COVID-19-Related Inflammatory Syndrome in Kids Needs Cardiac Follow-up

Children who develop the rare multisystem inflammatory syndrome linked with COVID-19 need to be followed for the development of cardiac abnormalities, two new patient series suggest—one from England and the other from New York City. Complicating matters, the proportion of young people actually hospitalized with the most severe form of this illness likely represent “just the tip of the iceberg,” a researcher says, stressing that the arterial abnormalities can occur even in children who recover quickly from a mild course of the disease.

This emerging constellation of symptoms is being called both multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). It came on the radar of cardiologists because many of the telltale features overlapped with severe Kawasaki disease and its associated shock syndrome.

As previously reported by TCTMD, a growing number of papers have documented the unique aspects of this “Kawasaki-like” illness and demonstrated—albeit in small numbers—that children treated with the same therapies used for Kawasaki disease tend to recover and do well. But the scope of the syndrome, who is vulnerable, and what the lasting impact may be remains unclear.

“It's such a new illness that we now need to do the research,” Michael Levin, MD (Imperial College London), senior author on the English series, stressed to TCTMD. “That involves patients being enrolled into research studies so that we have samples to do the work on, and obviously clinicians need to be taught to recognize it when they see it.”

Disease Characteristics

In one of two new papers published in JAMA this week, Levin, lead author Elizabeth Whittaker, MD (Imperial College London), and colleagues describe the symptoms and clinical course of 58 children hospitalized with PIMS-TS during the COVID-19 pandemic at eight English hospitals. Median age was 9 years, older than the typical Kawasaki disease patient; 49% were of black or Asian race. Most tested positive for current or prior SARS-CoV-2 infection, all had fever lasting anywhere from 3 to 19 days and different combinations of sore throat, headache, abdominal pain, rash, and additional symptoms similar to Kawasaki disease or toxic shock. Half of the patients had to be admitted to pediatric critical care units and 25 needed mechanical ventilation; 22% developed acute kidney injury and half developed shock, with most cases requiring inotropes.

Of the children who developed shock, 18 had associated left ventricular dysfunction, 19 had elevated troponin, and all 11 patients tested for NT-proBNP had elevated levels. Four patients in the entire cohort developed arrhythmias. Of the 55 children who underwent echocardiography, eight had abnormally dilated coronary arteries and two had giant (z score > 10) coronary artery aneurysms.

What the cardiology community needs to do is accept that echocardiograms will need to be done on quite a big number of patients who've had this illness across the spectrum of severity. Michael Levin

To TCTMD, Levin stressed that there is a spectrum of illness with this particular syndrome: ranging from the children who only develop fever and systemic inflammation to those who meet the criteria for Kawasaki disease and those who progress to shock and organ failure requiring intensive care. What’s critical to realize, he said, is that children across this range appear to develop coronary artery changes seen on echocardiogram, including aneurysms.

“This raises a very worrying research question because the number of children in the community that have persistent fever and inflammation is probably quite large, the number who then get hospitalized with Kawasaki features is much smaller, and the number that end up on intensive care critically ill are, in a way, the tip of the iceberg,” he explained. “But since there is a risk of coronary aneurysms in all three groups, we probably need to be following up and doing echocardiograms to establish the frequency of coronary artery aneurysms in the milder patients as well as the more severe.

“The research question for which we don’t know the answer is :what is the extent of coronary artery injury that patients are left with? And until the studies have been done, I don't think we'll know the answer,” Levin continued. “What the cardiology community needs to do is accept that echocardiograms will need to be done on quite a big number of patients who've had this illness across the spectrum of severity before we can answer that question with certainty.”

Of note, the second series of 17 pediatric patients from two New York hospitals, published in JAMA as a research letter with lead authors Eva W. Cheung, MD, and Philip Zachariah, MD (both Columbia University Irving Medical Center, New York, NY), also highlighted cardiac involvement. In all, 16 out of 17 patients had nonspecific ST/T-wave abnormalities on ECG, three patients had dysrhythmias, and seven had “prominent or echogenic” coronary arteries on echo performed at hospital admission, although all coronary artery measurements were normal. In Kawasaki disease, however, coronary artery involvement typically occurs weeks after the original diagnosis. As such, the authors conclude, “the occurrence of abnormal cardiac findings suggests the need for long-term surveillance.”

Triggers and Treatments

An editorial accompanying both papers, by Brian McCrindle, MD (Hospital for Sick Children, Toronto, Canada), and Cedric Manlhiot, PhD (Johns Hopkins University, Baltimore, MD), attempts to summarize the knowns and unknowns about PIMS-TS, and elaborating in particular on the ways in which its etiology and pathophysiology overlaps with or differs from Kawasaki disease, whose etiology also remains unknown. The three tenets accepted to date for Kawasaki, they write, is that it includes a genetic component, immunomodulation related to both habitual exposures and the environment, and some kind of triggering exposure. From this vantage point, they argue, SARS-COV-2 could be a direct trigger for this pediatric inflammatory syndrome, an intermediate player or co-stimulus, or even a portal of entry for the actual trigger.

“There has never been a global outbreak of Kawasaki disease where it might be traced to a specific trigger, but this may now be the case,” they write. “It might be that this is what a specific, unique, and ubiquitous form of Kawasaki disease looks like, providing an important opportunity for investigations to determine factors associated with variations. . . . Careful determination of the unique features of SARS-CoV-2 and the epidemiology, clinical features, genetic and immunologic susceptibility, and pathophysiologic pathways of both PIMS-TS and Kawasaki disease may help to inform the etiologic and pathophysiologic framework for both conditions.”

Speaking with TCTMD, Levin said that in his opinion, PIMS-TS is a syndrome that “has features in common with Kawasaki, in terms of causing rash, conjunctival injection and mucosal involvement. But it is not the same disease as Kawasaki disease.”

That has important implications for research and care, he continued. “We know what drugs work for Kawasaki disease and they are the drugs that have been used to treat patients with the new syndrome, but we don’t know that they work in the same way or have the same effects. Our interpretation of the data so far is that while clinicians all over the developed world have treated patients with the new syndrome with immunoglobulin, which works in Kawasaki disease, or with steroids or immunomodulators, I don't think we know for certain that these drugs will lessen the coronary artery aneurysm risk.”

One promising insight from their series, Levin added, is that patients who develop shock and cardiac failure appeared to have laboratory features not seen in patients who don’t develop shock—specifically, numerically higher C-reactive protein and neutrophil counts, lower albumin levels and lymphocyte counts, and elevated troponin and NT-proBNP concentrations. “This is a potential advance in that if the blood test can pick up who is going to go on to have shock, they might get cardiac imaging at an early stage, and that could be very helpful in managing this disease,” he said.

Of note, however, lab results could not differentiate which children would go on to develop coronary artery dilatation and aneurysms.

Children and Adults

Like others who’ve spoke with TCTMD, Levin said he believes that this unusual and rare presentation in children mirrors what happens in adults, but whereas the hyperinflammatory response in adults typically happens 7 days into the illness, in children it seems to take several weeks.

“That, to me, would raise the question of whether the adults are having a secondary immune response—they've been primed, maybe, by cross-reacting with coronary viruses that they've met before—whereas children are having a primary immune response which takes longer to develop. But this is a research question, and we really don't know the answer,” Levin said.

It would, however, have critical implications for vaccine development, particularly if the immune response is related to an individual’s underlying genetic risk, he noted. “We are quite worried that this new disease is an unusual acquired immune response to COVID and that really needs understanding, because it raises the possibility that a vaccine could also make some people sicker. And this is obviously an issue that's going to have to be looked at very carefully by the vaccine world, to be sure that vaccines protect rather than enhancing disease.”