Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

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Abstract

MIS-C is defined by lymphocyte activation, including elevated plasmablast frequencies and marked activation of CX3CR1+ CD8+ T cells.

Abstract

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

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Clinical and immunologic features in severe and moderate Coronavirus Disease 2019

Guang Chen, Di Wu, Wei. Guo … (2020)

Journal of Clinical Investigation

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Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

Leora Feldstein, Erica Rose, Steven M. Horwitz … (2020)

Abstract Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

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Clinical Characteristics of Covid-19 in New York City

Parag Goyal, Justin J Choi, Laura C Pinheiro … (2020)

To the Editor: The world is in the midst of the coronavirus disease 2019 (Covid-19) pandemic, 1,2 and New York City has emerged as an epicenter. Here, we characterize the first 393 consecutive patients with Covid-19 who were admitted to two hospitals in New York City. This retrospective case series includes adults 18 years of age or older with confirmed Covid-19 who were consecutively admitted between March 3 (date of the first positive case) and March 27, 2020, at an 862-bed quaternary referral center and an affiliated 180-bed nonteaching community hospital in Manhattan. Both hospitals adopted an early-intubation strategy with limited use of high-flow nasal cannulae during this period. Cases were confirmed through reverse-transcriptase–polymerase-chain-reaction assays performed on nasopharyngeal swab specimens. Data were manually abstracted from electronic health records with the use of a quality-controlled protocol and structured abstraction tool (details are provided in the Methods section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Among the 393 patients, the median age was 62.2 years, 60.6% were male, and 35.8% had obesity (Table 1). The most common presenting symptoms were cough (79.4%), fever (77.1%), dyspnea (56.5%), myalgias (23.8%), diarrhea (23.7%), and nausea and vomiting (19.1%) (Table S1 in the Supplementary Appendix). Most of the patients (90.0%) had lymphopenia, 27% had thrombocytopenia, and many had elevated liver-function values and inflammatory markers. Between March 3 and April 10, respiratory failure leading to invasive mechanical ventilation developed in 130 patients (33.1%); to date, only 43 of these patients (33.1%) have been extubated. In total, 40 of the patients (10.2%) have died, and 260 (66.2%) have been discharged from the hospital; outcome data are incomplete for the remaining 93 patients (23.7%). Patients who received invasive mechanical ventilation were more likely to be male, to have obesity, and to have elevated liver-function values and inflammatory markers (ferritin, d-dimer, C-reactive protein, and procalcitonin) than were patients who did not receive invasive mechanical ventilation. Of the patients who received invasive mechanical ventilation, 40 (30.8%) did not need supplemental oxygen during the first 3 hours after presenting to the emergency department. Patients who received invasive mechanical ventilation were more likely to need vasopressor support (95.4% vs. 1.5%) and to have other complications, including atrial arrhythmias (17.7% vs. 1.9%) and new renal replacement therapy (13.3% vs. 0.4%). Among these 393 patients with Covid-19 who were hospitalized in two New York City hospitals, the manifestations of the disease at presentation were generally similar to those in a large case series from China 1 ; however, gastrointestinal symptoms appeared to be more common than in China (where these symptoms occurred in 4 to 5% of patients). This difference could reflect geographic variation or differential reporting. Obesity was common and may be a risk factor for respiratory failure leading to invasive mechanical ventilation. 3 The percentage of patients in our case series who received invasive mechanical ventilation was more than 10 times as high as that in China; potential contributors include the more severe disease in our cohort (since testing and hospitalization in the United States is largely limited to patients with more severe disease) and the early-intubation strategy used in our hospitals. Regardless, the high demand for invasive mechanical ventilation has the potential to overwhelm hospital resources. Deterioration occurred in many patients whose condition had previously been stable; almost a third of patients who received invasive mechanical ventilation did not need supplemental oxygen at presentation. The observations that the patients who received invasive mechanical ventilation almost universally received vasopressor support and that many also received new renal replacement therapy suggest that there is also a need to strengthen stockpiles and supply chains for these resources.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Immunol

Journal ID (iso-abbrev): Sci Immunol

Journal ID (publisher-id): SciImmunol

Journal ID (hwp): immunology

Title: Science Immunology

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2470-9468

Publication date (Print): 02 March 2021

Publication date (Electronic): 02 March 2021

Volume: 6

Issue: 57

Electronic Location Identifier: eabf7570

Affiliations

[1 ]Division of Infectious Diseases, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[2 ]Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[3 ]Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[4 ]Parker Institute for Cancer Immunotherapy at University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[5 ]Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

[6 ]Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

[7 ]Immune Dysregulation Frontier Program, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[8 ]Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[9 ]Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[10 ]Division of Rheumatology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.

[11 ]Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

[12 ]Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

[13 ]Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA,19104, USA.

[14 ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

[15 ]Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.

Author notes

[#]

Equal contribution

[* ]Corresponding author. Email: vellal@ 123456chop.edu ; wherry@ 123456pennmedicine.upenn.edu

[†]

Members of the UPenn COVID Processing Unit can be found in the Acknowledgments.

Author information

Laura A. Vella https://orcid.org/0000-0002-8917-4845

Josephine R. Giles https://orcid.org/0000-0002-3713-338X

Amy E. Baxter https://orcid.org/0000-0002-1555-0713

Derek A. Oldridge https://orcid.org/0000-0003-2177-5633

Caroline Diorio https://orcid.org/0000-0002-8005-3836

Leticia Kuri-Cervantes https://orcid.org/0000-0002-2432-9500

Cécile Alanio https://orcid.org/0000-0003-2785-7445

M. Betina Pampena https://orcid.org/0000-0001-6665-4865

Jennifer E. Wu https://orcid.org/0000-0002-9302-8904

Yinghui Jane Huang https://orcid.org/0000-0003-0974-9539

Elizabeth M. Anderson https://orcid.org/0000-0002-1168-4773

Sigrid Gouma https://orcid.org/0000-0002-7853-8340

Kevin O. McNerney https://orcid.org/0000-0002-4359-3569

Julie Chase https://orcid.org/0000-0001-9486-3891

Sokratis A. Apostolidis https://orcid.org/0000-0002-0224-0097

Divij Mathew https://orcid.org/0000-0002-8323-7358

Oliva Kuthuru https://orcid.org/0000-0002-9435-9764

Madison E. Weirick https://orcid.org/0000-0003-2112-8102

Marcus J. Bolton https://orcid.org/0000-0002-6933-0548

Claudia P. Arevalo https://orcid.org/0000-0003-4062-1605

CJ Jasen https://orcid.org/0000-0001-9098-467X

Peyton E Conrey https://orcid.org/0000-0001-7766-9878

Samir Sayed https://orcid.org/0000-0003-4981-5721

Heather M. Giannini https://orcid.org/0000-0002-8979-3806

Kurt D’Andrea https://orcid.org/0000-0001-7005-3800

Nuala J. Meyer https://orcid.org/0000-0003-4597-5584

Edward M. Behrens https://orcid.org/0000-0002-4603-7963

Hamid Bassiri https://orcid.org/0000-0001-6532-8478

Scott E. Hensley https://orcid.org/0000-0002-2928-7506

Sarah E. Henrickson https://orcid.org/0000-0001-5569-4132

David T. Teachey https://orcid.org/0000-0001-7373-8987

Michael R. Betts https://orcid.org/0000-0002-7690-1484

E. John Wherry https://orcid.org/0000-0003-0477-1956

Article

Publisher ID: abf7570

DOI: 10.1126/sciimmunol.abf7570

PMC ID: 8128303

PubMed ID: 33653907

SO-VID: d8980680-1a78-4274-a376-4029db4879bf

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.