COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis

INTRODUCTION — A novel coronavirus was identified in late 2019 that rapidly reached pandemic proportions. The World Health Organization (WHO) has designated the disease COVID-19, which stands for coronavirus disease 2019 [1]. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

In children, COVID-19 is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults. In April of 2020, reports from the United Kingdom documented a presentation in children similar to incomplete Kawasaki disease (KD) or toxic shock syndrome [2,3]. Since then, there have been reports of similarly affected children in other parts of the world [4-11]. The condition has been termed multisystem inflammatory syndrome in children (MIS-C; also referred to as pediatric multisystem inflammatory syndrome [PMIS], pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [PIMS-TS], pediatric hyperinflammatory syndrome, or pediatric hyperinflammatory shock).

The epidemiology, pathophysiology, clinical presentation, evaluation, and diagnosis of MIS-C will be discussed here. The management and outcome of MIS-C and other aspects of COVID-19 in children and adults are discussed separately:

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

●(See "COVID-19: Clinical manifestations and diagnosis in children".)

●(See "COVID-19: Management in children".)

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Hypercoagulability".)

●(See "COVID-19: Evaluation of adults with acute illness in the outpatient setting" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

Understanding of COVID-19 and MIS-C continues to evolve. Interim guidance has been issued by the WHO and by the United States Centers for Disease Control and Prevention (CDC) [4,12,13]. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

EPIDEMIOLOGY — While the incidence of MIS-C is uncertain, it appears to be a relatively rare complication of COVID-19 in children, occurring in <1 percent of children with confirmed SARS-CoV-2 infection. In one report from New York State, the estimated incidence of laboratory-confirmed SARS-CoV-2 infection in persons <21 years old was 322 per 100,000, and the incidence of MIS-C was 2 per 100,000 [14]. However, the epidemiology of MIS-C may shift due to widespread exposure in the pediatric population with subsequent waves of COVID-19, especially the Omicron variant, as well as increasing vaccination rates [15]. Some data suggest that MIS-C is less common and less severe with the Omicron variant compared with earlier variants [16-21]. Accumulating evidence also suggests that vaccination for COVID-19 is rarely associated with development of MIS-C and may protect against it [22-24]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Vaccination for COVID-19' and "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection' and "COVID-19: Vaccines", section on 'Children'.)

The initial reports of MIS-C emerged from the United Kingdom in April 2020 [2,3]. Since then, there have been reports of similarly affected children in other parts of the world, including Europe, Canada, the United States, and South Africa [4-6,8-11,14,25-28]. Notably, there have been disproportionately few reports of MIS-C from China and other Asian countries with high rates of COVID-19 early in the pandemic [29].

While some children with MIS-C meet criteria for complete or incomplete Kawasaki disease (KD) (see 'Clinical manifestations' below), the epidemiology differs from that of classic KD. Most MIS-C cases have occurred in older children (≥5 years of age) and adolescents [2,8-11,16,25,26,30,31]. Black and Hispanic children were initially disproportionally affected [11,14,32], although this was probably due to increased risk of exposure to and infection with SARS-CoV-2, not increased risk for MIS-C, since rates have varied with subsequent waves [17]. By contrast, classic KD typically affects infants and young children and has a higher incidence in East Asia and in children of Asian descent. (See "Kawasaki disease: Epidemiology and etiology", section on 'Epidemiology'.)

The epidemiology of MIS-C also differs from that of severe acute COVID-19 illness in children, which more often occurs in children with underlying health problems. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Risk factors for severe disease'.)

The first report of MIS-C was a series of eight children seen at a tertiary center in South East England [2]. In subsequent larger case series from the United Kingdom and the United States, >70 percent of affected children were previously healthy [11,32]. The most common comorbidities were obesity and asthma. The median age was 8 to 11 years (range 1 to 20 years). There have been rare reports of an illness resembling MIS-C occurring in adults [33]. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for rheumatologic disease'.)

There is a lag of several weeks between the peak of COVID-19 cases within communities and the rise of MIS-C cases [8,9,11,14,34]. For example, in London, the peak of COVID-19 cases occurred in the first to second weeks of April, while the spike of MIS-C cases occurred in the first to second week of May [9,34]. This three- to four-week lag coincides with the timing of acquired immunity, suggesting that MIS-C represents a postinfectious complication of the virus rather than acute infection.

PATHOPHYSIOLOGY — The pathophysiology of MIS-C is not well understood.

●Immune dysregulation – It has been suggested that the syndrome results from an abnormal immune response to the virus, with some clinical similarities to Kawasaki disease (KD), macrophage activation syndrome (MAS), and cytokine release syndrome. However, based on the available studies, MIS-C appears to have an immunophenotype that is distinct from KD and MAS [35,36]. The exact mechanisms by which SARS-CoV-2 triggers the abnormal immune response are unknown. A postinfectious process is suggested based on the timing of the rise of these cases relative to the peak of COVID-19 cases in communities, as discussed above. (See 'Epidemiology' above.)

Preliminary studies suggest that patients with severe MIS-C have persistent immunoglobulin G (IgG) antibodies with enhanced ability to activate monocytes [37], persistent cytopenias (particularly T cell lymphopenia) [35,36,38], and greater activation of CD8+ T cells [38] that differ from findings in acute COVID-19 infection. The certainty of these findings is limited due to the small number of patients in these studies.

Understanding the mechanisms of the exaggerated immune response in MIS-C is an area of active investigation. The pathophysiology of KD, MAS, and cytokine release syndrome are discussed separately. (See "Kawasaki disease: Epidemiology and etiology", section on 'Immunologic response' and "Cytokine release syndrome (CRS)", section on 'Pathophysiology'.)

●SARS-CoV-2 virus – Many affected children have negative polymerase chain reaction (PCR) testing for SARS-CoV-2 but have positive serology, a finding that further supports the hypothesis that MIS-C is related to immune dysregulation occurring after acute infection has passed. However, some children do have positive PCR testing. In the early case series, there were 783 children in whom both PCR and serology were performed [8,9,11,27,30,39]. Of these, 60 percent had positive serology with negative PCR, 34 percent were positive on both tests, and 5 percent were negative on both tests.

A study examining SARS-CoV-2 viral sequences from 11 children with MIS-C did not detect any differences compared with the viral sequences from children with acute COVID-19 without MIS-C [40]. These preliminary data suggest that viral factors are less likely to explain why some children develop multisystem inflammation following SARS-CoV-2 infection, while others do not. It is more likely that host factors are responsible for the abnormal inflammatory response in MIS-C.

Additional details of the virology of SARS-CoV-2 and the immune response are provided separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Virology'.)

●Mechanisms of myocardial injury – The mechanisms of myocardial injury in MIS-C are not well characterized. Possible causes include injury from systemic inflammation, acute viral myocarditis, hypoxia, stress cardiomyopathy, and, rarely, ischemia caused by coronary artery (CA) involvement [41]. Cardiac dysfunction may result from a combination of these mechanisms in some patients. Given the variability in clinical presentation, it is likely that different mechanisms are responsible in different patients.

There are limited data characterizing cardiac histopathology in MIS-C. In a report of a fatal case of MIS-C, autopsy findings were notable for evidence of myocarditis, pericarditis, and endocarditis characterized by inflammatory cell infiltration [42]. In addition, SARS-CoV-2 virus was detected in cardiac tissue by electron microscopy and PCR. However, some clinical features in this patient were uncharacteristic of MIS-C (most notably, there was severe pulmonary involvement), and it is possible that these autopsy findings are more reflective of severe acute COVID-19 rather than MIS-C. As discussed below, there is considerable overlap in the presentation of MIS-C and severe acute COVID-19. (See 'Spectrum of disease' below.)

Mechanisms of myocardial injury in adult patients with COVID-19 are discussed separately. (See "COVID-19: Cardiac manifestations in adults", section on 'Etiology'.)

CLINICAL MANIFESTATIONS

Onset of symptoms — In children who have a known history of documented or suspected COVID-19, the usual duration between acute infection and onset of MIS-C symptoms is two to six weeks. However, rare cases of MIS-C occurring >6 weeks after the acute SARS-CoV-2 infection have been reported [43]. In such cases, thorough investigation for other causes of the presentation needs to be undertaken. In many cases in 2020, the duration of time between acute infection and onset of MIS-C symptoms was unknown because the child was asymptomatic at the time of acute infection. However, due to increased surveillance testing, patients in the later surges of MIS-C more often knew about their exposure and/or date of positive testing. (See 'Epidemiology' above.)

Presenting symptoms — The relative frequencies of various presenting symptoms in the available case series were as follows (table 1) [9,11,14,27,31,32,44-47]:

●Fever, usually persistent (median duration four to six days) – 100 percent

●Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) – 60 to 100 percent

●Rash – 45 to 76 percent

●Conjunctivitis – 30 to 81 percent

●Mucous membrane involvement (red or swollen lips, strawberry tongue) – 27 to 76 percent

●Neurocognitive symptoms (headache, lethargy, confusion) – 29 to 58 percent

●Respiratory symptoms – 21 to 65 percent

●Sore throat – 10 to 16 percent

●Myalgia – 8 to 17 percent

●Swollen hands/feet – 9 to 16 percent

●Lymphadenopathy – 6 to 16 percent

Common presenting symptoms include:

●Fever – Most patients present with three to five days of fever, though fewer days of fever have been reported. In one series of 186 patients, 10 percent had three days of fever, 12 percent had four days, and 78 percent had ≥5 days [11].

●Gastrointestinal symptoms – Gastrointestinal symptoms (abdominal pain, vomiting, diarrhea) are particularly common and prominent, with the presentation in some children mimicking appendicitis [28,30,48,49]. Some children have been noted to have terminal ileitis on abdominal imaging and/or colitis on colonoscopy. (See 'Other imaging findings' below.)

●Cardiorespiratory symptoms – As discussed below, cardiac involvement is common (see 'Echocardiography' below). Respiratory symptoms (tachypnea, labored breathing), when present, may be due to shock or cardiogenic pulmonary edema. Cough is uncommon. Though some children require supplemental oxygen or positive pressure ventilation for cardiovascular stabilization, severe pulmonary involvement (eg, acute respiratory distress syndrome) is not as prominent a feature.

●Neurocognitive symptoms – Neurocognitive symptoms are common and may include headache, lethargy, confusion, or irritability. A minority of patients present with more severe neurologic manifestations, including encephalopathy, seizures, coma, stroke, meningoencephalitis, muscle weakness, and brainstem and/or cerebellar signs [11,50,51]. In a report of 616 patients with MIS-C, 20 percent had documented neurologic involvement [51]. Life-threatening neurologic conditions occurred in 20 patients (3 percent), including severe encephalopathy (n = 8), central nervous system demyelination (n = 6), stroke (n = 3), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1).

Clinical findings — Common clinical findings reported in the available case series include (table 1) [11,27,31,32,41,42,50,52,53]:

●Shock – 32 to 76 percent

●Mucocutaneous findings (red or swollen lips, strawberry tongue) – 27 to 76 percent

●Criteria met for complete Kawasaki disease (KD) (table 2) – 22 to 64 percent

●Myocardial dysfunction (by echocardiogram and/or elevated troponin or brain natriuretic peptide [BNP]) – 51 to 90 percent

●Arrhythmia – 12 percent

●Acute respiratory failure requiring noninvasive or invasive ventilation – 28 to 52 percent

●Acute kidney injury (most cases were mild) – 8 to 52 percent

●Serositis (small pleural, pericardial, and ascitic effusions) – 24 to 57 percent

●Hepatitis or hepatomegaly – 5 to 21 percent

●Encephalopathy, seizures, coma, or meningoencephalitis – 6 to 7 percent

Different case definitions were used in different studies, which may explain some of the variability in the reported frequency of these findings. It is apparent that there is a wide spectrum of disease severity (see 'Spectrum of disease' below). Initial smaller case series largely reported the most severe end of the spectrum, resulting in a high reported incidence of shock, myocardial involvement, and respiratory failure. It is possible that as recognition of milder forms of MIS-C increases, the incidence of shock, left ventricular (LV) dysfunction, respiratory failure, and acute kidney injury will be lower.

Laboratory findings — Laboratory abnormalities noted in the available case series include (table 1) [2,5,8,11,27,30,32,39,54,55]:

●Abnormal blood cell counts, including:

•Lymphocytopenia – 80 to 95 percent

•Neutrophilia – 68 to 90 percent

•Mild anemia – 70 percent

•Thrombocytopenia – 31 to 80 percent

●Elevated inflammatory markers (often, these are markedly elevated), including:

•C-reactive protein (CRP) – 90 to 100 percent

•Erythrocyte sedimentation rate (ESR) – 75 to 80 percent

•D-dimer – 67 to 100 percent

•Fibrinogen – 80 to 100 percent

•Ferritin – 55 to 76 percent

•Procalcitonin – 80 to 95 percent

•Interleukin (IL) 6 – 80 to 100 percent

●Elevated cardiac markers:

•Troponin – 50 to 90 percent

•BNP or N-terminal pro-BNP (NT-pro-BNP) – 73 to 90 percent

●Hypoalbuminemia – 48 to 95 percent

●Mildly elevated liver enzymes – 62 to 70 percent

●Elevated lactate dehydrogenase – 10 to 60 percent

●Hypertriglyceridemia – 70 percent

Laboratory markers of inflammation appear to correlate with severity of illness [9,56]. For example, in one series, children who developed shock had higher CRP values (mean 32.1 versus 17.6 mg/dL), higher neutrophil counts (16 versus 10.8 x 10⁹/L), lower lymphocyte counts (0.7 versus 1.3 x 10⁹/L), and lower serum albumin (2.2 versus 2.7 g/dL) compared with children without shock [9]. In addition, children with shock more commonly had elevated cardiac markers.

Echocardiography — Echocardiographic findings may include [30,57-59]:

●Depressed LV function

●Coronary artery (CA) abnormalities, including dilation or aneurysm

●Mitral regurgitation

●Pericardial effusion

Cardiac involvement is common in MIS-C. In several large case series, approximately 30 to 40 percent of children had depressed LV function and 8 to 24 percent had CA abnormalities [9,11,27,31,59]. These reports included patients with severe MIS-C as well as milder cases. Case series including only severely affected patients reported considerably higher rates of depressed LV function (approximately 50 to 60 percent) and CA abnormalities (approximately 20 to 50 percent) [9,32,41]. As discussed below, cardiac involvement is a key feature that helps to distinguish MIS-C from severe acute COVID-19. (See 'Differentiating MIS-C and acute COVID-19' below.)

In a study that included 503 patients with MIS-C who underwent echocardiography, 34 percent had depressed LV ejection fraction (LVEF) and 13 percent had CA aneurysms [31]. Among patients with depressed LV function, LV was mildly depressed in 55 percent, moderately depressed in 23 percent, and severely depressed in 22 percent. Most CA aneurysms (93 percent) were mild; 7 percent were moderate; and there were no large or giant CA aneurysms. In 91 percent of patients, LV function normalized within 30 days, and nearly all patients with available 90-day follow-up data had normal LVEF. Outcomes for CA aneurysms were similarly favorable, regressing to normal (Z-score <2.5) in more than three-quarters of affected patients within 30 days and in all patients with available 90-day follow-up data.

In another study describing echocardiographic findings in 286 children with MIS-C, 34 percent had depressed LVEF, 42 percent had mild to moderate mitral regurgitation, 6 percent had mild to moderate tricuspid regurgitation, and 28 percent had pericardial effusions [59]. Cardiac magnetic resonance imaging (MRI) was performed in 42 patients and showed evidence of myocardial edema (ie, T2 hyperintensity) in one-third of patients who were evaluated; late gadolinium enhancement was seen in 14 percent.

In a study examining echocardiographic findings in 28 children with MIS-C compared with 20 children with classic KD, LV systolic and diastolic function were worse than in classic KD, but CA involvement was less common [57]. Functional parameters correlated with biomarkers of myocardial injury. During the subacute period, LV systolic function usually normalized over short-term follow-up, but diastolic dysfunction persisted in a subset of patients.

Several studies have reported abnormal strain patterns in patients with LV dysfunction [58,60]. In one small study involving 20 patients with MIS-C who underwent both echocardiography and cardiac MRI, almost all patients displayed abnormal strain and tissue Doppler indices at the time of admission and one-half had depressed LVEF [58]. On serial imaging, LVEF deteriorated before improving at discharge, with the worst cardiac function occurring a median of seven days after admission. Cardiac MRI was performed at a median of 20 days after admission, at which time LV function remained mildly depressed (EF <50 percent) in 20 percent. Cardiac MRI detected abnormal strain in all patients, myocardial edema in 50 percent, and a subendocardial infarct in one patient.

Other imaging findings — Findings on diagnostic imaging may include (table 1) [2,8,9,11,30,39,61]:

●Chest radiograph – Many patients had normal chest radiographs. Abnormal findings included pleural effusions, patchy consolidations, focal consolidation, and atelectasis. In a report describing findings in children with MIS-C (n = 539) compared with children with severe acute COVID-19 (n = 577), approximately one-third of patients in each group had infiltrates on the initial chest radiograph; however, patients with MIS-C more commonly had pleural effusions (27 versus 8 percent) [31]. Similar findings were noted in a smaller case series, in which ground-glass opacities were the most common finding in both groups [62].

●Computed tomography (CT) of chest – Chest CT (when obtained) generally had findings similar to those on chest radiograph. Ground-glass opacification was a common finding.

●Abdominal imaging – Findings on abdominal ultrasound or CT included free fluid, ascites, and bowel and mesenteric inflammation including terminal ileitis, mesenteric adenopathy/adenitis, and pericholecystic edema [48,63].

EVALUATION — Patients with suspected MIS-C should have laboratory studies performed to look for evidence of inflammation and to assess cardiac, kidney, and hepatic function (algorithm 1). Testing should also include polymerase chain reaction (PCR) and serology for SARS-CoV-2. In addition, patients should be assessed for other infectious or noninfectious conditions that may have a similar presentation.

Our approach outlined below is generally consistent with published guidance from the American College of Rheumatology, the American Academy of Pediatrics, and the pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) National Consensus Management Study Group in the United Kingdom [64-66].

Laboratory testing — The initial laboratory evaluation of a child with suspected MIS-C depends on the presentation (algorithm 1).

●Severe symptoms – For children with severe symptoms, we perform the following tests:

•Complete blood count (CBC) with differential

•C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR; procalcitonin is optional)

•Ferritin

•Liver function tests and lactate dehydrogenase

•Serum electrolytes and kidney function tests

•Urinalysis

•Coagulation studies (prothrombin time/international normalized ratio, activated partial thromboplastin time, D-dimer, fibrinogen)

•Troponin

•Brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-pro-BNP)

Inflammatory markers (CRP, ESR, procalcitonin, ferritin) are measured at the time of admission and then serially to monitor progression. The ESR is not useful for serial monitoring, because most patients with MIS-C are treated with intravenous immune globulin (IVIG), which can elevate the ESR. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Intravenous immune globulin'.)

Cardiac markers (troponin and BNP) should also be monitored serially if they are elevated on initial evaluation or if the patient's cardiac status worsens.

●Mild to moderate symptoms – For patients presenting with fever for ≥3 days and who are well-appearing (ie, normal vital signs and reassuring physical examination) with only mild to moderate symptoms suggestive of MIS-C, we suggest a more limited evaluation initially. We typically start with the following:

•CBC with differential

•CRP

•Serum electrolytes and kidney function tests

If these results are abnormal, additional testing is performed (listed above).

The clinician should also assess for other common causes of fever (eg, streptococcal pharyngitis, mononucleosis, influenza, respiratory syncytial virus), particularly with children and adolescents back to in-person school and common childhood infections circulating widely. Having an alternative diagnosis essentially excludes MIS-C, particularly in an otherwise well-appearing child. If additional testing does not identify another cause, the patient should be monitored for evolving signs of MIS-C. (See 'Differential diagnosis' below.)

In a report of 67 children who underwent outpatient laboratory evaluation for febrile illness, findings that were more common in patients with MIS-C (n = 44) compared with those with other febrile illnesses (n = 23) included lymphopenia, thrombocytopenia, and markedly elevated CRP [67]. In another report of 39 patients who underwent evaluation for MIS-C at a single center, alternate diagnoses made among children found not to have MIS-C included staphylococcal toxic shock syndrome, lymphadenitis, urinary tract infection, Epstein-Barr virus, Lyme disease, herpangina, human metapneumovirus upper respiratory infection, and intussusception with small bowel perforation [68]. (See 'Differential diagnosis' below.)

Testing for SARS-CoV-2 — All patients with suspected MIS-C should be tested for SARS-CoV-2, including both serology and reverse transcription PCR (RT-PCR) on a nasopharyngeal swab [52]. However, positive serologies for SARS Co-V-2 are no longer as informative for a diagnosis of MIS-C given widespread native infections as well as increasing vaccination. The baseline rate of seropositivity for SARS-CoV-2 has increased significantly. Thus, there will be an increasing number of febrile children who may incidentally have positive serologies.

As previously discussed, approximately 60 percent of patients have positive serology with negative PCR, and approximately 30 to 35 percent are positive on both tests. (See 'Pathophysiology' above.)

A minority of patients (approximately 5 to 10 percent) have negative results on both tests. In these cases, the diagnosis of MIS-C requires an epidemiologic link to SARS-CoV-2 (eg, exposure to an individual with known COVID-19 within the four weeks prior to the onset of symptoms). (See 'Case definition' below.)

Quantitative SARS-CoV-2 serology may help distinguish MIS-C from acute COVID-19 since higher titers are seen in MIS-C [69]. (See 'Differentiating MIS-C and acute COVID-19' below.)

It should be noted that several different serologic tests are available, and their sensitivity and specificity are variable. (See "COVID-19: Diagnosis", section on 'Serology to identify prior/late infection'.)

Testing for SARS-CoV-2 is summarized in the table (table 3) and discussed in greater detail separately. (See "COVID-19: Diagnosis".)

Testing for other pathogens — Testing for other viral and bacterial pathogens includes [55]:

●Blood culture

●Urine culture

●Throat culture

●Stool culture

●Nasopharyngeal aspirate or throat swab for respiratory viral panel

●Epstein-Barr virus serology and PCR

●Cytomegalovirus serology and PCR

●Enterovirus PCR

●Adenovirus PCR

This testing is appropriate for children with moderate to severe MIS-C (ie, children who require hospitalization). However, an extensive infectious work-up is generally not necessary in well-appearing children presenting with mild symptoms. In such patients, microbiologic testing should be done as clinically indicated according to the age of the child and their specific symptoms (eg, throat culture if the child has sore throat, respiratory viral panel if there are respiratory symptoms). Testing should follow the same general approach as is used for fever evaluation more broadly. (See "Fever without a source in children 3 to 36 months of age: Evaluation and management".)

Detection of other respiratory pathogens (eg, rhinovirus, influenza, respiratory syncytial virus) in nasopharyngeal specimens does not exclude COVID-19.

Additional testing for other pathogens may be warranted, depending on the geographic location and exposure history. This may include:

●Murine typhus [70]

●Leptospirosis serology

Cardiac testing — In addition to troponin and BNP/NT-pro-BNP levels, the cardiac evaluation of a patient with suspected MIS-C includes a 12-lead electrocardiogram (ECG) and echocardiography [41]. Echocardiography is also recommended for children with documented SARS-CoV-2 who do not meet all criteria for MIS-C but who have either shock or features consistent with incomplete or complete Kawasaki disease (KD).

Children and adolescents with mild COVID-19 without signs of systemic inflammation are unlikely to have coronary artery (CA) changes or myocarditis. In such children, echocardiography is generally not necessary but may be considered if there are specific clinical concerns.

●ECG findings – In children with MIS-C, baseline ECGs may be nonspecific (eg, repolarization changes with abnormal ST- or T-wave segments), though arrhythmia and heart block have been described [2,53,59,71]. First-degree atrioventricular block occurs in approximately 20 percent of hospitalized patients [72]. Telemetry monitoring is appropriate in such cases since this can progress to high-degree atrioventricular block.

●Echocardiographic evaluation – The echocardiographic evaluation includes the following:

•Quantitative assessment of LV size and systolic function (LV end-diastolic volume, ejection fraction [EF])

•Qualitative assessment of right ventricular systolic function

•CA abnormalities (dilation or aneurysm)

•Assessment of valvar function

•Evaluation for the presence and size of pericardial effusion

•Evaluation for intracardiac thrombosis and/or pulmonary artery thrombosis, particularly apical thrombus in severe LV dysfunction

•Strain imaging and LV diastolic function (optional)

CA assessment is based on Z-scores, with the same classification schema used in KD (table 4), as discussed separately. (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Echocardiography'.)

The timing of follow-up echocardiography is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Follow-up'.)

Echocardiographic findings are described above. (See 'Echocardiography' above.)

CASE DEFINITION

CDC and WHO case definitions — The criteria used for case definitions has varied between different health agencies [4,6,55,73,74]. However, the Council of State and Territorial Epidemiologists/Centers for Disease Control (CSTE/CDC) MIS-C case definition that was implemented as of January 1, 2023 aligns closely with the World Health Organization (WHO) MIS-C criteria [6,73,74]. Both definitions require fever (though they differ with respect to duration), elevated inflammatory markers, at least two signs of multisystem involvement, evidence of SARS-CoV-2 infection or exposure, and exclusion of other potential causes. The case definitions put forth by the CDC and the WHO are summarized in the table (table 5). Whereas the 2020 CDC MIS-C case definition did not designate Kawasaki disease (KD) as an alternative diagnosis, the CTSE/CDC MIS-C case definition does specify KD as an alternative diagnosis that should trigger reporting to the CDC KD passive surveillance system. The CSTE/CDC MIS-C case definition was constructed in part to facilitate data extraction by nonclinically trained public health workers. Accordingly, the new definition has fewer organ systems to define multisystem involvement and has simpler definitions for the individual criteria. The CDC case definition requires that the child have severe symptoms requiring hospitalization, whereas the WHO case definition does not. An analysis of application of the two definitions to two large cohorts of MIS-C patients did not reveal significant differences in the number of children meeting the definitions [75].

Spectrum of disease — Initial reports of MIS-C described mostly severely affected children. However, as more is learned about COVID-19 and MIS-C in children, it is becoming apparent that the spectrum of COVID-19-associated disease ranges from mild to severe [9,39]. It remains unclear how common each presentation is, how frequently children progress from mild to more severe manifestations, and what the risk factors are for such progression. In addition, clinicians are probably identifying MIS-C earlier, and there may be differences in severity due to SARS CoV-2 variants, vaccination, or other environmental factors [16-21].

In a study of 570 children with MIS-C reported to the CDC through July 2020, investigators used a statistical modeling technique called latent class analysis to identify different subtypes of the syndrome [27]. The study had important limitations, chiefly that it relied on state public health reports with limited and incomplete clinical data. Nevertheless, the analysis identified three subgroups based on underlying similarities:

●MIS-C without overlap with KD or acute COVID-19 – This group comprised 35 percent of the cohort. Nearly all patients in this group had cardiovascular and gastrointestinal involvement, and one-half had ≥4 additional organ systems involved. Patients in this group were more likely to have shock, cardiac dysfunction, and markedly elevated C-reactive protein (CRP) and ferritin. Nearly all patients in this group had positive SARS-CoV-2 serology (with or without positive polymerase chain reaction [PCR]).

●MIS-C overlapping with KD – This group comprised 35 percent of the cohort. Children in this group were younger than the other two groups (median age 6 versus 9 and 10 years, respectively). They more commonly had rash and mucocutaneous involvement and less commonly had shock or myocardial dysfunction. Approximately two-thirds of patients in this group had positive SARS-CoV-2 serology with negative PCR, and one-third were positive on both tests. (See 'Differentiating MIS-C and Kawasaki disease' below.)

●MIS-C overlapping with severe acute COVID-19 – This group comprised 30 percent of the cohort. Many children in this group presented with respiratory involvement, including cough, shortness of breath, pneumonia, and acute respiratory distress syndrome. Most of these children had positive SARS-CoV-2 PCR without seropositivity. The mortality rate was higher in this subgroup compared with the other two subgroups (5.3 versus 0.5 and 0 percent, respectively). In our experience, patients in this category tend to be older than those with KD-like features, and they more commonly have comorbidities. (See 'Differentiating MIS-C and acute COVID-19' below.)

Importantly, the incidence of coronary artery (CA) abnormalities was similar in all three subgroups (21, 16, and 18 percent, respectively), highlighting the importance of routine echocardiography in all children with MIS-C, regardless of apparent subphenotype. (See 'Cardiac testing' above.)

Differentiating MIS-C and Kawasaki disease — There is some phenotypic overlap with MIS-C and KD. In the available case series, approximately 40 to 50 percent of children with MIS-C met criteria for complete or incomplete KD (table 2) [8,9,11,14,76]. In particular, there are similarities between MIS-C and the well-recognized KD shock syndrome (KDSS), which occurs in approximately 5 percent of KD cases and is characterized by prominent cardiovascular involvement. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Complications", section on 'Shock' and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Features of Kawasaki disease'.)

Key distinctions between MIS-C and KD include:

●MIS-C commonly affects older children and adolescents, whereas classic KD typically affects infants and young children. (See 'Epidemiology' above.)

●In MIS-C, Black and Hispanic children appear to be disproportionally affected, and Asian children account for only a small number of cases. By contrast, classic KD has a higher incidence in East Asia and in children of Asian descent. (See 'Epidemiology' above and "Kawasaki disease: Epidemiology and etiology", section on 'Epidemiology'.)

●Gastrointestinal symptoms (particularly abdominal pain) are very common in MIS-C, whereas these symptoms are less prominent in classic KD. (See 'Presenting symptoms' above.)

●Myocardial dysfunction and shock occur more commonly in MIS-C compared with classic KD [11]. Though, as mentioned above, these are characteristic findings in KDSS. (See 'Clinical findings' above.)

●Inflammatory markers (especially CRP, ferritin, and D-dimer) tend to be more elevated in MIS-C compared with classic KD and KDSS [9]. Importantly, absolute lymphocyte and platelet counts tend to be lower in MIS-C compared with KD [64]. (See 'Laboratory findings' above.)

●CA aneurysms appear to be less frequent and resolve more quickly in MIS-C than what is typically seen in KD [31,77].(See 'Other imaging findings' above.)

As the COVID-19 pandemic has evolved, distinguishing patients with KD-like MIS-C from those with true KD has become more difficult. The baseline incident rate of true KD continues as more children are exposed to SARS-CoV-2 and/or are vaccinated, with subsequent seroconversion. Accordingly, classifying patients who have KD features and positive antibodies as MIS-C versus KD is challenging. Quantitative antibody was helpful in making the distinction earlier in the pandemic [69]. Ultimately, better characterizing the distinct immunophenotypes of these syndromes may help clinicians distinguish one from the other [35,36]. Importantly, any child who meets criteria for KD should be treated with intravenous immune globulin (IVIG) to provide the best protection against CA aneurysms in KD. (See 'Testing for SARS-CoV-2' above and "Kawasaki disease: Initial treatment and prognosis", section on 'Treatment for all patients' and 'Pathophysiology' above.)

Differentiating MIS-C and acute COVID-19 — The clinical features of MIS-C and severe acute COVID-19 overlap. However, differing patterns of clinical presentation and organ system involvement may help differentiate MIS-C from severe acute COVID-19 [27,31,78]:

●Most MIS-C cases have occurred in children who were previously healthy, whereas most cases of severe acute COVID-19 occur in children with underlying health problems. (See 'Epidemiology' above.)

●Children with MIS-C may have a history of known or suspected SARS-CoV-2 infection in the weeks preceding the onset of febrile/inflammatory symptoms.

●The pattern of organ system involvement differs [27,31]:

•Severe pulmonary involvement (ie, pneumonia, acute respiratory distress syndrome) is a prominent feature in severe acute COVID-19. While respiratory symptoms are common in patients with MIS-C, they are more often secondary to shock and/or impaired cardiac function.

•Myocardial dysfunction and shock are more common in MIS-C than in severe acute COVID-19.

•Gastrointestinal symptoms (particularly abdominal pain) are more common in MIS-C.

•Mucocutaneous findings are common in MIS-C and are rarely seen in severe acute COVID-19.

●Inflammatory markers (CRP, ferritin, and D-dimer) tend to be more elevated in MIS-C compared with severe acute COVID-19 [31]. In addition, lymphopenia and thrombocytopenia are more common in MIS-C. (See 'Laboratory findings' above.)

●SARS-CoV-2 antibody titers are higher in patients with MIS-C compared with acute COVID-19 [69].

In a multicenter case series of 1116 pediatric patients hospitalized with MIS-C (n = 539) or severe acute COVID-19 (n = 577), children with MIS-C were younger (median age 8.9 versus 11.7 years), less likely to have underlying medical conditions (31 versus 62 percent), and more likely to have multiple organ systems involved (median 4 versus 2) [31]. More than one-half of patients with MIS-C had combined cardiovascular and respiratory involvement, and 24 percent had respiratory involvement without cardiovascular involvement. Among children with severe acute COVID-19, 71 percent had respiratory involvement without cardiovascular involvement, and only 9 percent had combined cardiorespiratory involvement.

The clinical presentation of acute COVID-19 in children is discussed in detail separately. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Clinical manifestations'.)

CASE REPORTING — Health care providers who have cared or are caring for patients younger than 21 years of age meeting MIS-C criteria (table 5) should report suspected cases to their local, state, or territorial health department. Additional information can be found on the Centers for Disease Control and Prevention (CDC) website and the World Health Organization (WHO) website.

DIFFERENTIAL DIAGNOSIS — In children presenting with signs and symptoms consistent with MIS-C, the differential diagnosis is broad and includes other infectious and inflammatory conditions:

●Kawasaki disease (KD) – Some children along the MIS-C spectrum meet criteria for complete or incomplete KD (table 2). Key distinctions between MIS-C and KD are discussed above. (See 'Differentiating MIS-C and Kawasaki disease' above.)

●Severe acute COVID-19 – The clinical features of MIS-C and severe acute COVID-19 overlap. Key distinctions between MIS-C and severe acute COVID-19 are discussed above. (See 'Differentiating MIS-C and acute COVID-19' above.)

●Bacterial sepsis – Bacterial sepsis is an important consideration in children presenting with fever, shock, and elevated inflammatory markers. For most patients with these manifestations, it is appropriate to obtain blood cultures and start empiric antibiotics pending culture results. Certain clinical features (eg, cardiac involvement, coronary artery [CA] abnormalities) may suggest the diagnosis of MIS-C rather than bacterial sepsis, but, ultimately, microbiologic tests (ie, SARS-CoV-2 testing, bacterial cultures) are necessary to make the distinction. (See "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis" and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Empiric antibiotic therapy'.)

●Toxic shock syndrome – Staphylococcal and streptococcal toxic shock syndromes share many similarities with MIS-C (table 6). Microbiologic tests (ie, SARS-CoV-2 testing, bacterial cultures) are necessary to make the distinction. (See "Staphylococcal toxic shock syndrome" and "Invasive group A streptococcal infection and toxic shock syndrome: Epidemiology, clinical manifestations, and diagnosis".)

●Appendicitis – As discussed above, many children with MIS-C present with fever associated with abdominal pain and vomiting (see 'Presenting symptoms' above). This can mimic the presentation of acute appendicitis. Abdominal imaging may be necessary to make the distinction. (See 'Other imaging findings' above and "Acute appendicitis in children: Clinical manifestations and diagnosis".)

●Other viral infections – Other viral pathogens that may manifest with multisystem involvement and/or myocarditis include Epstein-Barr virus, cytomegalovirus, adenovirus, and enteroviruses. These viruses rarely cause severe multisystem disease in immunocompetent children. Serology and polymerase chain reaction (PCR) testing can distinguish these from COVID-19-related MIS-C. (See "Clinical manifestations and treatment of Epstein-Barr virus infection" and "Overview of cytomegalovirus infections in children" and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection".)

●Other infections – Other infections that may present with persistent fevers and multisystem findings include Lyme disease and rickettsial infections (eg, murine typus, Rocky Mountain spotted fever) [70]. Appropriate serologies and PCR testing can distinguish these from COVID-19-related MIS-C. (See "Lyme disease: Clinical manifestations in children" and "Murine typhus" and "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Other spotted fever group rickettsial infections".)

●Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) – HLH and MAS are aggressive and life-threatening conditions that have some features in common with MIS-C. HLH/MAS are syndromes of excessive immune activation that can occur in previously healthy children (often triggered by an infection) and in children with underlying rheumatologic conditions. Most children with HLH/MAS are acutely ill with multiorgan involvement, cytopenias, liver function abnormalities, and neurologic symptoms. Cardiac and gastrointestinal involvement are less common, and neurologic symptoms are more prominent. The diagnosis of HLH/MAS requires specialized immunologic testing, as discussed separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Specialized testing' and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)

●Systemic lupus erythematosus (SLE) – SLE can present with fulminant multisystem illness. Such patients generally have considerable kidney and central nervous system involvement, which are not common features of MIS-C. In addition, though patients with SLE may present acutely with fulminant illness, most report feeling fatigued and unwell for a period of time prior to the onset of severe symptoms. This is not the case with MIS-C, in which most children are completely well prior to acute onset of febrile illness. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)

●Vasculitis – Vasculitides other than KD can present with fevers, rash, and elevated inflammatory markers. Rashes seen in COVID-19-associated illness can have an appearance that can mimic vasculitis (eg, pernio [chilblain] like lesions of acral surfaces, sometimes referred to as "COVID toes"), but they are not vasculitic. (See "Vasculitis in children: Evaluation overview" and "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kawasaki disease" and "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword[s] of interest.)

●Basics topics:

•(See "Patient education: COVID-19 and children (The Basics)".)

•(See "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)".)

•(See "Patient education: Kawasaki disease (The Basics)".)

SUMMARY AND RECOMMENDATIONS

●Overview – Coronavirus disease 2019 (COVID-19) in children is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults. Multisystem inflammatory syndrome in children (MIS-C) is an uncommon complication of COVID-19 that is characterized by prominent cardiovascular, gastrointestinal, and mucocutaneous signs and symptoms. (See 'Introduction' above.)

●Epidemiology – MIS-C appears to be a relatively rare complication of COVID-19 in children. MIS-C can occur at any age from infancy through late adolescence, but most cases have occurred in previously healthy children between the ages of 6 to 12 years. Cases of MIS-C typically peak several weeks after surges of COVID-19 in the community. (See 'Epidemiology' above.)

●Pathophysiology – The pathophysiology of MIS-C is not well understood. It is thought to result from an abnormal immune response to the virus, with some clinical similarities to Kawasaki disease (KD), macrophage activation syndrome (MAS), and cytokine release syndrome. However, MIS-C appears to have an immunophenotype that is distinct from KD and MAS. Most affected children have positive serology for SARS-CoV-2 with negative polymerase chain reaction (PCR), a finding that further supports the hypothesis that MIS-C is related to immune dysregulation occurring after acute infection has passed. However, some children do have positive PCR testing. (See 'Pathophysiology' above.)

●Clinical presentation – The clinical presentation of MIS-C may include persistent fevers, gastrointestinal symptoms (abdominal pain, vomiting, diarrhea), rash, and conjunctivitis. Patients typically present with three to five days of fever, followed by development of shock and/or multisystem involvement. Laboratory findings include lymphocytopenia, elevated inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], D-dimer), and elevated cardiac markers (troponin, brain natriuretic peptide [BNP]). Other clinical findings are summarized in the table (table 1). (See 'Clinical manifestations' above.)

●Evaluation – The approach to evaluating a child with suspected MIS-C is summarized in the algorithm (algorithm 1) and described in greater detail above. (See 'Evaluation' above.)

●Case definition – Case definitions for MIS-C are summarized in the table (table 5). There is a spectrum of disease severity. (See 'Case definition' above and 'Spectrum of disease' above.)

●Differential diagnosis – Important considerations in the differential diagnosis of MIS-C include KD not related to SARS-CoV-2, bacterial sepsis, severe acute COVID-19, toxic shock syndrome, and appendicitis. Other less common conditions that can present with similar manifestations are discussed above. (See 'Differential diagnosis' above.)