SARS-CoV-2 triggers similar inflammatory syndromes in children and adults
Last April, clinicians in London reported a cluster of eight children in 10 days who developed hyperinflammatory shock with multiorgan involvement, which they described in The Lancet as being similar to Kawasaki disease shock syndrome.
All eight patients were severely ill, presenting with high fever, rash, conjunctivitis, peripheral edema, generalized extremity pain and gastrointestinal symptoms, the authors of the report explained. Several of the children later tested positive for SARS-CoV-2, and the authors suggested that the illness represented “a new phenomenon affecting previously asymptomatic children with SARS-CoV-2 infection.” The cluster of cases triggered national health alerts in England.
Within a month, New York announced that it was investigating dozens of similar cases, including three deaths, and that all of the children had either tested positive for SARS-CoV-2 or had evidence of a past infection.
This was a new illness, experts said. The CDC gave it a name: multisystem inflammatory syndrome in children, or MIS-C.
“We first detected cases after the start of the COVID-19 pandemic, and almost all patients have evidence of SARS-CoV-2 infection,” Ermias Belay, MD, one of the MIS unit leads for the CDC’s COVID-19 response team, told Infectious Disease News.
Infectious Disease News spoke with Belay and other experts about the known and unknown clinical aspects of MIS-C and a similar illness in adults called MIS-A.
What is MIS-C?
As of Feb. 8, 2,060 cases of MIS-C had been reported in the United States, mostly among children and adolescents aged between 1 and 14 years, with a median age of 9 years, according to the CDC.
The CDC case definition for MIS-C is any patient aged younger than 21 years presenting with fever, laboratory evidence of inflammation, evidence of clinically severe illness requiring hospitalization, with two or more organs involved, who has no alternative plausible diagnosis and has tested positive for current or recent SARS-CoV-2 infection, or reports exposure to a suspected or confirmed case of COVID-19.
A study involving more than 1,100 patients aged younger than 21 years identified cardiac involvement, age and race as attributes that could differentiate MIS-C from severe COVID-19, according to results reported in JAMA.
The patients were hospitalized in 31 states from March 15 through Oct. 31 — 48% with MIS-C and 52% with acute COVID-19. Among presenting symptoms and signs, researchers found that only mucocutaneous findings differed in prevalence, appearing in 66.8% of patients with MIS-C vs. 10.2% of patients with COVID-19.
Cardiac involvement was more common among participants with MIS-C than COVID-19, 66.7% vs. 11.8%. In both cohorts, 80% of patients had severe respiratory involvement. Additionally, patients diagnosed with MIS-C were more likely to be aged 6 to 12 years, be Black and have no underlying conditions. They were more likely to have cardiorespiratory involvement, cardiovascular without respiratory involvement and mucocutaneous without cardiorespiratory involvement.
Ten patients with MIS-C (1.9%) and eight with COVID-19 (1.4%) died during hospitalization.
David Cennimo, MD, a clinician and assistant professor of adult infectious disease at Rutgers New Jersey Medical School, said the study “helps delineate the clinical pattern distinguishing severe COVID-19 from MIS-C and gives us some comfort that most patients suffering from MIS-C do well in the long run.”
“This fits with many of our real-world experiences of seeing both manifestations of the infection,” he told Infectious Disease News. “The presenting signs and symptoms were similar, with the exception of significantly more mucocutaneous findings in MIS-C. This is unsurprising because MIS-C was initially felt to strongly resemble Kawasaki disease for the same reasons. Both groups had significant respiratory involvement, but cardiac involvement was much more common in patients with MIS-C.”
In a presentation at last fall’s American Academy of Pediatrics annual meeting, Sandy Hong MD, FAAP, co-author of the AAP’s MIS-C guidelines, said it remains unclear how SARS-CoV-2 causes MIS-C and what parts of the immune system trigger the abnormal response.
“We don’t know why this happens,” Hong said. “We think it is due to an abnormal and intense immune response.”
“I think it’s an overexuberant immune reaction that’s being kicked off by the recent SARS-CoV-2 infection,” he said in an interview. “So, it’s not so much that the virus is attacking in the moment — that’s why we’re seeing that the virus is often gone, you can’t find it — but it sets the stage for your body to really overreact.”
Symptoms generally present 2 to 4 weeks after infection or reported contact with someone who has COVID-19, evidence that a delayed response is likely the cause.
“If you look at the timeline of how the pandemic spread across the country, across Europe, and how it was followed by these reports a few weeks later, the activity of MIS-C really mirrors the activity of COVID-19,” Cennimo said. “All of that together makes it highly suggestive that it is the triggering infection.”
According to the CDC, there have not been any studies comparing treatments for MIS-C, which “have consisted primarily of supportive care and directed care against the underlying inflammatory process,” including fluid resuscitation, inotropic support, respiratory support and, rarely, extracorporeal membrane oxygenation.
“Anti-inflammatory measures have included the frequent use of IVIg and steroids,” the CDC notes. “The use of other anti-inflammatory medications and the use of anticoagulation treatments have been variable. Aspirin has commonly been used due to concerns for coronary artery involvement, and antibiotics are routinely used to treat potential sepsis while awaiting bacterial cultures. Thrombotic prophylaxis is often used given the hypercoagulable state typically associated with MIS-C.”
Stanford T. Shulman, MD, a physician specializing in Kawasaki disease at Lurie Children’s Hospital of Chicago, said he is personally aware of cases in patients up to the age of 19 years. Among more than 50 cases of MIS-C at his hospital, he said every patient has done well following treatment.
“You can’t say the same thing about adults with COVID-19, where there’s a subpopulation that gets extremely ill despite therapies and just don’t do well at all,” he said.
Disparities in prevalence of MIS-C
Last summer, the CDC reported that MIS-C was predominantly occurring in non-Hispanic Black, Hispanic or Latino children. As of Feb. 8, those groups experienced 69% of MIS-C cases in the U.S.
“The most likely reason is systemic racism and its impact on who is most likely to be infected with SARS-CoV-2,” Audrey Odom John, MD, PhD, chief of the division of pediatric infectious diseases at The Children’s Hospital of Philadelphia, told Infectious Disease News. “The proportion of children with MIS-C parallels the proportion of individuals in those communities who get coronavirus infection in the first place.”
According to Shulman, multigenerational housing and genetics also may account for the disproportionate number of cases of MIS-C among Black, Hispanic or Latino children. Shulman noted that Kawasaki disease is most common in Asians, but “then you flip it over, and MIS-C is not occurring in Asians at all, but overrepresented in the Black and Hispanic populations.”
“From the very first report of MIS-C in London, the original patients were predominantly categorized as Afro-Caribbean. That would shine the spotlight on patients with Black ethnicity in many different countries as having increased risk,” Shulman said.
“But we have to be careful,” he said. “In Kawasaki, it’s proven that there’s a genetic basis. In MIS-C, it’s an observation that people of Black and Hispanic populations are more commonly affected. If we get into the health disparity issue, that makes it much more complicated. I’d be surprised if there’s not some genetic factors contributing to the MIS-C racial breakdown.”
MIS-C also has disproportionately affected different age groups, with 84% of cases occurring among children aged between 0 and 14 years, according to early data from the CDC. Experts said it was unclear why. Odom John believes the age difference will be key to understanding the pathophysiology of MIS-C. She hopes the lessons learned from studying MIS-C can be applied to understanding other postinfectious conditions, like Kawasaki disease.
In October, researchers reported in MMWR that SARS-CoV-2 could also cause a multisystem inflammatory syndrome in adults that resembles MIS-C. The report included 27 cases of MIS-A with patients ranging in age from 21 to 50 years.
Like MIS-C, most of the patients presented with fever and gastrointestinal symptoms, and all patients had elevated laboratory markers of inflammation.
“I remain surprised at how uncommon MIS-A is,” Odom John said. “We see MIS-C in older teens who are frankly not that immunologically different [from] young adults. However, the CDC case series of MIS-A from across the U.S. only reported a total of 27 cases. Teasing out that difference in susceptibility to MIS disease between teens and young adults may be key to understanding the underlying pathophysiology.”
Shulman noted that, just like MIS-C, symptoms of MIS-A seem to develop after some time.
“There’s a large number of patients who are sick with COVID-19, and then somewhere in that 10- to-14-day period, when they’ve been improving, all of a sudden many of these patients take a turn for the worse and get much sicker, and that seems to be an immune-mediated second phase of COVID-19 infection,” Shulman said.
According to the CDC, the way MIS-A appears in patients may be more complicated than MIS-C. Like MIS-C, it is unclear why it happens to some patients and not others, the agency said.
The CDC has a team dedicated to investigating both MIS-C and MIS-A so it can communicate information quickly to health departments, health care providers, parents and caregivers, said Angela Campbell, MD, MPH, FPIDS, FIDSA, also an MIS unit lead for the CDC’s COVID-19 response team.
“The CDC has created a system to track cases in children and has studies in place to identify and evaluate risk factors and social determinants for developing MIS-C associated with COVID-19, such as race/ethnicity, age, sex, and medical history,” Campbell told Infectious Disease News.
Additionally, the CDC is collaborating with selected U.S. jurisdictions “to learn more about MIS-A, better define its clinical manifestation, and describe its distinguishing characteristics from severe acute COVID-19,” Belay said.
Of the three COVID-19 vaccines authorized for use in the U.S., only the shot from Pfizer-BioNTech is available for any pediatric group — children aged 16 years or older.
“Vaccination is important to prevent severe complications of COVID-19 in children,” Campbell said. “Since MIS-C is a complication of COVID-19, vaccinations may also help prevent MIS-C. However, data are still being gathered on whether COVID-19 vaccines prevent infection as well as disease. Since MIS-C can occur among children who have had asymptomatic infection, we don’t yet know with certainty whether vaccination will prevent MIS-C.”
Even though it remains uncertain how SARS-CoV-2 is triggering the syndrome, Odom John said there is good reason to hope the vaccines will prevent MIS-C.
“Vaccination elicits a robust immune response to a single viral protein, the spike protein,” Odom John said. “Real infection elicits responses to all viral components. Because vaccination likely reduces the ability of virus to replicate, the immune system of vaccinated individuals will see less of all proteins of the virus that appear during natural infection, one or more of which are likely the problem.”
Belay said COVID-19 vaccines are expected to prevent MIS-A by preventing widespread transmission of SARS-CoV-2.
- CDC. Health department – Reported cases of multisystem inflammatory syndrome in children (MIS-C) in the United States. https://www.cdc.gov/mis-c/cases/index.html. Accessed February 15, 2021.
- CDC. Infographic: Early cases of MIS-C: Multisystem inflammatory syndrome in U.S. children. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/infographic-mis-c.html. Accessed February 15, 2021.
- CDC. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS-C). https://www.cdc.gov/mis-c/hcp/. Accessed February 15, 2021.
- Feldstein LR, et al. JAMA. 2021;doi:10.1001/jama.2021.2091.
- Morris SB, et al. MMWR Morb Mortal Wkly Rep. 2020;doi:10.14485.mmwr.mm6940e1.
- Riphagen S, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31094-1.
- For more information:
- Ermias Belay, MD, can be reached via email@example.com.
- Angela Campbell, MD, MPH, FPIDS, FIDSA, can be reached via firstname.lastname@example.org.
- David Cennimo, MD, can be reached at email@example.com.
- Audrey Odom John, MD, PhD, can be reached at firstname.lastname@example.org.
- Stanford T. Shulman, MD, can be reached at email@example.com.
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