Wednesday, August 19, 2020

Nature Med: Peripheral Immunophenotypes in Children with Multisystem Inflammatory Syndrome


Just over 10 days ago, in MMWR: COVID-19–Associated Multisystem Inflammatory Syndrome in Children — U.S., March–July 2020, we looked at the CDC's latest data on a rare, and poorly understood syndrome in children - one that appears to be linked to SARS-CoV-2 infection - that has affected (at last count) roughly 600 children in the United States.

We first saw this condition described in the UK back in April (see PICS: NHS Alert On Possible Severe Pediatric COVID-19 Complication), and while it is referred to as MIS-C in the United States, it is called PIMS-TS in the UK.

The CDC describes the syndrome on their MIS-C website as:

What is MIS-C?

Multisystem inflammatory syndrome in children (MIS-C) is a condition where different body parts can become inflamed, including the heart, lungs, kidneys, brain, skin, eyes, or gastrointestinal organs. Children with MIS-C may have a fever and various symptoms, including abdominal (gut) pain, vomiting, diarrhea, neck pain, rash, bloodshot eyes, or feeling extra tired. We do not yet know what causes MIS-C. However, many children with MIS-C had the virus that causes COVID-19, or had been around someone with COVID-19. 

The link to SARS-CoV-2 infection has been reasonably well established - and the general assumption has been this syndrome is some sort of autoimmune response to infection (see Autoimmune and inflammatory diseases following COVID-19) - but the mechanisms behind that response are less than clear. 

Yesterday, a letter published in Nature Medicine, reports that an analysis of blood samples taken from 25 affected children reveals a sharp rise in cytokines - along with a depletion of lymphocytes - which strongly points to an autoimmune syndrome. 

The report itself (warning, lengthy & highly technical) can be read at the link below.  I've only posted the abstract.  Following that, I have a considerably less technical press release. 

Published: 18 August 2020
Michael J. Carter, Matthew Fish, Aislinn Jennings, Katie J. Doores, Paul Wellman, Jeffrey Seow, Sam Acors, Carl Graham, Emma Timms, Julia Kenny, Stuart Neil, Michael H. Malim, Shane M. Tibby & Manu Shankar-Hari 

Nature Medicine (2020) Cite this article

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1—multisystem inflammatory syndrome in children (MIS-C)—which comprises multiorgan dysfunction and systemic inflammation2,3,4,5,6,7,8,9,10,11,12,13.
We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute (n = 23; worst illness within 72 h of admission), resolution (n = 14; clinical improvement) and convalescent (n = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections14,15, and these children had more severe disease.
In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4+CCR7+ T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness1 and appears distinct from Kawasaki disease.

(Continue . . . )



Researchers have uncovered how the immune system is altered in a rare COVID-19 related illness in children referred to as paediatric inflammatory multisystem syndrome (PIMS-TS).

PIMS-TS is a rare syndrome which has emerged in a small number of children during the COVID-19 pandemic. The condition causes severe inflammation in blood vessels and can lead to heart damage.

The team from Evelina London Children's Hospital and King's College London analysed blood samples from 25 children who had PIMS-TS and compared these to healthy children. The study, supported by the NIHR Guy's and St Thomas' BRC and published in Nature Medicine, showed that in the acute stage of PIMS-TS, children have raised levels of molecules called cytokines, and reduced levels of white blood cells called lymphocytes. They saw that by the time the children had recovered, the immune system changes had gradually returned to normal.

Although the number of children in the study was small, this is the first evidence about the role of the immune system in the disease. It provides vital evidence for future research and will indicate what treatments may help patients with the condition.

The first cases of PIMS-TS were treated at Evelina London in mid-April 2020. Initial reports suggested the condition may be similar to existing conditions such as Kawasaki disease. However, the new research confirms that PIMS-TS affects the body in a different way to other known conditions and has been identified as a new syndrome.

The research, led by Dr Shankar-Hari within the King's College London School of Immunology and Microbial Sciences, worked to understand the immune system changes underlying this new condition.

Blood samples were analysed from 25 children who had tested positive for the Sars-COV2 virus, had symptoms of COVID-19, had been in close contact with someone who had tested positive, or whose parent was a healthcare worker.

Blood samples were tested from children these children at different stages of the disease, from the acute phase when they first came onto hospital, through to their outpatient appointments. The researchers compared these results to those of seven healthy age-matched children.

Dr Manu Shankar-Hari is a consultant in intensive care medicine at Guy's and St Thomas' and NIHR Clinician Scientist and Reader and Consultant in Intensive Care Medicine at King's College London. He said: "PIMS-TS is a new syndrome. Our research has allowed us to provide the first description of the profound immune system changes in severely ill children with this new illness.

"These immune changes are complex. The innate, otherwise known as the rapidly responding, immune cells are activated. The lymphocytes, a particular type of white cell involved in specific protective immunity, are depleted, but appear to be actively fighting infection.

"Clinically, these children respond to treatments that calm the immune system such as corticosteroid and immunoglobulins. Although there are similarities to existing conditions such as Kawasaki Disease, these clinical and immunological changes that we observe imply that PIMS-TS is a distinct illness associated with SARS-Co-V-2 infections."

Dr Shane Tibby, paediatric ICU consultant at Evelina London said: "When we first saw the immunophenotyping results in this paper, it confirmed our clinical impression: that this was neither Toxic Shock nor Kawasaki Disease, but rather a new entity that likely requires both organ support and careful, targeted immunotherapy."

Dr Michael Carter is a Paediatric NIHR Academic Clinical Lecturer and sub-speciality registrar in paediatric intensive care at Evelina London. He said: "The support of children and young people with PIMS-TS was crucial in this study. Their help enabled us to monitor changes in the immune system during their illness and recovery and may contribute towards developing targeted immune therapy for children with PIMS-TS in the future."