Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children

Andargie, Temesgen E.; Roznik, Katerina; Redekar, Neelam; Hill, Tom; Zhou, Weiqiang; Apalara, Zainab; Kong, Hyesik; Gordon, Oren; Meda, Rohan; Park, Woojin; Johnston, Trevor S.; Wang, Yi; Brady, Sheila; Ji, Hongkai; Yanovski, Jack A.; Jang, Moon K.; Lee, Clarence M.; Karaba, Andrew H.; Cox, Andrea L.; Agbor-Enoh, Sean

doi:10.1172/jci171729

Cited by 4 publications

(3 citation statements)

References 55 publications

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“…Other studies have suggested that MIS-C may reflect more exuberant innate immune responses. This latter notion is supported by an epigenomics analyses of plasma cell-free DNA (cfDNA) that compared healthy children and children with acute COVID-19 to those with MIS-C and found higher levels of cfDNA originating from innate immune cells in the MIS-C patients, but no differences in cfDNA from adaptive immune cells [ 26 ]. In support of a role for adaptive immune responses, a different study comparing peripheral blood immune responses in hospitalized SARS-CoV-2-infected pediatric patients and those with MIS-C found that MIS-C was associated with greater T cell activation, including CX3CR1+ CD8+ T cells, which decreased with clinical recovery, suggesting a role for activated CD8+ T cells in the disease pathogenesis [ 27 ].…”

Section: Multisystem Inflammatory Syndromementioning

confidence: 99%

Differences in the Clinical Manifestations and Host Immune Responses to SARS-CoV-2 Variants in Children Compared to Adults

Demirhan,

Goldman,

Herold

2023

JCM

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The COVID-19 pandemic challenged the medical field to rapidly identify and implement new approaches to the diagnosis, treatment and prevention of SARS-CoV-2 infections. The scientific community also needed to rapidly initiate basic, translational, clinical and epidemiological studies to understand the pathophysiology of this new family of viruses, which continues to evolve with the emergence of new genetic variants. One of the earliest clinical observations that provided a framework for the research was the finding that, in contrast to most other respiratory viruses, children developed less severe acute and post-acute disease compared to adults. Although the clinical manifestations of SARS-CoV-2 infection changed with each new wave of the pandemic, which was dominated by evolving viral variants, the differences in severity between children and adults persisted. Comparative immunologic studies have shown that children mount a more vigorous local innate response characterized by the activation of interferon pathways and recruitment of innate cells to the mucosa, which may mitigate against the hyperinflammatory adaptive response and systemic cytokine release that likely contributed to more severe outcomes including acute respiratory distress syndrome in adults. In this review, the clinical manifestations and immunologic responses in children during the different waves of COVID-19 are discussed.

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Section: Multisystem Inflammatory Syndromementioning

confidence: 99%

Differences in the Clinical Manifestations and Host Immune Responses to SARS-CoV-2 Variants in Children Compared to Adults

Demirhan,

Goldman,

Herold

2023

JCM

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“…However, there are many situations when genetic differences cannot be used to identify allograft-derived DNA; for example, when the genotype is unknown, multiple genotypes exist in the host, and when the donor is closely related to the recipient (13). Instead, epigenetic modifications can be used to identify cfDNA that is recipient or allograft-derived by using tissue-and cell-type specific marks that are independent of genotype differences between the donor and recipient (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Allograft injury can thus be detected in an organ specific fashion, which is of critical importance in recipients of multi-organ transplants and recipients of hematopoietic cell transplant (HCT) who develop Graft-versus-Host disease (GvHD) (30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

“…DNA methylation is highly cell-type-specific and has been found to reveal the origins of tissue damages and altered cell turnover from cfDNA samples in a wide-range of applications (27,28,30,31,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). DNA methylation patterns are stable epigenetic marks for cells maintained throughout DNA replication and cell proliferation (46).…”

Section: Introductionmentioning

confidence: 99%

Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant

McNamara,

Jain,

Oza

et al. 2024

Preprint

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Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to patterns established to identify cell types in different organs. For liver cell types DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and regulatory regions functionally important for the respective cell types. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA beyond the first week indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and timely intervention.

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The Spectrum of Postacute Sequelae of COVID-19 in Children: From MIS-C to Long COVID

Kane,

Godfrey,

Noval Rivas

et al. 2024

Annual Review of Virology

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The effects of SARS-CoV-2 infection on children continue to evolve following the onset of the COVID-19 pandemic. Although life-threatening multisystem inflammatory syndrome in children (MIS-C) has become rare, long-standing symptoms stemming from persistent immune activation beyond the resolution of acute SARS-CoV-2 infection contribute to major health sequelae and continue to pose an economic burden. Shared pathophysiologic mechanisms place MIS-C and long COVID within a vast spectrum of postinfectious conditions characterized by intestinal dysbiosis, increased gut permeability, and varying degrees of immune dysregulation. Insights obtained from MIS-C will help shape our understanding of the more indolent and prevalent postacute sequelae of COVID and ultimately guide efforts to improve diagnosis and management of postinfectious complications of SARS-CoV-2 infection in children.

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Cell-free DNA reveals distinct pathology of multisystem inflammatory syndrome in children

Cited by 4 publications

References 55 publications

Differences in the Clinical Manifestations and Host Immune Responses to SARS-CoV-2 Variants in Children Compared to Adults

Differences in the Clinical Manifestations and Host Immune Responses to SARS-CoV-2 Variants in Children Compared to Adults

Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant

The Spectrum of Postacute Sequelae of COVID-19 in Children: From MIS-C to Long COVID

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