Two US research reports on multi-system inflammation syndrome in children

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Two US research groups have reported finding nearly 300 cases of an alarming apparent side effect of COVID-19 in children, a condition called multisystem inflammation syndrome (MIS-C). While researchers have previously reported on the condition, the papers mark the first attempt to measure how frequently the side effect occurs and how it affects children who develop it.

The studies describe children who develop severe inflammation affecting multiple organ systems after having had COVID-19, sometimes between two and four weeks after the infection. The majority of the children were previously healthy.

In one of the studies, led by researchers at Boston Children’s Hospital, 80% of the children who developed the condition required intensive care, 20% required mechanical ventilation, and four children, or 2%, died. In the second study, from researchers from New York state, a similar percentage of 99 children who developed the syndrome required ICU care and two children died. In both studies, many of the children developed cardiovascular and clotting problems and many had gastrointestinal symptoms. A high proportion also had skin rashes.

“Ours were really sick kids,” said Adrienne Randolph, an ICU physician at Boston Children’s Hospital and senior author on one of the papers, which was based on reports from 26 states.

Manish Patel, from the US Centres for Disease Control and Prevention’s COVID-19 response team, said the message to parents is they should be on the lookout for fever and rash in children who have recently had COVID-19.

“I think being a little vigilant is important,” said Patel, who is an author on Randolph’s paper. “Fever, rash and I think especially in the setting of areas where you have a lot of coronavirus infections, SARS-CoV-2 infections – have a lower threshold for seeking care, I would say.”

On the whole, children appear to contract SARS-CoV-2 less often than adults and have a milder course of disease when they do.

But in late April, doctors in London alerted the world to the possibility that some children who had COVID-19 appeared to go on to develop something that looked like Kawasaki’s disease, an inflammatory condition that can attack the heart. KD, as it is called, is generally seen in children under the age of 5. Shortly thereafter, doctors in New York began to report cases as well.

In mid-May, the CDC asked doctors across the country to be on the lookout for cases of multisystem inflammatory syndrome in children.

The nearly 300 cases identified in these two studies share some similarities with KD, but there are also differences. Few of the children are under the age of 5. The average age of children in the larger study was 8; 42% of the children in the New York cohort were aged 6 to 12.

Another difference: While KD disproportionately affects children of Asian descent, MIS-C cases in the New York cohort were of all racial and ethnic backgrounds, the researchers reported.

“Among our patients, predominantly from the New York metropolitan region, 40% were Black and 36% were Hispanic. This may be a reflection of the well-documented elevated incidence of SARS CoV-2 infection among black and Hispanic communities,” they wrote.

The New York group estimated that the majority of MIS-C cases occurred about one month after the peak of Covid-19 cases in the state. They estimated that between 1 March and 10 May, two of every 100,000 people under the 21 years of age who had laboratory-confirmed SARS-CoV-2 virus developed MIS-C in the state. The infection rate in people under the age of 21 years was 322 in 100,000 over that period.

An editorial written by Michael Levin, from the department of infectious diseases at Imperial College London, said there have been roughly 1,000 paediatric cases of the condition reported worldwide to date. He suggested more are likely going unrecorded, because case definitions require evidence of prior COVID-19 infection.

“There is concern that children meeting current diagnostic criteria for MIS-C are the ‘tip of the iceberg,’ and a bigger problem may be lurking below the waterline,” Levin wrote.

Abstract 1
Background: Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome.
Methods: We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms.
Results: We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%).
Conclusions: Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

Authors
Leora R Feldstein, Erica B Rose, Steven M Horwitz, Jennifer P Collins, Margaret M Newhams, Mary Beth F Son, Jane W Newburger, Lawrence C Kleinman, Sabrina M Heidemann, Amarilis A Martin, Aalok R Singh, Simon Li

Abstract 2
Background: A multisystem inflammatory syndrome in children (MIS-C) is associated with coronavirus disease 2019. The New York State Department of Health (NYSDOH) established active, statewide surveillance to describe hospitalized patients with the syndrome.
Methods: Hospitals in New York State reported cases of Kawasaki’s disease, toxic shock syndrome, myocarditis, and potential MIS-C in hospitalized patients younger than 21 years of age and sent medical records to the NYSDOH. We carried out descriptive analyses that summarized the clinical presentation, complications, and outcomes of patients who met the NYSDOH case definition for MIS-C between March 1 and May 10, 2020.
Results: As of May 10, 2020, a total of 191 potential cases were reported to the NYSDOH. Of 95 patients with confirmed MIS-C (laboratory-confirmed acute or recent severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection) and 4 with suspected MIS-C (met clinical and epidemiologic criteria), 53 (54%) were male; 31 of 78 (40%) were black, and 31 of 85 (36%) were Hispanic. A total of 31 patients (31%) were 0 to 5 years of age, 42 (42%) were 6 to 12 years of age, and 26 (26%) were 13 to 20 years of age. All presented with subjective fever or chills; 97% had tachycardia, 80% had gastrointestinal symptoms, 60% had rash, 56% had conjunctival injection, and 27% had mucosal changes. Elevated levels of C-reactive protein, D-dimer, and troponin were found in 100%, 91%, and 71% of the patients, respectively; 62% received vasopressor support, 53% had evidence of myocarditis, 80% were admitted to an intensive care unit, and 2 died. The median length of hospital stay was 6 days.
Conclusions: The emergence of multisystem inflammatory syndrome in children in New York State coincided with widespread SARS-CoV-2 transmission; this hyperinflammatory syndrome with dermatologic, mucocutaneous, and gastrointestinal manifestations was associated with cardiac dysfunction.

Authors
Elizabeth M Dufort, Emilia H Koumans, Eric J Chow, Elizabeth M Rosenthal, Alison Muse, Jemma Rowlands, Meredith A Barranco, Angela M Maxted, Eli S Rosenberg, Delia Easton, Tomoko Udo, Jessica Kumar

 

Stat News report

 

NEJM abstract 1

 

NEJM abstract 2

 

NEJM editorial

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