COVID-19, the source of the current pandemic, may be caused by a single virus, but it has a variety of presentations that make treatment difficult. Children, for example, almost exclusively experience mild or asymptomatic COVID-19, while adults can develop severe or even fatal COVID-19.
But children who contract COVID-19 are at risk for a rare but serious syndrome called multisystem inflammatory syndrome in children (MIS-C). Severe cases of MIS-C can lead to cardiac disease and ventricular failure, and require hospitalization and intense medical support.
Researchers Galit Alter, Ph.D., core member of the Ragon Institute of MGH, MIT and Harvard, and Lael Yonker, MD, director of the Massachusetts General Hospital Cystic Fibrosis Center, are working to understand why COVID-19 can lead to such distinctly different outcomes in different populations.
In a study recently published in Nature Medicine, they and their team identified specific types of antibodies that may be driving these different responses, including one specific to severe disease in adults and another specific to MIS-C in children.
“We noticed children who developed MIS-C after COVID disease or exposure had high levels of a specific type of antibody called IgG,” says Yonker. “
Normally, IgG acts to control an infection, but with MIS-C, the IgG is triggering activation of immune cells, which may be driving the severe illness seen in MIS-C.”
Specifically, explains Yonker, IgG antibodies interact with cells called macrophages, which live throughout the body’s tissues. If there are too many IgG bodies activating these macrophages, this could cause inflammation in many different organs and systems, which is seen in MIS-C. These high levels of IgG antibodies were only found in children who developed MIS-C after contracting or being exposed to COVID-19.
Yonker, a pediatric pulmonologist at MGH and assistant professor at Harvard Medical School (HMS), runs a biorepository that collects samples from pediatric cystic fibrosis patients. When the pandemic hit, she began to collect samples from children with mild cases of COVID-19.
When Yonker and other pediatricians began seeing children hospitalized with what is now called MIS-C, which typically onsets three to six weeks after developing COVID-19, she quickly began collecting those samples too. She wanted to understand how a mild case of COVID-19 could lead to severe MIS-C weeks after recovery.
Seeking a detailed understanding of the immune response, Yonker teamed up with Alter, who is also a professor at HMS and an immunologist in the Department of Infectious Diseases at MGH.
Alter’s team used her unique “systems serology” technology to carefully perform a detailed comparison of the immune responses in children – 17 with MIS-C and 25 with mild COVID-19 – to the responses of 26 adults with severe disease and 34 adults with mild disease.
“We were expecting the children’s immune responses to look drastically different from the adults’, regardless of the severity of disease,” says Alter.
“But instead, we found that adults with mild COVID-19 and children with COVID-19 had remarkably similar immune responses. It was only the adults with severe COVID-19 whose immune responses looked different.”
For adults with severe COVID-19, Alter explains, they saw increased levels of IgA antibodies, which interact with a type of immune cells called neutrophils and cause the neutrophils to release cytokines. If there are too many IgA antibodies, the neutrophils may be pushed to release too many cytokines, which could contribute to a cytokine storm, one of the symptoms of severe COVID-19.
In both cases, the study shows, it may be a high level of a specific type of antibody causing the disease severity. “In MIS-C, high levels of IgG antibodies may be activating macrophages, which can drive inflammation in organs throughout the body,” says Yannic Bartsch, Ph.D., the study’s first author and a research fellow at the Ragon Institute.
“In adults with severe COVID-19, high levels of IgA antibodies could be driving neutrophils to release too many cytokines, with the potential of causing a cytokine storm.”
Identifying the immune mechanisms of multiple, distinct responses to the same virus is the first step to understanding why it mounts different responses in divergent populations. Discovering how the immune system’s response shapes the disease and its outcome in both children and adults can help researchers develop treatments that can prevent or modulate the immune response, keeping its protective functions but lessening the unintentional, yet harmful, ones.
In the early stages of the COVID-19 pandemic, healthy children were thought to have mild SARS-CoV-2 infections with favourable outcomes. In April 2020, reports began to emerge from COVID-19 epicenters describing clusters of children with features of Kawasaki disease and toxic shock syndrome1,2.
This newly identified entity has many names and ultimately became known as multisystem inflammatory syndrome in children (MIS-C), as used by the WHO and CDC. As additional reports of MIS-C have surfaced, the clinical spectrum of this syndrome has broadened3–5, and studies have begun to unveil its immune landscape, which could help in our understanding of this condition6–10.
Emerging data show that MIS-C is characterized by the classic findings of inflammation, with fever as the cardinal feature, and multi-organ dysfunction that not only involves the skin, mucous membranes and heart but that also frequently affects the gastrointestinal, respiratory and neurologic systems (Fig. 1).
However, the full clinical continuum of MIS-C is still being defined, and validated diagnostic criteria do not yet exist. As a result, researchers have employed varying case definitions of MIS-C so that patient populations are not necessarily comparable across studies5. This selection bias is important to consider because it affects our understanding of MIS-C.
MIS-C is temporally linked to SARS-CoV-2, and occurs as a late manifestation of or response to the infection, with cases peaking 3–6 weeks after the highest rate of SARS-CoV-2 infection (as measured by PCR positivity) in a given location3,4. The majority of patients had neutralizing antibodies to SARS-CoV-2, with greater titres of IgG antibodies than IgM antibodies, further indicating a preceding SARS-CoV-2 infection2,3,6–10.
Building on these findings, Diorio et al.8 evaluated the clinical and laboratory features of children with SARS-CoV-2 infections to clarify the differences between the early infectious phase of COVID-19 (severe COVID-19) and MIS-C. Compared with severe COVID-19, the PCR cycle thresholds for SARS-CoV-2 were higher for MIS-C, indicating a reduced viral burden and supporting the concept that MIS-C is a post-infectious process.
Furthermore, this report identified demographics that differed between these two groups: patients with MIS-C were younger and less medically complex than patients with severe COVID-19. High levels of soluble C5b-9 (the membrane attack complex of the complement system) and evidence of microangiopathy on blood smears also suggested that endothelial dysfunction was central in the pathophysiology of both severe COVID-19 and MIS-C.
In a similar approach, Lee and colleagues evaluated the immunologic profile of MIS-C and identified the presence of T cell, B cell and natural killer cell cytopenias7. By comparing MIS-C to historic cohorts of Kawasaki disease (pre-pandemic Kawasaki disease), Lee et al. identified similarities and differences between these two childhood hyperinflammatory syndromes.
Many patients with MIS-C had features of Kawasaki disease. However, the patients with MIS-C presented over a broader age range, had a greater degree of myocardial dysfunction, had more profound lymphopenia and thrombocytopenia, and more often showed signs of coagulopathy than the patients with pre-pandemic Kawasaki disease2,7,10.
Whether MIS-C is distinct from Kawasaki disease or whether these two entities represent a continuum of the same clinical syndrome remains to be determined. Both reports by Diorio et al. and Lee et al. provide potentially useful diagnostic profiles of MIS-C; however, the results were derived from a small number of patients, and their generalizability awaits validation.
To gain further understanding of MIS-C, deeper immunophenotyping is required. Carter et al.6 undertook this approach by studying 25 patients with MIS-C from the acute phase of illness through to convalescence using high dimensional cytokine and flow cytometry panels.
At disease onset, treatment-naive patients with MIS-C had high serum levels of multiple cytokines, and the acute phase was associated with activated neutrophils and monocytes that expressed high levels of FcγRI. Circulating levels of CD4+, CD8+ and γδT cells were decreased early in the course of MIS-C compared with age-matched healthy individuals, with the exception of CD4+CCR7+ T cells.
Although patients with MIS-C are able to generate neutralizing antibodies to SARS-CoV-2, the patients had lower levels of total B cells, effector B cells and class switched memory B cells in the blood than healthy individuals. After resolution of MIS-C, these observed innate and adaptive immune system changes normalized, and the frequency of plasmablasts and regulatory T cells increased.
This work by Carter and colleagues identified a shifting immune landscape over the course of illness in MIS-C and highlighted several immune cell populations that might be important in either promoting disease or mediating recovery in MIS-C.
Multi-dimensional immune profiling was also employed in two other important publications from 2020 — Gruber et al.9, and Consiglio et al.10 — that evaluated immune responses in MIS-C compared with pre-pandemic Kawasaki disease and/or acute COVID-19.
In principal component analysis (PCA) of circulating immune proteins, patients with MIS-C clustered separately from adults and children with acute COVID-19 (refs9,10). Mass cytometry data from Gruber et al. showed a trend towards increased frequencies of circulating memory T cells in patients with acute COVID-19 compared with in patients with MIS-C, although most patients with MIS-C in this study were already being treated with immunomodulatory medications9.
Comparisons of MIS-C with Kawasaki disease by Consiglio and colleagues yielded less conclusive findings. Patients with Kawasaki disease and patients with MIS-C clustered together in a PCA analysis of plasma proteins10. However, evaluation of immune cells by flow cytometry in MIS-C versus Kawasaki disease was limited owing to the small numbers of patients in the MIS-C group (n = 3).
Importantly, the work by Gruber et al.9 and Consiglio et al.10 has furthered our understanding of the humoral response in MIS-C. Both studies confirmed that patients with MIS-C generate appropriate antibody responses to SARS-CoV-2, as well as to other viruses.
Compared with healthy individuals, patients with MIS-C had enrichment of both IgG and IgA autoantibodies directed towards peptides expressed in the endothelial, cardiac and gastrointestinal tissue as well as autoantibodies directed toward immune mediators9.
Autoantibodies from both patients with Kawasaki disease and patients with MIS-C shared some targets, including proteins expressed by endothelial cells, whereas some autoantibodies were upregulated only in MIS-C or Kawasaki disease. Although these results are intriguing, the sample sizes were small, and it remains to be determined if these autoantibodies are primary mediators of disease in MIS-C or are generated secondarily as a result of tissue damage in the setting of infection.
Since MIS-C materialized as a complication of SARS-CoV-2 infections in children in early 2020, great strides have been made in characterizing the clinical presentation and immunophenotype of this syndrome, pointing to both innate and adaptive immunity together with vascular inflammation and endothelial dysfunction as important contributors to pathobiology.
Yet, these studies represent only a beginning in our endeavour to understand MIS-C. To gain ground in this journey, future work will need to interrogate larger numbers of treatment-naive patients with MIS-C, along with appropriate febrile controls. To date, studies have focused on circulating immune perturbations; however, some cell populations of interest might have extravasated into affected tissues.
Furthermore, the genetic susceptibilities that predispose patients to MIS-C are unknown, and the relationship between Kawasaki disease and MIS-C remains unresolved. The preliminary data generated by these translational research studies highlight the need for data sharing and cross-validation to bring disease understanding to a new level. Harmonizing case definitions and international collaborations will help accelerate the pace of advancement in MIS-C and make real change possible in the care and outcomes of this emerging condition.
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More information: Yannic C. Bartsch et al, Humoral signatures of protective and pathological SARS-CoV-2 infection in children, Nature Medicine (2021). DOI: 10.1038/s41591-021-01263-3
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