In Adults, CV Pathology Dominates COVID-19 Multisystem Inflammatory Syndrome

Amid growing evidence that the rare multisystem inflammatory syndrome (MIS) stemming from COVID-19 can develop in adults, not just children, researchers from the US Centers for Disease Control and Prevention (CDC) are urging physicians to be aware of its clinical presentation and offer tips for appropriate management.

When MIS in children, dubbed MIS-C, was identified early on in the COVID-19 pandemic as a rare complication of SARS-CoV-2 infection, the constellation of symptoms was described as “Kawasaki-like,” with implications for coronary artery aneurysms or ectasia, ischemic heart disease, and sudden death. Over the ensuing months, reports of a similar syndrome in adults began cropping up, given the acronym MIS-A.

According Pragna Patel, MD, MPH (CDC, Atlanta, GA), lead author on the new review, cardiologists should be on the alert for MIS-A, even if the syndrome is even more rare in adults than in children.

“When we looked at the clinical phenomena, it really did seem like the cardiac pathology was most prominent,” Patel told TCTMD, “particularly things like myocarditis, which we see more commonly in adults compared to children. I do think that this is an important phenomenon for cardiologists to be aware of and stay abreast of, particularly because it's really hard to tease out MIS-A from severe COVID, which sometimes has a biphasic presentation.”

What’s more, she added, “people who experienced MIS-A may have some long-COVID symptoms related to the pathological findings during their MIS episode, particularly because we are seeing a lot of cardiac pathology among the adults. I do think even the follow-up may be important for the cardiology community.”

The review was published earlier this week in JAMA Network Open.

Clues from Kids

The review Patel et al combines data on 221 patients worldwide, drawn from the published medical literature as well as voluntary reports about adult cases made to the CDC’s surveillance system for MIS in children.

As Patel and colleagues summarize in their paper, the syndrome typically manifests 4 weeks or so after an acute COVID-19 infection. Although fewer than 70% of patients in the series reported a prior, symptomatic COVID-19-like illness, 98% had a positive test result on the basis of either an RT-PCR test or serology.

Median age in this series was 21 but ranged from 19 to 34 years, more than two-thirds of patients were men, 30% were Hispanic, and 36% were non-Hispanic Black. Most patients presented with fever (96%) but more than half had cardiac dysfunction (54%), shortness of breath (52%), hypotension (60%), and diarrhea (52%).

Crucially, the median number of organ systems involved was five, most commonly hematologic (92%), cardiovascular (87%), gastrointestinal tract (83%), and respiratory (74%). Myocarditis was reported in 30% of patients and pericardial effusion in 25%.

Blood tests showed that most patients had elevated markers of coagulopathy and/or inflammation, with elevated levels of interleukin-6 (98%), ferritin (91%), fibrinogen (91%), C-reactive protein (90%), BNP (74%) and, NT-proBNP (90%), among those for whom lab values were reported.

Comparing symptoms and outcomes in this MIS-A cohort with MIS-C patients, using 18 years as the cutoff, adult patients were more likely to present with myocarditis, cardiac dysfunction, arterial thrombosis, and pulmonary embolism and/or deep vein thrombosis. MIS-A patients also tended to have longer hospital stays and a greater need of ventilation, and to die of their condition (7% vs 1%).

The most common treatments in this series were intravenous immunoglobulin (IVIG) in 55% of patients, corticosteroids in 74%, and anticoagulation in 57%.

Consider the Diagnosis

MIS-A “may be difficult to discern from acute biphasic COVID-19 and postacute sequelae of SARS-CoV-2 infection,” Patel et al warn. “Clinicians should consider a diagnosis of MIS-A among persons with hyperinflammatory illness and severe extrapulmonary multiorgan dysfunction, particularly cardiovascular, occurring within 2 to 5 weeks of antecedent COVID-19 or exposure to a person with diagnosed COVID-19. Because data on known SARS-CoV-2 infection or exposure are not always available at the time of hospital admission, clinicians should maintain a high index of suspicion for MIS-A among patients in whom a history of illness is not known.”

To TCTMD, Patel noted that “further studies need to be done for us to look at biomarkers beyond the interleukins and TNF alpha, just to get a sense of whether there is a particular biomarker that may help us to diagnose this more definitively.”

Getting an accurate diagnosis is harder among adults than children, she added, because adults have more underlying chronic disease complicating the clinical picture.

Patel also pointed out that while MIS-A in adults is very rare, numbers will likely rise as clinicians become more aware of the phenomenon. Cases, she urged, should be reported to the CDC using the MIS-C case form on the CDC website, despite the fact that the form was initially intended for patients under the age of 21. They are still using these forms to collect data on older patients, Patel said: “We're just doing that ad hoc; we don't have a traditional surveillance system in place for it right now.”

Timing is Everything

Commenting on the paper for TCTMD, Kevin Friedman, MD (Boston Children’s Hospital, MA), vice chair of the American Heart Association’s Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, said the paper should help raise awareness of MIS-A. “I think it's important to have it out there that the phenomenon we see in kids is the same exact phenomenon happening in adults as well, but probably at a lower frequency. Everything, initially, was being blamed on acute COVID, especially in adults, and now having more clarity that this is a different disease pathology and pathophysiology and that it does happen in adults, too, is helpful.”

Since blood tests alone would not be useful in differentiating MIS-A from acute COVID and its multiorgan effects, Friedman stressed that symptom timing should be the tip-off.

“A lot of these adults had acute COVID symptoms, then about a month later get this,” he said. And, as is seen in kids, they may not test positive on PCR tests if the acute infection has cleared. “A recent history of COVID infection that got better and then recurred with different symptoms would be the key distinguisher, rather than labs,” he said.

And that differential diagnosis is critical, he stressed, because the treatment course is different. As Patel et al point out, interim treatment recommendations for MIS-C include corticosteroids, IVIG, and possibly other immunomodulators—all therapies that were also used successfully in many of these adult patients.

“Getting that data out there might help people realize, okay, this is one of the rare instances where we actually know more about this disease in children than in adults—it’s usually the other way around,” said Friedman. “And we know from our experience in kids that they get better with steroids and IVIG.”

For a viral illness in which so few experimental treatments have proved efficacious, having an inkling of how to help adult patients with MIS-A is a win, Patel agreed. “What we really wanted cardiologists and clinicians to take away from this is to get a better idea of what the clinical picture of MIS-A looks like so that they could diagnose and treat it as soon as possible. And it could be that the treatment is lifesaving.”

Both Patel and Friedman stressed that MIS-A is very rare, but Patel said she believes the publication of the paper is timely, given the surge of infections seen with the more-transmissible Delta variant, which may ultimately lead to more cases of MIS-A.