guarino, Alfredo

AU - Pierri, Luca

AU - Catzola, Andrea

AU - Biondi, Andrea

AU - Bonfanti, Paolo

AU - Harlowe, Maria C.Poli

AU - Espinosa, Yasmin

AU - Astudillo, Camila

AU - Rey-Jurado, Emma

AU - Vial, Cecilia

AU - de la Cruz, Javiera

AU - Gonzalez, Ricardo

AU - Pinera, Cecilia

AU - Mays, Jacqueline W.

AU - Ng, Ashley

AU - Platt, Andrew

AU - Drolet, Beth

AU - Moon, John

AU - Cowen, Edward W.

AU - Kenney, Heather

AU - Weber, Sarah E.

AU - Castagnoli, Riccardo

AU - Magliocco, Mary

AU - Stack, Michael A.

AU - Montealegre, Gina

AU - Barron, Karyl

AU - Fink, Danielle L.

AU - Kuhns, Douglas B.

AU - Hewitt, Stephen M.

AU - Arkin, Lisa M.

AU - Chertow, Daniel S.

AU - Su, Helen C.

AU - Notarangelo, Luigi D.

AU - Kaplan, Mariana J.

PY - 2022/8/22

Y1 - 2022/8/22

N2 - Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes,"remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

AB - Dysregulation in neutrophil extracellular trap (NET) formation and degradation may play a role in the pathogenesis and severity of COVID-19; however, its role in the pediatric manifestations of this disease, including multisystem inflammatory syndrome in children (MIS-C) and chilblain-like lesions (CLLs), otherwise known as "COVID toes,"remains unclear. Studying multinational cohorts, we found that, in CLLs, NETs were significantly increased in serum and skin. There was geographic variability in the prevalence of increased NETs in MIS-C, in association with disease severity. MIS-C and CLL serum samples displayed decreased NET degradation ability, in association with C1q and G-actin or anti-NET antibodies, respectively, but not with genetic variants of DNases. In adult COVID-19, persistent elevations in NETs after disease diagnosis were detected but did not occur in asymptomatic infection. COVID-19-affected adults displayed significant prevalence of impaired NET degradation, in association with anti-DNase1L3, G-actin, and specific disease manifestations, but not with genetic variants of DNases. NETs were detected in many organs of adult patients who died from COVID-19 complications. Infection with the Omicron variant was associated with decreased NET levels when compared with other SARS-CoV-2 strains. These data support a role for NETs in the pathogenesis and severity of COVID-19 in pediatric and adult patients.

UR - http://www.scopus.com/inward/record.url?scp=85135777978&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.160332

DO - 10.1172/jci.insight.160332

M3 - Article

C2 - 35852866

AN - SCOPUS:85135777978

SN - 2379-3708

VL - 7

JO - JCI Insight

JF - JCI Insight

IS - 16

M1 - e160332

ER -

Multicenter analysis of neutrophil extracellular trap dysregulation in adult and pediatric COVID-19

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