‘Striking Similarities’ for COVID-19 Inflammatory Syndromes in Children, Adults

Reports of a Kawasaki-like disease in children following infection with SARS-CoV-2 eventually led to the development of an official diagnosis: multisystem inflammatory syndrome in children (MIS-C). But a similar myocarditis-like syndrome has also been seen in adults, leading some to question whether they’re two completely separate conditions or manifestations of the same process at different ages.

“These two syndromes are being reported as distinct entities, but they have several overlapping clinical features, which suggests that these conditions may be due to related pathophysiology in two different age groups,” lead author Zachary Most, MD (University of Texas Southwestern Medical Center, Dallas), and colleagues write in a commentary published online last week in Circulation. They dub the adult condition acute COVID-19 cardiovascular syndrome (ACovCS).

There are “striking similarities” between the pediatric and adult syndromes, which suggests “similar pathogenesis and a spectrum of illness from children to adults,” they say, pointing to a Venn diagram showing the overlap between Kawasaki disease, MIS-C, and ACovCS. “The more prominent mucocutaneous symptoms and lymphadenopathy in pediatric versus adult patients may reflect a poorly understood predilection for children to have such responses to viral syndromes,” Most et al write. “We advocate for considering the spectrum of COVID-19-associated cardiovascular complications as a continuum which includes both MIS-C and ACovCS.”

Pediatric, Adult Syndrome Overlap

MIS-C—also called pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) in the United Kingdom—is characterized by fever, abdominal pain, and mucocutaneous disease, including rash, conjunctivitis, and oral lesions, the authors explain. Many patients develop coronary dilation and inflammatory markers are elevated, as in Kawasaki disease. Key differences between MIS-C and Kawasaki disease, however, include a greater frequency of cardiac complications like troponin elevations, cardiogenic shock, and reduced biventricular function in MIS-C. Also, the average age of affected children is higher for MIS-C versus Kawasaki disease.

The timing of MIS-C development has “led to the hypothesis that MIS-C is due to a postinfectious inflammatory state that occurs several weeks after a primary infection with SARS-CoV-2,” the authors say.

Adults with COVID-19 also frequently present with cardiovascular complications, ranging from ACS to the myocarditis-like syndrome Most et al are calling ACovCS. Indeed, several case reports have been published raising the alarm that MIS-C also can occur in adults. “Patients often do not have a history of prior cardiac disease and can present with fever, elevated troponin, acute systolic biventricular heart failure, cardiogenic shock, and/or electrocardiograms with acute ST-segment changes,” they write. Inflammatory markers are elevated in these adults, much like what is seen with MIS-C.

“The higher prevalence of pneumonia, compared to cardiac complications, in adults may have led to less attention directed towards the latter (in contrast, the relative paucity of pneumonia in children may have resulted in widespread recognition of MIS-C),” they suggest.

The similarities between adult and pediatric patients with the inflammatory syndromes “raise the question of whether ACovCS, like MIS-C, is due to a postinfectious inflammatory response,” they write. They note, too, that even though by definition MIS-C occurs in patients younger than 21, “to our knowledge there has been no effort to explain why a firm dichotomous age threshold is appropriate.”

Arbitrary Age Cutoff

Commenting for TCTMD, Kevin Friedman, MD (Boston Children’s Hospital, MA), agreed that “there’s no real reason to think that at 21 or 18 or some specific age the response to COVID-19 changes. I think it’s a big spectrum and it kind of evolves over age. Certainly what we see in infants is different than in 60-year-olds, but there’s got to be overlap in the young adult to teenage range.” He said his group has diagnosed MIS-C in patients in their early 20s, noting: “We didn’t hesitate to diagnose them just because of the age. . . . I think in this case there might be an opportunity for [physicians treating adults] to realize what they’re seeing is actually a similar disease to what we’re seeing in children, especially in the young adults.”

Leslie Cooper Jr, MD (Mayo Clinic, Jacksonville, FL), echoed that idea. “At least from puberty, age 12 or 13, through young adulthood, say 30s to 40s, there is not a lot of hormonal difference,” he said, adding that the clinical picture is likely different in younger children. “If I were to draw a line, I’d say let’s draw it around age 12 or 13” instead of at age 21.

Still, despite the similarities described between patients with MIS-C and adults with the myocarditis-like syndrome, “I would be very cautious on saying they’re the same disease or even the same pathology until we know more,” said Friedman, who is vice chair of the American Heart Association’s Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. “We don’t know very much, honestly, about either yet.”

Two big differences between the pediatric and adult conditions are in timing and underlying comorbidities. MIS-C typically develops in previously healthy children an average of 4 weeks after they clear the viral infection, whereas the adult inflammatory condition often occurs closer to the time of the acute infection and in the sickest patients with the most comorbidities, Friedman said, adding that there remains a question about whether the same cause is responsible for the syndromes in the two age groups. “To call it on the same spectrum, it has to be the same cause,” he pointed out.

Speaking to what’s causing these syndromes, Cooper said the idea that there’s a post-inflammatory autoimmune reaction independent of the virus to blame is speculative both in the pediatric population and in adults. There is also the possibility that some of the problems can be traced to coinfection with other pathogens, an issue researchers are currently exploring.

Moving Forward

Most et al say there are clinical implications to considering MIS-C and ACovCS as conditions on the same disease spectrum. “First, for epidemiologic surveillance, the case definition of MIS-C would not need to include age,” they say. “Second, investigators should be aware that insights into the natural history of or therapeutics for one of these syndromes may also be applicable to the other.”

And finally, they write, “considering these two entities as occurring along the same continuum may facilitate identification of shared mechanisms by which SARS-CoV-2 causes severe cardiac disease in both children and adults, thereby advancing our understanding of the underlying pathophysiology of this complication.”

Cooper said there are two main areas that still need to be explored—why children with MIS-C get coronary artery aneurysms, a phenomenon not seen in adults, and what’s going on with arrhythmias in relation to these inflammatory syndromes in the different age groups.

For Friedman, the idea proposed by Most et al should be considered hypothesis-generating because so little is known about what’s causing the inflammatory syndromes in the pediatric and adult populations. In particular, “the adult picture is very clouded by all the different ways the heart can be involved,” Friedman said. It’s possible that there are subtypes of ACovCS and that there is one that is most similar to MIS-C, he continued. “We’re just at the beginning of learning about these diseases.”