Even Very Sick Kids Fare Well Despite Kawasaki-Like COVID-19 Symptoms

New research from France and Switzerland suggests that even children who have a severe case of the multiorgan inflammatory condition linked with COVID-19—including cardiogenic shock and acute LV dysfunction requiring intensive care—can do well when managed with treatments borrowed from the experience with Kawasaki disease.

That news comes on the heels of reports from around the globe of children developing symptoms similar to Kawasaki disease and toxic shock syndrome, leading to the new diagnostic term—multisystem inflammatory syndrome (MIS-C)—as well as a health alert by the US Centers for Disease Control and Prevention detailing its association with COVID-19.

Of 35 such patients admitted to pediatric ICUs over the course of about a month, all received IV immunoglobulin and about one-third received IV corticosteroids. LV function was restored in 71% of patients within a median of 2 days. There were no deaths.

Senior author Damien Bonnet, MD, PhD (Necker-Enfants Malades Hospital, Paris, France), stressed that MIS-C, particularly the severe form, is rare and is likely to remain so because there has not been an acceleration in the number of children presenting with the condition, at least in France. In that country, there are currently about 150 recorded cases of MIS-C.

That said, because cases can be severe it’s important for pediatricians and general practitioners to recognize the presenting symptoms so they can refer affected children appropriately and avoid delays in treatment, he told TCTMD. “The public should be reassured that it is very rare, and they also should be reassured that the treatment is efficient, at least from what we know today. But it’s important that the information circulates to [enable] early diagnosis.”

Kevin Friedman, MD (Boston Children’s Hospital, MA), a member of the American Heart Association’s Council on Lifelong Congenital Heart Disease and Heart Health in the Young (Young Hearts), echoed those sentiments. “Kids are largely spared but not entirely, as this study shows, and even for the kids who are getting the most sick, which is what this study focused on, we do have treatments that seem to be working,” he said.

“We just need to learn more about why it’s happening so it sheds light on both [Kawasaki disease] and this new disease and what the best treatments are,” he continued. “Most kids are getting better, although some can get very sick, so if parents are seeing high fevers and real lethargy and other concerning symptoms it does need to be checked out.”

A New Inflammatory Syndrome in Children

Though initial studies of COVID-19 have indicated that SARS-CoV-2 infection is usually associated with minimal symptoms in children, the recent reports of a new inflammatory syndrome associated with the outbreak, with some features shared with toxic shock syndrome and atypical Kawasaki disease, show that children are feeling at least some of the health impact of the pandemic.

As the outbreak progressed, Belhadjer, Bonnet, and colleagues noticed a spike in the number of children hospitalized in ICUs for cardiogenic shock or acute LV dysfunction on the background of a multisystem inflammatory state, most of whom were positive for SARS-CoV-2. The investigators decided to explore the phenomenon further.

For the current study, published online May 17, 2020, ahead of print in Circulation with lead author Zahra Belhadjer, MD (Necker-Enfants Malades Hospital), they retrospectively collected information on 35 patients (median age 10) admitted to pediatric ICUs at 12 centers in France and one in Switzerland with fever (> 38°C) and either cardiogenic shock or acute LV dysfunction (LVEF < 50%) in the setting of increased inflammation (C-reactive protein > 100 mg/mL); 88% had a positive SARS-CoV-2 test.

All patients presented with severe inflammation, indicated by elevated levels of C-reactive protein, D-dimer, and interleukin-6.

None of the children had underlying cardiac disease or RV dysfunction. Dilatation of the coronary arteries was seen in six patients (17%), but there were no coronary aneurysms. Troponin I elevations were mild to moderate, the researchers report.

Consistent with previous reports, some of the features of MIS-C in this cohort overlapped with those of Kawasaki disease, although none of the patients met criteria for the classical form of the latter condition. For instance, in the current study, fever and asthenia were present in all patients and other classical signs of Kawasaki disease—like adenopathy, skin rash, inflammation of the lips, and meningism—were commonly observed. In contrast, 83% of patients in this MIS-C cohort presented with GI symptoms that included pain, vomiting, and diarrhea, which are not typically associated with Kawasaki disease.

Moreover, patients with MIS-C tended to be older and required more cardiac support than is usual in a Kawasaki disease cohort. In fact, 80% of the patients in the current study were in cardiogenic shock that required IV inotropes on admission to the ICU. Ten patients (28%) were treated with—and eventually weaned off of—extracorporeal membrane oxygenation.

LV function was restored rapidly in most patients in response to treatment primarily with IV immunoglobulin and corticosteroids, and that, “together with mild-to-moderate troponin elevation, suggests that the mechanism of heart failure is not consistent with myocardial damage as seen in adults associated with acute infection with SARS-CoV-2,” the investigators note in their paper. Instead, they write, “myocardial involvement with acute heart failure is likely due to myocardial stunning or edema rather than to inflammatory myocardial damage.”

Long-term Consequences?

When asked about the potential for lingering effects of MIS-C among recovered children, Bonnet noted that a major complication of Kawasaki disease is coronary aneurysm. No aneurysms have yet been seen in the cohort of patients studied here, but follow-up is necessary. “We are confident for those that we have diagnosed within the past 2 months that their ventricular function is recovering well and completely, but we have to check the coronary arteries,” he said, noting that CT or MRI scans are planned.

Friedman said it’s good news that most affected children, even those with the worst cases, are getting better with current therapies. “Even though there’s no trial to show what the optimal therapy is, the current therapies that we’re giving, which are largely derived from other inflammatory diseases like Kawasaki disease, are fairly effective.”

But there remain questions about what else might be needed to manage MIS-C, because of the key ways in which it differs from Kawasaki disease. Initial reports show that patients with MIS-C tend to be older and come from different racial/ethnic groups and are more likely to have cardiac involvement, Friedman said.

IV immunoglobulin is being used widely for MIS-C now, and most patients are getting better, but researchers are currently seeking funding for studies of adjunctive therapies that might be needed for the sicker patients, he said.

Another active area of research, Friedman said, will be the potential downstream effects after recovery from MIS-C. Children with small aneurysms of the coronary arteries are not a huge concern over the long term, “but there is a subset of kids, a very small number, . . . who are getting very large aneurysms and those will be a lifelong problem and put those kids at risk for early myocardial infarction from coronary stenosis or thrombosis.”

There is also interest in studying the potential for lingering myocardial effects associated with acute LV dysfunction, even if function recovers in the short term, he added.