Authors
Angela Allen, MD, Department of Emergency Medicine, University of North Carolina, Chapel Hill
Daniel Migliaccio, MD, Clinical Assistant Professor, Ultrasound Fellowship Director, Department of Emergency Medicine, University of North Carolina, Chapel Hill
Peer Reviewer
Catherine A. Marco, MD, FACEP, Professor, Emergency Medicine and Surgery, Wright State University, Dayton, OH
Pediatric SARS-CoV-2 infections are mild compared to adult infections. However, MIS-C, which typically develops four to six weeks after the initial infection, may be severe and characterized by multiorgan dysfunction resulting from hyperinflammation. The authors provide critical information regarding MISC-C recognition and management.
— Ann M. Dietrich, MD, FAAP, FACEP, Editor
Introduction
In April 2020, descriptions of a multisystem inflammatory syndrome in children (MIS-C) were reported in literature from multiple countries where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were highly concentrated.1-5 When it was first identified, MIS-C was characterized as a Kawasaki-like disease in several case reports and case series from the United States, Italy, the United Kingdom, and France because of its similar presentation to Kawasaki disease (KD), such as fever, rash, conjunctivitis, and lymphadenopathy.2,3,5 In Italy alone, a 30-fold increase in this Kawasaki-like disease in relation to actual KD was reported. However, noticeable differences were observed in this new disease, now identified as MIS-C, including higher rates of cardiac dysfunction, hypotension, and coagulopathy.1,2,5-7 These differences from classic KD and the temporal relation of MIS-C to SARS-CoV-2 infection led to its ultimate discovery. While initial SARS-CoV-2 infections in children generally are mild compared to adults, MIS-C, which typically develops four to six weeks after initial infection, is severe and characterized by multiorgan dysfunction as the result of fever and hyperinflammation.2,5,8-11
Three major organizations have defined MIS-C with many overlapping characteristics. The Royal College of Pediatrics and Child Health in the United Kingdom defines MIS-C as a child presenting with fever greater than 38.5°C, evidence of single or multiorgan dysfunction, and signs of inflammation, including neutrophilia, elevated C-reactive protein (CRP), and lymphopenia. Alternative microbial causes must be excluded, and SARS-CoV-2 reverse-transcriptase polymerase chain reaction (RT-PCR) test results may be positive or negative.
The Centers for Disease Control and Prevention (CDC) defines MIS-C using six criteria: The patient is < 21 years of age; presents with > 24 hours of subjective or objective fever > 38°C prior to or within the first three days of hospitalization; has severe illness necessitating hospitalization with at least two organ systems affected; has laboratory evidence of inflammation; exhibits evidence of SARS-CoV-2 infection by RT-PCR, serology for anti-SARS-CoV-2 antibodies, antigen testing, or exposure within four weeks prior to the onset of symptoms; and has no alternative diagnosis.12
The World Health Organization (WHO) defines MIS-C as children and adolescents 0-19 years of age with fever for more than three days and two of the following: rash, bilateral non-purulent conjunctivitis, or mucocutaneous inflammatory signs; hypotension, shock, or features of myocardial dysfunction; pericarditis, valvulitis, or coronary abnormalities; evidence of coagulopathy; and/or acute gastrointestinal (GI) problems. Additionally, the patient must have elevated inflammatory markers, no other obvious microbial cause, and evidence of SARS-CoV-2 infection by RT-PCR, serology, or close contact with an infected person.13 All three organizations’ definitions are summarized in Table 1.
Table 1. Definitions of Multisystem Inflammatory Syndrome in Children | ||
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Royal College of Pediatrics and Child Health |
Centers for Disease Control and Prevention |
World Health Organization |
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|
|
CRP: C-reactive protein; RT-PCR: reverse-transcriptase polymerase chain reaction Adapted from Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: A comprehensive review and proposed clinical approach. Eur J Pediatr 2021;180:307-322. | ||
Epidemiology
As of January 2022, almost 6,500 cases of MIS-C have been reported by the CDC in the United States.14 The incidence of MIS-C has been reported to be up to 316 per 1 million SARS-CoV-2 infections in the pediatric population (0.032%).15 No significant difference in incidence between males and females has been observed. While the CDC includes patients younger than 21 years old in their definition of MIS-C, the most common age range of presentation has been found to be from 5 to 13 years of age, with the CDC reporting a median age of 9 years.5,8,9,14,15 According to CDC national surveillance programs, the incidence of MIS-C corresponds racially to the overall incidence of SARS-CoV-2 infections, being most prevalent among Black, Hispanic, Asian, and Pacific Islander populations.15
Although aggressive treatment in the intensive care unit (ICU) often is required, overall mortality is low and ranges from about 1.5% to 2%, and most children are discharged from the hospital.1,8,9,16-18 Given the severity of illness and requirement for ICU support, it is critical that the emergency medicine physician recognize MIS-C and understand the appropriate disposition, since clinical decline can occur rapidly.
Etiology
MIS-C is associated with SARS-CoV-2 infection either by reported exposure or laboratory confirmation. The rate of patients with MIS-C who test positive for SARS-CoV-2 infection by either RT-PCR or serology for anti-SARS-CoV-2 antibodies has been found to be anywhere from 60% to 90%, with the remainder of patients reporting exposure.9,10,16 Of patients with antibodies discovered via serology, most are found to have higher titers of immune globulin (Ig) G antibodies, compared to IgM antibodies. IgG antibodies generally take a few weeks to become detectable, which correlates with the timeframe in which MIS-C occurs, four to six weeks after the initial infection.2,6,19-21 Additionally, higher levels of IgG antibody titers have been found to be associated with worse disease severity in MIS-C.22 In patients who test positive by RT-PCR, their cycle numbers for SARS-CoV-2 are high. High cycle numbers indicate reduced viral load and, thus, resolving infection, further supporting the delayed timeframe in which MIS-C develops.23
Unlike children who develop severe SARS-CoV-2 infections, most children with MIS-C do not have underlying medical conditions.1,16 The most frequently reported comorbid condition is obesity, with one international systematic review finding the rate to be 7.7%.16 It is postulated that obesity is a risk factor because of the accumulation of inflammatory cells in adipose tissue, the presence of proinflammatory cytokines in adipose tissue, and the fact that angiotensin-converting enzyme 2 (ACE 2), the receptor for SARS-CoV-2, is largely expressed in adipose cells, leading to potentially higher overall viral loads.18,24
Pathophysiology
The pathophysiology of MIS-C is thought to be related to a hyperactive innate and adaptive immune response to SARS-CoV-2 infection. It is characterized by a cytokine storm with hyperinflammation leading to multiorgan system dysfunction. SARS-CoV-2 is an enveloped, single-stranded RNA betacoronavirus that enters the body via its spike protein, which binds to the ACE 2 receptor in the body.17,25,26 While ACE 2 expression is decreased in younger children, once infected, children have been found to carry higher viral loads of SARS-CoV-2 compared to adults, implying that viral replication may be more robust in these patients.17,27
Higher viral loads are not necessarily correlated with disease severity of initial SARS-CoV-2 infection in children, since many remain asymptomatic. However, it has been postulated that the varying ability of this virus to successfully infect and reproduce within specific tissues, such as myocardial, mucosal, and epithelial cells in the lining of the lungs and GI tract, leads to the development of the postinfectious hyperinflammatory response seen in MIS-C, even when initial SARS-CoV-2 infection appears clinically benign.17 This is evidenced by the increased IgG and IgA autoantibodies to peptides and cytokine molecules expressed in these tissues found in MIS-C patients.6,17
While much is left to be explored, several cell populations are associated with MIS-C. It is thought that the autoantibodies formed by initial infection bind to Fc gamma receptors on neutrophils and macrophages, leading to activation and secretion of pro-inflammatory cytokines and the production of immune complexes that go on to cause multisystem dysfunction.8,20,23,28
Circulating levels of activated neutrophils, monocytes, and inflammatory cytokines (interleukin [IL]-18/-6, tumor necrosis factor-alpha) are elevated, while B cells, T cells, and natural killer cells are decreased, suggesting possible exit from peripheral blood and into affected tissues.6,28,29
The pathophysiology behind MIS-C myocarditis can be understood in the same ways in which other forms of postviral myocarditis are explained. Viral propagation in myocardial cells during initial infection leads to cellular damage, exposing the body to intrinsic antigens of the cardiac tissue to which it otherwise would not be exposed. While the initial infection may appear clinically resolved, viral genomic material may remain within damaged cardiac myocytes and propagate a cascade of immune activation and tissue inflammation. Autoantibodies, overactivated monocytes, and macrophages lead to the additional cardiac inflammation and damage seen in myocarditis.17,30 In addition to myocarditis, children are susceptible to coronary artery aneurisms, which are thought to be because younger arteries have more elastin and, thus, decreased mechanical strength during growth and development, making them susceptible to aneurism formation.17,31
Clinical Features
Previous SARS-CoV-2 exposure (with or without confirmed infection) is a requirement for the diagnosis of MIS-C and is a key component of a patient’s history. Additionally, since most cases of MIS-C occur four to six weeks after initial infection, providers should obtain a detailed timeline of prior exposure with or without infection. To date, there are no other significant risk factors highly associated with MIS-C other than obesity. As such, the provider must use the patient’s presenting symptoms, general appearance, and infection or exposure history to determine if further laboratory workup and/or admission is warranted.
While presentations vary between children who present with MIS-C, several key clinical features have been identified. Reported or measured fever is ubiquitous in those presenting to the emergency department, with most patients presenting with fever for several days.1,2,8,16,32
The GI and cardiovascular systems are two of the most common organ systems affected in MIS-C. GI involvement, with symptoms of abdominal pain, diarrhea, nausea, and/or vomiting, is found in 70% to 90% of cases.1,8,9,11,16,21 In fact, there have been cases in which the abdominal pain was so severe that emergency abdominal surgery for presumed acute abdomen was performed, only to reveal mesenteric lymphadenitis.33,34 Cardiac involvement with symptoms of chest pain and dyspnea is seen in up to 80% of patients, with cardiovascular compromise being the most frequent physiologic abnormality reported in those admitted to the ICU.1,8,9,16 A proportion of patients present with hypotension from cardiac dysfunction and/or hyperinflammation with systemic vasodilation. Approximately 60% to 70% of all patients with MIS-C develop hypotension requiring ionotropic support in addition to volume resuscitation.1,13,21
Other common organ systems involved in patients with MIS-C include the hematologic system with findings of coagulopathy, as evidenced by laboratory markers (elevated D-dimer, prothrombin time, and partial thromboplastin time) in 76% of cases; the mucocutaneous system with symptoms of conjunctivitis, rash, or stomatitis (42% to 74% of cases); the respiratory system with symptoms such as cough, sore throat, hypoxemia, or pulmonary infiltrates (5% to 70% of cases); and the neurologic system, with symptoms such as headache, encephalopathy, or lethargy in 22% of cases.1,8,16,35-37 (See Table 2.)
Table 2. Symptoms of Multisystem Inflammatory Syndrome in Children | ||
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Organ System |
Signs and Symptoms |
Laboratory Studies and Imaging |
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Gastrointestinal |
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Cardiovascular |
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Hematologic |
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Mucocutaneous |
|
|
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Respiratory |
|
|
|
Neurological |
|
|
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Other |
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|
|
AST: aspartate aminotransferase; ALT: alanine aminotransferase; BNP: B-natriuretic peptide; PT: prothrombin time; PTT: partial thromboplastin time; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; LDH: lactate dehydrogenase; IL-6: interleukin-6; CPK: creatine phosphokinase; AKI: acute kidney injury Adapted from Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: Review of clinical presentation, hypothetical pathogenesis, and proposed management. Children 2020;7:69. | ||
Diagnostic Studies
Several diagnostic laboratory tests and imaging studies have been recommended in the evaluation of MIS-C. The American College of Rheumatology (ACR) recommends a two-tier system for testing, but all of the following tests are recommended immediately from both tiers if patients meet criteria for suspected MIS-C and present with shock of unclear etiology.10 Tier one consists of laboratory tests easily obtained in any emergency department setting: complete blood count (CBC) with differential, complete metabolic panel (CMP), erythrocyte sedimentation rate (ESR), CRP, and testing for SARS-CoV-2 by RT-PCR and/or serology.10 MIS-C patients are consistently found to have neutrophilic leukocytosis (with occasional leukopenia), thrombocytopenia, hyponatremia, and elevated ESR and CRP.5,8,9,11,32
Additional studies report findings of acute kidney injury.1 The ACR recommends tier two testing for patients with findings of elevated ESR and/or CRP with at least one of the following: lymphopenia, neutrophilia, thrombocytopenia, hyponatremia, or hypoalbuminemia.10 Tier two testing includes measures of additional inflammatory markers, such as D-dimer, ferritin, procalcitonin, cytokine panels, and lactate dehydrogenase (LDH), all of which typically are elevated in MIS-C.10,11,32,33,38,39 It also includes the evaluation of cardiac involvement with troponin and B-type natriuretic peptide (BNP), an electrocardiogram (ECG), and an echocardiogram. Point-of-care ultrasound (POCUS) is an efficient and elucidating tool that can be used in the emergency department for evaluation of undifferentiated shock.
One cross-sectional study of POCUS performed by emergency physicians on patients with MIS-C revealed not only cardiac dysfunction, but also intraperitoneal free fluid and pericardial and pleural effusions.40 Studies have found troponin to be elevated in 68% to 81% of patients and elevated BNP in 70% to 83% of patients.1,16,32 ECG abnormalities that have been identified include a prolonged PR interval, ST and T segment changes, QTc prolongation, premature atrial or ventricular beats, first- and second-degree atrioventricular blocks, and atrial fibrillation.8,13,32 Left ventricular dysfunction has been found to be present in 20% to 55% of cases and coronary artery dilation or aneurysms have been present in about 9% to 24% of patients, with valvular dysfunction and pericardial effusions less frequently described.1-3,5,8,9,11,32,33 Repeat ECG and echocardiogram should be performed every 48 hours while the patient is hospitalized if any abnormalities are observed.10
In cases where abdominal pain is the presenting feature, appropriate imaging for other suspected sources of pain should be obtained. Results from ultrasound, computed tomography, and magnetic resonance imaging studies performed on MIS-C patients most commonly identify ascites, intestinal/colonic inflammation, and mesenteric adenopathy.11,18,21,29,34,41-43
In cases with respiratory features, a chest X-ray (CXR) should be obtained. Most reported findings include airspace opacities, perihilar opacities, and peribronchial thickening.42,44 In cases where CT scans were obtained, pleural effusions were the most common finding.44
Several institutions have created protocols for the detection of MIS-C. These protocols typically consist of obtaining a combination of the aforementioned laboratory and imaging studies in all patients suspected to have MIS-C. In one review of protocols from 40 U.S. hospitals, half required fever for only one day before starting a tiered approach to diagnostic studies for MIS-C.45 Recommendations for the workup of MIS-C should not replace clinical judgment. MIS-C is a diagnosis of exclusion, and all other potential causes of a patient’s presentation should be investigated thoroughly. Nakra et al created a table denoting a recommended diagnostic workup for a patient suspected of having MIS-C, which includes factors that aid in ruling out other sources of infection such as blood cultures, urinalysis with culture, and CXR. (See Table 3.)
Table 3. Recommended Workup for Multisystem Inflammatory Syndrome in Children | |
|
Laboratory Studies |
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Imaging |
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Other Testing |
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|
CBC: complete blood count; CMP: complete metabolic panel; BNP: B-natriuretic peptide; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; IL-6: interleukin-6; PT: prothrombin time; PTT: partial thromboplastin time; LDH: lactate dhydrogenase; RT-PCR: reverse-transcriptase polymerase chain reaction; RPP: respiratory pathogen panel; MAS: macrophage activation syndrome; NK: natural killer; CT: computed tomography Adapted from Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: Review of clinical presentation, hypothetical pathogenesis, and proposed management. Children 2020;7:69. | |
Differential Diagnosis
MIS-C shares several features with other inflammatory conditions, such as sepsis, KD, toxic shock syndrome (TSS), and macrophage activation syndrome (MAS). The diagnosis of KD includes the presence of fever lasting at least five days without any other explanation and at least four of the following criteria: conjunctival injection, oral mucous membrane changes (fissured lips, injected pharynx, strawberry tongue), peripheral extremity changes (erythema of palms/soles, edema of hands/feet, periungual desquamation), polymorphous rash, and/or cervical lymphadenopathy. MIS-C most resembles KD, and many of the recommendations on treatment and surveillance have been based on their similarities.
In contrast to MIS-C, where the average presenting age is 6 to 11 years, the presenting age for KD is younger, ranging from 6 months to 5 years of age. There is male predominance in KD (no predominance in MIS-C), and the incidence is highest in Japan, China, South Korea, and Taiwan as opposed to MIS-C, which is seen concentrated in areas and populations where SARS-CoV-2 infections are highest.46 Overlapping clinical features include fever, rash, lymphadenopathy, extremity changes, and neurologic symptoms.
However, in MIS-C, there is a higher incidence of GI symptoms, myocarditis, shock, and coagulopathy compared to KD, which has a higher predominance of conjunctival injection and mucous membrane changes.5,6,8,12,46 KD shock syndrome, in which patients develop hypotension, develops in less than 5% of children compared to the majority of patients in MIS-C. Coronary artery abnormalities seem to be more common in KD than the hypotension and myocarditis seen in MIS-C.1,7 There are several laboratory similarities between the two syndromes, but, most notably, KD will not involve SARS-CoV-2 antibodies. Management of both syndromes includes intravenous immune globulin (IVIG) and steroids, among other immunomodulators. (See Table 4.)
Table 4. Comparison of MIS-C and Kawasaki Disease | ||
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MIS-C |
Kawasaki Disease |
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Average Age Range |
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Sex |
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Racial/Ethnic Predominance |
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Trigger |
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Clinical Features |
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Laboratory Studies |
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Treatment |
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MIS-C: multisystem inflammatory syndrome in children; GI: gastrointestinal; PT: prothrombin time; PTT: partial thromboplastin time; BNP: B-natriuretic peptide; CRP: C-reactive protein; IVIG: intravenous immune globulin Adapted from Sharma C, Ganigara M, Galeotti C, et al. Multisystem inflammatory syndrome in children and Kawasaki disease: A critical comparison. Nat Rev Rheumatol 2021;17:731-748. | ||
MIS-C also resembles features of TSS, a syndrome characterized by high fever, vomiting, diarrhea, muscle cramps, diffuse erythema, and multiorgan failure. Most often linked to Staphylococcus aureus, TSS is associated with activation of the immune system by invasive proteins, or superantigens, that stimulate T cells and lead to massive cytokine release and resulting inflammation. Just as the exotoxin from S. aureus infections acts as a superantigen in TSS, research has shown that viruses also can act as superantigens.1,46 In studies of SARS-CoV-2, the viral S protein appears to have a high affinity for specific receptors, and the resultant chemical pathways observed in MIS-C resemble superantigen-mediated T cell activation.38,46-48
Unlike TSS, however, which occurs almost immediately following initial infection, MIS-C most commonly occurs weeks after initial infection. Other notable differences include older age in TSS and the classic diffuse erythroderma in TSS vs. a wide range of possible rashes or absence of rash seen in MIS-C. Treatment for TSS includes volume resuscitation, treatment with appropriate antimicrobial agents based on etiology, and, occasionally, IVIG.
Lastly, MIS-C shares features with MAS, also known as hemophagocytic lymphohistiocytosis, which also has clinical and laboratory features including sustained fever, hyperferritinemia, pancytopenia, coagulopathy, and liver dysfunction.49 MAS is triggered by either an infection or a chronic inflammatory state, such as systemic juvenile idiopathic arthritis or lupus. It is hypothesized to be caused by a genetic mutation in cytolytic pathway genes that leads to an inability of natural killer cells and CD8 T cells to lyse infected antigen presenting cells. With prolonged cell-to-cell interactions, macrophages become activated via a cytokine cascade, which leads to hemophagocytosis and organ damage.49 The major differences seen in the two syndromes include a higher degree of hyperferritinemia in MAS and other differences in immunologic features.29 Treatment for MAS involves addressing the underlying trigger, if possible (i.e., treating an infection), and immunosuppressive medications, such as steroids and cyclosporine.49
Management
Management of MIS-C involves immediate stabilization and supportive care in the emergency department followed by further inpatient interventions once the diagnosis of MIS-C is confirmed. (See Table 5.) MIS-C is a diagnosis of exclusion. As such, many patients are started on antibiotics for presumed sepsis while in the emergency department, which often are continued inpatient.18 Patients presenting with hypotension should be managed with fluid resuscitation and/or ionotropic support. A subset of patients require extracorporeal membrane oxygenation (ECMO) once hospitalized (ranging from 4% to 28%).8,13,16 If there is evidence of ventricular dysfunction, such as dyspnea or signs of volume overload, smaller fluid boluses of 10 mg/kg should be administered, with careful reevaluation between boluses for signs of hypervolemia, and early ionotropic support is recommended.13 Hypoxia should be treated with appropriate oxygen therapy, and one systematic review found that mechanical ventilation is necessary in up to 22.2% of patients.18 These initial stabilization measures are the most common interventions emergency physicians can perform, since the diagnosis of MIS-C is not typically confirmed while in the emergency department.
Table 5. Management and Treatment Options for MIS-C | ||
|
|
Treatment |
Indication/Notes |
|
Initial |
Fluid resuscitation ± ionotropic support ± antibiotics |
Hypotension |
|
After Confirmation of MIS-C |
IVIG 2 g/kg (may require repeat dosing) |
All patients |
|
IV methylprednisolone 10-30 mg/kg/day for 3-7 days with 2-3-week taper |
Patients not responding to IVIG alone | |
|
Aspirin 3-5 mg/kg/day up to 81 mg |
KD features, coronary artery aneurysms, thrombocytosis | |
|
Anakinra |
Refractory to IVIG and glucocorticoids | |
|
Tocilizumab, infliximab |
Have been trialed with success | |
|
MIS-C: multisystem inflammatory syndrome in children; IVIG: intravenous immune globulin; KD: Kawasaki disease | ||
Because MIS-C is a relatively new diagnosis and there have been no randomized controlled trials or approved treatments, recommendations for therapeutic interventions are largely based on established treatments of KD and other pediatric inflammatory conditions.13
Once the diagnosis of MIS-C is confirmed by meeting either large organization or local institutional criteria (typically once the patient is already admitted), the ACR recommends treatment with IVIG alone or in conjunction with low-to-moderate doses (1-2 mg/kg/day) of glucocorticoids.8,10 Based on data extrapolated from KD showing prevention of coronary artery aneurisms, the dose of IVIG is 2 g/kg.10,13,50 IVIG should be given after serology testing for SARS-CoV-2 is obtained.8 The most common adverse effects from IVIG include mild symptoms, such as flushing, headache, malaise, and fevers, which often can be alleviated by slowing the infusion rate.51
Anywhere from 30% to 80% of patients do not respond to IVIG alone and require additional therapies, such as a second dose of IVIG, glucocorticoids, and/or immunomodulators.1,5,9-11 The ACR recommends IV methylprednisolone 10-30 mg/kg/day for three to seven days followed by gradual tapering over a two- to-three-week period to prevent rebound inflammation.8,10 Low-dose aspirin of 3-5 mg/kg/day up to 81 mg is recommended for all MIS-C patients with KD features, coronary artery aneurisms, and thrombocytosis.10
The IL-1 antagonist anakinra is recommended by the ACR for patients who are refractory to IVIG and/or glucocorticoids, which is based on the success seen in MIS-C case reports and because of its safety profile in pediatric patients.10,11,32,33,39 Other cytokine blockers have been trialed with success, including tocilizumab, an IL-6 inhibitor, and infliximab, a tumor necrosis factor-alpha blocker.13
Disposition and Follow-Up
Most patients with MIS-C will require admission to the hospital, especially those with abnormal vital signs, concerning physical exam findings, significantly elevated inflammatory markers, or signs of cardiac involvement.8,10,16 Patients with MIS-C may deteriorate quickly, and the majority (68% to 80%) require admission to an ICU.1,9,16 ICU admission typically is required when there is need for advanced cardiovascular (vasoactive medication, ECMO) and/or respiratory support (ventilator-dependent or hospital set oxygen requirement cut-offs through noninvasive ventilatory support devices). The average length of stay in the hospital has been found to be seven to nine days.18
While overall mortality is low, and most children are discharged from the hospital after appropriate support and treatment, those with cardiac involvement require follow-up for repeat echocardiography.8,17,18 Based on recommendations for and findings in KD, the ACR recommends repeat echocardiograms for all patients at days 7-14 and at weeks 4-6. Those with any cardiac involvement found during initial echocardiograms require repeat echocardiograms in one year.10 Repeat echocardiography around 12 days showed residual mild-moderate left ventricular systolic function in 14% of patients in one study, with other studies showing a return to baseline function at six weeks in most patients.5,8,9,33 One study found that, at a three-month follow-up, one out of nine patients had residual myocardial edema on cardiac magnetic resonance imaging but no fibrosis and normal systolic function on echocardiogram.52 Results generally have been reassuring that cardiac function improves for most children.
Additional Considerations
While MIS-C is associated with a low mortality overall because of successful hospital-based interventions, the long-term sequelae of this illness remain unknown, given its recent discovery. At this time, KD is the leading cause of acquired heart disease in children, and 25% of those untreated develop coronary aneurysms.50 Given the similarities between MIS-C and KD, it is important to recognize and treat MIS-C to reduce similar potential long-term complications.
Additionally, while one study found that those with MIS-C myocarditis had more significant hematologic derangements and worse inflammation compared to those with classic myocarditis caused by other viruses, it did show a faster resolution of symptoms and improvement of cardiac function.53 It is possible that there may be some degree of myocardial fibrosis and scarring similar to what is seen in classic myocarditis cases, which is associated with long-term systolic or diastolic dysfunction.10,54,55
To prevent MIS-C, avoidance of SARS-CoV-2 infection is necessary. The CDC recommends that schools require universal indoor masking as studies confirm that schools with known mask mandates have significantly lower rates of SARS-CoV-2 infections after controlling for age, race, ethnicity, vaccination rate, community transmission, population density, social and community vulnerability index scores, percentage uninsured, and percentage living in poverty.56 The Pfizer vaccine is the only approved vaccine for children 5 years of age and older, with a randomized controlled trial demonstrating both safety and efficacy.57 The Moderna vaccine is available for those 18 years and older and also demonstrates safety and efficacy.58 As of December 2021, the CDC recommended patients not receive the Johnson and Johnson vaccine if the Pfizer and Moderna vaccines are available, given their favorable safety profiles.
Conclusion
MIS-C is a new diagnosis that has emerged from the SARS-CoV-2 pandemic. While information about its pathophysiology, clinical features, diagnosis, and treatment is evolving, much has been learned about this syndrome since it was originally reported. Consider MIS-C in children presenting with fever and recent SARS-CoV-2 exposure with or without confirmed infection regardless of whether they were ever symptomatic or tested. Diagnostic protocols vary between institutions but typically involve laboratory and imaging studies, including CBC, CMP, inflammatory markers, blood cultures, urinalysis and culture, cardiac and coagulation studies, CXR, and echocardiography. It is essential that the emergency provider understand that MIS-C is a diagnosis of exclusion; workup of alternative causes of a patient’s presentation must be completed if clinically indicated.
While MIS-C can be differentiated from KD by several laboratory findings and clinical presentations, their similarities have allowed for the development of treatment and surveillance recommendations in MIS-C. In addition to supportive care, IVIG (with or without glucocorticoids) is the most reported treatment provided. Additional immunomodulators also have been trialed with success. Patients with cardiac abnormalities on echocardiography require repeat echocardiography at follow-up appointments to evaluate for ongoing dysfunction or resolution.
Fortunately, the mortality rate in MIS-C is low. However, this is because of the aggressive treatment provided to stabilize these patients. Patients with MIS-C often require ICU admission, can decompensate quickly, and can have significant cardiac complications, so recognition is essential to ensure appropriate disposition, cardiac evaluation, treatment, and surveillance.
Ultimately, continued attempts to prevent further spread of SARS-CoV-2 infection in the community via mask wearing and widespread vaccination is necessary to prevent and decrease MIS-C occurrence.
REFERENCES
- Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: Review of clinical presentation, hypothetical pathogenesis, and proposed management. Children 2020;7:69.
- Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: An observational cohort study. Lancet 2020;395:1771-1778.
- Riphagen S, Gomez X, Gonzalez-Martinez C, et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020;395:1607-1608.
- DeBiasi RL, Song X, Delaney M, et al. Severe coronavirus disease-2019 in children and young adults in the Washington, D.C., metropolitan region. J Pediatr 2020;223:199-203.e1.
- Pouletty M, Borocco C, Ouldali N, et al. Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): A multicentre cohort. Ann Rheum Dis 2020;79:999-1006.
- Henderson LA, Yeung RSM. MIS-C: Early lessons from immune profiling. Nat Rev Rheumatol 2021;17:75-76.
- Shulman ST. Pediatric coronavirus disease-2019-associated multisystem inflammatory syndrome. J Pediatric Infect Dis Soc 2021;9:285-286.
- Kabeerdoss J, Pilania RK, Karkhele R, et al. Severe COVID-19, multisystem inflammatory syndrome in children, and Kawasaki disease: Immunological mechanisms, clinical manifestations and management. Rheumatol Int 2021;41:19-32.
- Feldstein LR, Rose EB, Horwitz SM, et al. Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 2020;383:334-346.
- Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology clinical guidance for multisystem inflammatory syndrome in children associated with SARS–CoV-2 and hyperinflammation in pediatric COVID-19: Version 1. Arthritis Rheumatol 2020;72:1791-1805.
- Toubiana J, Poirault C, Corsia A, et al. Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: Prospective observational study. BMJ 2020;369:m2094.
- World Health Organizatoin. Multisystem Inflammatory Syndrome in Children and Adolescents Temporally Related to COVID-19. World Health Organization;2020.
- Sperotto F, Friedman KG, Son MBF, et al. Cardiac manifestations in SARS-CoV-2-associated multisystem inflammatory syndrome in children: A comprehensive review and proposed clinical approach. Eur J Pediatr 2021;180:307-322.
- National Center for Immunization and Respiratory Diseases. Health department-reported cases of multisystem inflammatory syndrome in children (MIS-C) in the United States. Published May 11, 2021. https://stacks.cdc.gov/view/cdc/106439
- Payne AB, Gilani Z, Godfred-Cato S, et al. Incidence of multisystem inflammatory syndrome in children among U.S. persons infected with SARS-CoV-2. JAMA Netw Open 2021;4:e2116420.
- Radia T, Williams N, Agrawal P, et al. Multi-system inflammatory syndrome in children & adolescents (MIS-C): A systematic review of clinical features and presentation. Paediatr Respir Rev 2021;38:51-57.
- McMurray JC, May JW, Cunningham MW, Jones OY. Multisystem inflammatory syndrome in children (MIS-C), a post-viral myocarditis and systemic vasculitis — A critical review of its pathogenesis and treatment. Front Pediatr 2020;8:626182.
- Ahmed M, Advani S, Moreira A, et al. Multisystem inflammatory syndrome in children: A systematic review. EClinicalMedicine 2020;26:100527
- Carter MJ, Fish M, Jennings A, et al. Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection. Nat Med 2020;26:1701-1707.
- Consiglio CR, Cotugno N, Sardh F, et al. The immunology of multisystem inflammatory syndrome in children with COVID-19. Cell 2020;183:968-981.e7.
- Dufort EM, Koumans EH, Chow EJ, et al. Multisystem inflammatory syndrome in children in New York State. N Engl J Med 2020;383:347-358.
- Rostad CA, Chahroudi A, Mantus G, et al. Serology in children with multisystem inflammatory syndrome (MIS-C) associated with COVID-19. Pediatrics 2020;146:e2020018242.
- Diorio C, Henrickson SE, Vella LA, et al. Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J Clin Invest 2020;130:5967-5975.
- Iannelli A, Favre G, Frey S, et al. Obesity and COVID-19: ACE 2, the missing tile. Obes Surg 2020;30:4615-4617.
- Lan J, Ge J, Yu J, et al. Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215-220.
- Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-280.e8.
- Yonker LM, Neilan AM, Bartsch Y, et al. Pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Clinical presentation, infectivity, and immune responses. J Pediatr 2020;227:45-52.e5.
- Gruber C, Patel R, Trachman R, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C). medRxiv 2020 Jul 6;2020.07.04.20142752. doi: 10.1101/2020.07.04.20142752. [Preprint].
- Lee PY, Day-Lewis M, Henderson LA, et al. Distinct clinical and immunological features of SARS–CoV-2–induced multisystem inflammatory syndrome in children. J Clin Invest 2020;130:5942-5950.
- Maisch B. Cardio-immunology of myocarditis: Focus on immune mechanisms and treatment options. Front Cardiovasc Med 2019;6:48.
- Thijssen DHJ, Carter SE, Green DJ. Arterial structure and function in vascular ageing: Are you as old as your arteries? J Physiol 2016;594:2275-2284.
- Whittaker E, Bamford A, Kenny J, et al. Clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2. JAMA 2020;324:259-269.
- Belhadjer Z, Méot M, Bajolle F, et al. Acute heart failure in multisystem inflammatory syndrome in children in the context of global SARS-CoV-2 pandemic. Circulation 2020;142:429-436.
- Dasgupta K, Finch SE. A case of pediatric multisystem inflammatory syndrome temporally associated with COVID-19 in South Dakota. S D Med 2020;73:246-251.
- Abel D, Shen MY, Abid Z, et al. Encephalopathy and bilateral thalamic lesions in a child with MIS-C associated with COVID-19. Neurology 2020;95:745-748.
- LaRovere KL, Riggs BJ, Poussaint TY, et al. Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or multisystem inflammatory syndrome. JAMA Neurol 2021;78:536-547.
- Jones VG, Mills M, Suarez D, et al. COVID-19 and Kawasaki disease: Novel virus and novel case. Hospital Pediatr 2020;10:537-540.
- Cheung EW, Zachariah P, Gorelik M, et al. Multisystem inflammatory syndrome related to COVID-19 in previously healthy children and adolescents in New York City. JAMA 2020;324:294-296.
- Capone CA, Subramony A, Sweberg T, et al. Characteristics, cardiac involvement, and outcomes of multisystem inflammatory syndrome of childhood associated with severe acute respiratory syndrome coronavirus 2 infection. J Pediatr 2020;224:141-145.
- Kennedy TM, Dessie A, Kessler DO, et al. Point-of-care ultrasound findings in multisystem inflammatory syndrome in children: A cross-sectional study. Pediatr Emerg Care 2021;37:334-339.
- Chiotos K, Bassiri H, Behrens EM, et al. Multisystem inflammatory syndrome in children during the coronavirus 2019 pandemic: A case series. J Pediatr Infect Dis Soc 2020;9:393-398.
- Waltuch T, Gill P, Zinns LE, et al. Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department. Am J Emerg Med 2020;38:2246.e3-2246.e6.
- Miller J, Cantor A, Zachariah P, et al. Gastrointestinal symptoms as a major presentation component of a novel multisystem inflammatory syndrome in children that is related to coronavirus disease 2019: A single center experience of 44 cases. Gastroenterology 2020;159:1571-1574.e2.
- Palabiyik F, Akcay N, Sevketoglu E, et al. Imaging of multisystem inflammatory disease in children (MIS-C) associated with COVID-19. Acad Radiol 2021;28:1200-1208.
- Dove ML, Jaggi P, Kelleman M, et al. Multisystem inflammatory syndrome in children: Survey of protocols for early hospital evaluation and management. J Pediatr 2021;229:33-40.
- Sharma C, Ganigara M, Galeotti C, et al. Multisystem inflammatory syndrome in children and Kawasaki disease: A critical comparison. Nat Rev Rheumatol 2021;17:731-748.
- Rivas MN, Porritt RA, Cheng MH, et al. COVID-19–associated multisystem inflammatory syndrome in children (MIS-C): A novel disease that mimics toxic shock syndrome—the superantigen hypothesis. J Allergy Clin Immunol 2021;147:57-59.
- Porritt RA, Paschold L, Rivas MN, et al. HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children. J Clin Invest 2021;131:e146614.
- Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019;10:119.
- McCrindle BW, Rowley AH, Newburger JW, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A scientific statement for health professionals from the American Heart Association. Circulation 2017;135:e927-e999.
- Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol 2018;9:1299.
- Matsubara D, Chang J, Kauffman HL, et al. Longitudinal assessment of cardiac outcomes of multisystem inflammatory syndrome in children associated with COVID‐19 infections. J Am Heart Assoc 2022;11:e023251.
- Patel T, Kelleman M, West Z, et al. Comparison of MIS-C related myocarditis, classic viral myocarditis, and COVID-19 vaccine related myocarditis in children. medRxiv 2021; Oct 7. doi:10.1101/2021.10.05.21264581. [Preprint].
- Soni PR, Rivas MN, Arditi M. A comprehensive update on Kawasaki disease vasculitis and myocarditis. Curr Rheumatol Rep 2020;22:6.
- Pilania RK, Jindal AK, Bhattarai D, et al. Cardiovascular involvement in Kawasaki disease is much more than mere coronary arteritis. Front Pediatr 2020;8:526969.
- Budzyn SE, Panaggio MJ, Parks SE, et al. Pediatric COVID-19 cases in counties with and without school mask requirements-United States, July 1-September 4, 2021. MMWR Morb Mortal Wkly Rep 2021;70:1377-1378.
- Walter EB, Talaat KR, Sabharwal C, et al. Evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age. N Engl J Med 2022;386:35-46.
- Baden LR, el Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384:403-416.
Pediatric SARS-CoV-2 infections are mild compared to adult infections. However, MIS-C, which typically develops four to six weeks after the initial infection, may be severe and characterized by multiorgan dysfunction resulting from hyperinflammation. This article includes critical information regarding MISC-C recognition and management.
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