CDC releases report on COVID-19–associated multisystem inflammatory syndrome in children
Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe condition that has been reported approximately two to four weeks after the onset of COVID-19 in children and adolescents, states a Centers for Disease Control and Prevention (CDC) press release.
Most cases of MIS-C have features of shock, with cardiac involvement, gastrointestinal symptoms, and significantly elevated markers of inflammation, with positive laboratory test results for SARS-CoV-2. Of the 565 patients who underwent SARS-CoV-2 testing, all had a positive test result by RT-PCR or serology. Distinguishing MIS-C from other severe infectious or inflammatory conditions poses a challenge to clinicians caring for children and adolescents. As the COVID-19 pandemic continues to expand in many jurisdictions, health care provider awareness of MIS-C will facilitate early recognition, early diagnosis, and prompt treatment.
In April 2020, during the peak of the coronavirus disease 2019 (COVID-19) pandemic in Europe, a cluster of children with hyperinflammatory shock with features similar to Kawasaki disease and toxic shock syndrome was reported in England. The patients’ signs and symptoms were temporally associated with COVID-19 but presumed to have developed two to four weeks after acute COVID-19; all children had serologic evidence of infection with SARS-CoV-2, the virus that causes COVID-19.
The clinical signs and symptoms present in this first cluster included fever, rash, conjunctivitis, peripheral edema, gastrointestinal symptoms, shock, and elevated markers of inflammation and cardiac damage. On May 14, 2020, CDC published an online Health Advisory that summarized the manifestations of reported multisystem inflammatory syndrome in children (MIS-C), outlined a case definition, and asked clinicians to report suspected U.S. cases to local and state health departments. As of July 29, a total of 570 U.S. MIS-C patients who met the case definition had been reported to CDC. A total of 203 (35.6%) of the patients had a clinical course consistent with previously published MIS-C reports, characterized predominantly by shock, cardiac dysfunction, abdominal pain, and markedly elevated inflammatory markers, and almost all had positive SARS-CoV-2 test results. The remaining 367 (64.4%) of MIS-C patients had manifestations that appeared to overlap with acute COVID-19, had a less severe clinical course, or had features of Kawasaki disease. Median duration of hospitalization was 6 days; 364 patients (63.9%) required care in an intensive care unit (ICU), and 10 patients (1.8%) died. As the COVID-19 pandemic continues to expand in many jurisdictions, clinicians should be aware of the signs and symptoms of MIS-C and report suspected cases to their state or local health departments; analysis of reported cases can enhance understanding of MIS-C and improve characterization of the illness for early detection and treatment.
Local and state health departments reported suspected MIS-C patients to CDC using CDC’s MIS-C case report form, which included information on patient demographics, clinical findings, and laboratory test results. Patients who met the MIS-C case definition and were reported to CDC as of July 29, 2020, were included in the analysis. Latent class analysis (LCA), a statistical modeling technique that can divide cases into groups by underlying similarities, was used to identify and describe differing manifestations in patients who met the MIS-C case definition. The indicator variables used in the LCA were the presence or absence of SARS-CoV-2–positive test results by reverse transcription–polymerase chain reaction (RT-PCR) or serology, shock, pneumonia, and involvement of organ systems (i.e., cardiovascular, dermatologic, gastrointestinal, hematologic, neurologic, renal, or respiratory). Three-class LCA was conducted using the R software package “poLCA” with 100 iterations to identify the optimal classification scheme. Clinical and demographic variables were reported for patients by LCA class. Chi-squared or Fisher’s exact tests were used to compare proportions of categorical variables; numeric variables, with medians and interquartile ranges, were compared using the Kruskal-Wallis rank sum test.
As of July 29, 2020, a total of 570 MIS-C patients with onset dates from March 2 to July 18, 2020, had been reported from 40 state health departments, the District of Columbia, and New York City. The median patient age was eight years (range = two weeks–20 years); 55.4% were male, 40.5% were Hispanic or Latino (Hispanic), 33.1% were non-Hispanic black (black), and 13.2% non-Hispanic white (white). Obesity was the most commonly reported underlying medical condition, occurring in 30.5% of Hispanic, 27.5% of black, and 6.6% of white MIS-C patients.
Overall, the illness in 490 (86.0%) patients involved four or more organ systems. Approximately two thirds did not have preexisting underlying medical conditions before MIS-C onset. The most common signs and symptoms reported during illness course were abdominal pain (61.9%), vomiting (61.8%), skin rash (55.3%), diarrhea (53.2%), hypotension (49.5%), and conjunctival injection (48.4%). Most patients had gastrointestinal (90.9%), cardiovascular (86.5%), or dermatologic or mucocutaneous (70.9%) involvement. Substantial numbers of MIS-C patients had severe complications, including cardiac dysfunction (40.6%), shock (35.4%), myocarditis (22.8%), coronary artery dilatation or aneurysm (18.6%), and acute kidney injury (18.4%). The majority of patients (63.9%) were admitted to an ICU. The median length of ICU stay was five days (interquartile range = three to seven days).
Of the 565 (99.1%) patients who underwent SARS-CoV-2 testing, all had a positive test result by RT-PCR or serology; 46.1% had only serologic evidence of infection and 25.8% had only positive RT-PCR test results. Five patients (0.9%) did not have testing performed but had an epidemiologic link as indicated in the MIS-C case definition.
Among all 570 patients, 527 (92.5%) were treated, including 424 (80.5%) who received intravenous immunoglobulin (IVIG), 331 (62.8%) who received steroids, 309 (58.6%) who received antiplatelet medication, 233 (44.2%) who received anticoagulation medication, and 221 (41.9%) who were treated with vasoactive medication. Ten (1.8%) patients were reported to have died.
LCA identified three classes of patients, each of which had significantly different illness manifestations related to some of the key indicator variables.
· Class 1 represented 203 (35.6%) patients who had the highest number of involved organ systems. Within this group, 99 (48.8%) had involvement of six or more organ systems; those most commonly affected were cardiovascular (100.0%) and gastrointestinal (97.5%). Compared with the other classes, patients in class 1 had significantly higher prevalences of abdominal pain, shock, myocarditis, lymphopenia, markedly elevated C-reactive protein (produced in the liver in response to inflammation), ferritin (an acute-phase reactant), troponin (a protein whose presence in the blood indicates possible cardiac damage), brain natriuretic peptide (BNP), or proBNP (indicative of heart failure). Almost all class 1 patients (98.0%) had positive SARS-CoV-2 serology test results with or without positive SARS-CoV-2 RT-PCR test results. These cases closely resembled MIS-C without overlap with acute COVID-19 or Kawasaki disease.
· Class 2 included 169 (29.6%) patients; among those in this group, 129 (76.3%) had respiratory system involvement. These patients were significantly more likely to have cough, shortness of breath, pneumonia, and acute respiratory distress syndrome (ARDS), indicating that their illnesses might have been primarily acute COVID-19 or a combination of acute COVID-19 and MIS-C. The rate of SARS-CoV-2 RT-PCR positivity (without seropositivity) in this group (84.0%) was significantly higher than that for class 1 (0.5%) or class 3 (2.0%) patients (p<0.01). The case fatality rate among class 2 patients was the highest (5.3%) among all three classes (p<0.01).
· Class 3 included 198 (34.7%) patients; the median age of children in this group (six years) was younger than that of the class 1 patients (9 years) or class 2 patients (10 years). Class 3 patients also had the highest prevalence of rash (62.6%), and mucocutaneous lesions (44.9%). Although not statistically significant, the prevalence of coronary artery aneurysm and dilatations (18.2%) was higher than that in class 2 patients (15.8%), but lower than that in class 1 patients (21.1%). Class 3 patients more commonly met criteria for complete Kawasaki disease (6.6%) compared with class 1 (4.9%) and class 2 (3.0%) patients, and had the lowest prevalence of underlying medical conditions, organ system involvement, complications (e.g., shock, myocarditis), and markers of inflammation and cardiac damage. Among class 3 patients, 63.1% had positive SARS-CoV-2 serology only and 33.8% had both serologic confirmation and positive RT-PCR results.
Initial reports of MIS-C patients described varied clinical signs and symptoms at initial evaluation, but most cases included features of shock, cardiac dysfunction, gastrointestinal symptoms, significantly elevated markers of inflammation and cardiac damage, and positive test results for SARS-CoV-2 by serology. Because the case definition is nonspecific and confirmatory laboratory testing does not exist, it might be difficult to distinguish MIS-C from other conditions with overlapping clinical manifestations such as severe acute COVID-19 and Kawasaki disease. Latent class analysis is particularly well-suited to describe differing manifestations of a novel clinical syndrome. It divides patients into groups that might have been previously unrecognized, based on shared characteristics, allowing for an unbiased determination of disease manifestations. Patients identified in class 1 had little overlap with acute COVID-19 or Kawasaki disease, whereas patients in class 2 had clinical and laboratory manifestations that overlapped with acute COVID-19. This overlap might result from the development of MIS-C soon after symptomatic acute COVID-19 illness. However, the presence of isolated severe acute COVID-19 illness cannot be ruled out in some of these patients. Patients in class 3 generally seemed to have less severe MIS-C illness and clinical manifestations that overlapped with Kawasaki disease, and distinguishing class 3 patients from those with true Kawasaki disease could be difficult. As the COVID-19 pandemic spreads, and more children are exposed to SARS-CoV-2 with subsequent seroconversion, patients with Kawasaki disease might be misidentified as MIS-C because of an incidental finding of antibodies to SARS-CoV-2.
As the COVID-19 pandemic continues, with the number of cases increasing in many jurisdictions, health care providers should continue to monitor patients to identify children with a hyperinflammatory syndrome with shock and cardiac involvement. Suspected MIS-C patients should be reported to local and state health departments. Distinguishing patients with MIS-C from those with acute COVID-19 and other hyperinflammatory conditions is critical for early diagnosis and appropriate management. It is also critical for monitoring potential adverse events of a COVID-19 vaccine when one becomes widely available. Studies to define the clinical and laboratory characteristics of MIS-C should continue, including identification of parameters that will help distinguish the illness from other similar conditions.
