Multisystem Inflammatory Syndrome in Children (MIS-C)

Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious hyperinflammatory condition that typically develops 2-6 weeks after SARS-CoV-2 infection or exposure — often even when the preceding infection itself was mild, asymptomatic, or unrecognized — presenting with persistent fever, markedly elevated inflammatory markers, and dysfunction across multiple organ systems.^[1][2]

The single most important evidence-based treatment shift in this chapter: IVIG 2 g/kg plus an upfront corticosteroid, started together, is now the preferred first-line approach — a real change from earlier practice that used IVIG alone and reserved corticosteroids for treatment failure. In a propensity-matched cohort, the combination reduced treatment failure from 38% (IVIG alone) to 9%, alongside less need for second-line therapy, less hemodynamic support, less post-treatment left ventricular dysfunction, and a shorter PICU stay.^[4][5][6] Low-dose aspirin is given to essentially every patient for antithrombotic prophylaxis, reflecting MIS-C's hypercoagulable state, rather than the higher anti-inflammatory dosing used acutely in classic Kawasaki disease.^[6] Biologic escalation (anakinra or infliximab) is reserved for IVIG/corticosteroid-refractory disease — and, importantly, refractory MIS-C is not routinely managed by simply repeating IVIG, given the volume-overload and hemolytic-anemia risk of a second large infusion in a population already prone to myocardial dysfunction.^[5] Because shock occurs in a genuinely much larger share of MIS-C patients than classic Kawasaki disease, early recognition of hypoperfusion and a low threshold for critical-care involvement are central themes throughout this chapter.^[3]

Epidemiology and timing

MIS-C skews toward school-age children and adolescents — a median age of roughly 7-9 years, spanning as young as infancy to age 20 — a genuinely older distribution than classic Kawasaki disease, whose mean age is around 3 years, with roughly three-quarters of cases under age 5.^[3] Onset typically follows SARS-CoV-2 infection or exposure by 2-6 weeks, and the preceding infection is frequently mild, asymptomatic, or entirely unrecognized by the family, which can make the temporal link easy to miss unless specifically asked about.^[1]

Three clinical presentations

The Canadian Paediatric Society frames MIS-C as presenting in one of three overlapping patterns, useful for organizing the clinical picture: fever with hyperinflammation (persistent fever with elevated inflammatory markers, without a dominant mucocutaneous or shock picture), a Kawasaki-disease-like presentation (meeting or approaching the classic KD mucocutaneous criteria — conjunctival injection, oral changes, rash, extremity changes, lymphadenopathy), and a shock presentation (hypotension or poor perfusion, sometimes resembling toxic shock syndrome).^[6] Gastrointestinal symptoms — abdominal pain, vomiting, diarrhea — are genuinely prominent across all three patterns, present in roughly 80% of MIS-C cases, and are comparatively uncommon in classic Kawasaki disease.^[3]

The WHO preliminary case definition

The World Health Organization's original scientific brief established the syndrome's international case definition: children and adolescents with fever, elevated inflammatory markers, and evidence of single or multi-organ dysfunction, together with evidence of current or recent SARS-CoV-2 infection or a likely contact, and after other obvious microbial causes of inflammation have been excluded.^[7] This preliminary framework remains broadly consistent with, but less granular than, the current CDC/CSTE surveillance definition below, which is the version used for the detailed criteria in this chapter.

The CDC/CSTE surveillance case definition (effective 2023)

All of the following are required, in the absence of a more likely alternative diagnosis:

^[2] SARS-CoV-2 evidence is required for a confirmed case (a positive molecular/NAAT or antigen test within 60 days before or during hospitalization, or SARS-CoV-2-specific antibodies associated with the current illness) or, for a probable case, close contact with a confirmed or probable COVID-19 case within the 60 days before hospitalization can substitute for direct laboratory evidence.^[2] Important exclusion a documented final diagnosis of Kawasaki disease is specifically considered an alternative diagnosis under this definition — such cases should not be classified or reported as MIS-C, underscoring that these two conditions are meant to be distinguished, not conflated.^[2]

• Age: MIS-C skews toward school-age children and adolescents (median roughly 7-9 years), a genuinely older distribution than classic Kawasaki disease, which predominantly affects children under 5.^[3]
• Timing: onset typically follows SARS-CoV-2 infection or exposure by 2-6 weeks, often even when the preceding infection itself was mild, asymptomatic, or unrecognized by the family.^[1]
• Unvaccinated or incompletely vaccinated status against COVID-19 at the time of infection — vaccination reduces the risk of subsequent MIS-C, a genuinely useful point when counselling families who are hesitant about ongoing COVID-19 vaccination.^[1]
• No single genetic or ethnic predisposition is established for MIS-C in the way East Asian ancestry is associated with classic Kawasaki disease; MIS-C's demographic pattern has differed across surveillance cohorts and continues to be actively studied.^[3]
• A clinically convincing shock or Kawasaki-like presentation temporally linked to COVID-19 should itself be treated as a risk marker for MIS-C requiring urgent work-up, rather than waiting for additional risk factors to accumulate.^[6]

Diagnosis rests on clinical, laboratory, and epidemiologic criteria together

See Recognize the Condition for the complete WHO and CDC/CSTE case-definition criteria. No single test is diagnostic; the diagnosis requires the fever/severity/inflammation criteria, at least 2 of the 5 organ-system categories, and SARS-CoV-2 laboratory or epidemiologic-linkage evidence, together with exclusion of a more likely alternative diagnosis.^[2]

Laboratory findings

Beyond the CRP ≥3.0 mg/dL (30 mg/L) case-definition threshold, MIS-C typically shows markedly elevated ferritin, elevated D-dimer and other markers of coagulopathy, and — in a pattern that is a genuinely useful bedside distinguisher from Kawasaki disease — lymphopenia and thrombocytopenia rather than Kawasaki disease's characteristic subacute-phase thrombocytosis.^[3][2] Mean ferritin has been reported around 610 ng/mL in MIS-C versus roughly 200 ng/mL in Kawasaki disease; mean lymphocyte counts around 800/µL in MIS-C versus roughly 2,800/µL in Kawasaki disease; and platelet counts around 151,000/µL (thrombocytopenic) in MIS-C versus a Kawasaki disease pattern of thrombocytosis exceeding 450,000/µL in the subacute phase.^[3]

Cardiac evaluation

Obtain baseline echocardiography, ECG, troponin, and BNP/NT-proBNP in every patient at diagnosis, without delaying IVIG/corticosteroid treatment to do so.^[6][1] Troponin and BNP/NT-proBNP elevations are typically far more pronounced in MIS-C than in Kawasaki disease, reflecting genuine myocardial involvement rather than coronary vasculitis alone — mean troponin around 45 ng/L (range 8-294) in MIS-C versus minimal elevation in Kawasaki disease, and mean BNP around 788 pg/mL in MIS-C versus roughly 41 pg/mL in Kawasaki disease.^[3] Coronary artery involvement can still occur in MIS-C (reported in roughly 16.5% of cases) but is generally less frequent and less severe than in untreated Kawasaki disease.^[3]

The central differential: MIS-C versus Kawasaki disease

These two conditions are related but genuinely distinct, and the CDC/CSTE case definition explicitly excludes a documented final diagnosis of Kawasaki disease from MIS-C classification.^[2] The table below summarizes the key distinguishing features; use it together with the SARS-CoV-2 evidence/exposure requirement, which Kawasaki disease does not share.

^[3] For the full Kawasaki disease diagnostic criteria, principal clinical features, and acute-phase management, see this platform's separate Kawasaki Disease chapter — it is deliberately not duplicated here.

Other differential diagnoses to exclude

Bacterial sepsis and toxic shock syndrome (staphylococcal/streptococcal), acute appendicitis or another surgical abdomen (given how prominent GI symptoms are in MIS-C), macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis from a cause other than MIS-C, acute COVID-19 pneumonia/myocarditis, and — in the adolescent age range — COVID-19-vaccine-associated myocarditis, which can present with some overlapping features but lacks MIS-C's multisystem/inflammatory-marker pattern and generally follows vaccination rather than infection.^[2][3]

• Control systemic hyperinflammation early and effectively — the combination approach (IVIG plus upfront corticosteroid) exists specifically to reduce treatment failure compared with IVIG alone.^[4]
• Recognize and treat shock or hemodynamic instability early — genuinely more common in MIS-C than in classic Kawasaki disease, and the complication most likely to drive ICU admission and short-term morbidity.^[3]
• Provide antithrombotic prophylaxis for essentially every patient given MIS-C's hypercoagulable state, and escalate to therapeutic anticoagulation in the subset at highest thrombosis risk.^[6][5]
• Reduce the risk and severity of coronary artery involvement, applying the same underlying principle as Kawasaki disease even though the absolute risk and pattern differ.^[3]
• Identify treatment failure early and escalate appropriately — favouring corticosteroid intensification or a biologic over reflexively repeating IVIG, given the volume-overload/hemolytic-anemia risk of a second large infusion in a population prone to myocardial dysfunction.^[5]
• Assess cardiac function and fluid status before the first IVIG infusion, not only after a complication develops.^[5]
• Support the family through a genuinely frightening, often ICU-level acute illness, including honest counselling that some aspects of MIS-C's long-term outcome data are still accumulating since it is a comparatively new condition.

Antithrombotic therapy — low-dose aspirin for essentially everyone

Start low-dose aspirin (3-5 mg/kg/day PO, maximum 81 mg/day) in essentially every MIS-C patient for antithrombotic prophylaxis, reflecting the hypercoagulable state of MIS-C, and continue until the platelet count has normalized and a follow-up echocardiogram beyond 4 weeks confirms normal coronary arteries.^[6]

Escalating antithrombotic therapy for higher thrombosis risk

For patients with a giant coronary aneurysm (Z-score ≥10), an ejection fraction under 35%, or a documented thrombus, escalate from aspirin alone to therapeutic anticoagulation (e.g. enoxaparin), specialist-directed.^[5]

Biologic escalation for refractory disease — and why a second IVIG dose is not the default

For inadequate response to IVIG plus corticosteroid, escalate to a biologic — anakinra is generally preferred, particularly with macrophage-activation-syndrome features, while infliximab is a reasonable alternative, particularly for a more Kawasaki-like or GI-predominant refractory phenotype; the choice between the two is specialist-directed.^[5] Do not reflexively repeat a full second dose of IVIG in refractory MIS-C the way a second IVIG dose is sometimes used in refractory Kawasaki disease — the large infused volume (roughly 40 mL/kg) carries a genuine risk of volume overload and hemolytic anemia, a risk that is amplified in MIS-C's much higher background rate of myocardial dysfunction. See Treatment Failure/Next Step for the full escalation pathway.^[5]

• Admit every patient with confirmed or probable MIS-C — given the substantially higher shock rate than Kawasaki disease, have a low threshold for ICU-level admission from the outset rather than only after deterioration.^[3]
• Assess cardiac function and fluid status before the first IVIG infusion in every patient, not only those who already look unwell — this specifically shapes whether a single 2 g/kg infusion or a divided 1 g/kg/day-over-2-days regimen is safer.^[5]
• For shock or significant hemodynamic instability: careful, judicious fluid resuscitation (rather than the more liberal boluses used in typical pediatric septic shock, given the higher prevalence of myocardial dysfunction), inotropic or vasopressor support as needed, and possible intubation/mechanical ventilation, managed in an ICU setting.^[6]
• Involve pediatric cardiology, critical care, and rheumatology or infectious diseases early and continuously — MIS-C management is genuinely multidisciplinary from the point of diagnosis, more so than typical Kawasaki disease.^[6]
• Anticipate and monitor for fluid overload after large-volume IVIG in a patient with depressed ejection fraction; be prepared to add diuresis once the patient is hemodynamically stabilized (see Pharmacologic Treatment Options).
• Confirm the aspirin dose and its specific stop criterion (normalized platelets plus a ≥4-week echocardiogram confirming normal coronaries) are documented and communicated before discharge.^[6]
• Arrange the full serial echocardiography follow-up schedule and a first outpatient cardiology visit starting 2-3 weeks after discharge before the patient leaves hospital — do not leave this to be arranged later.^[6][1]
• Provide clear caregiver education: the deliberate, guideline-endorsed reason for using aspirin despite the usual Reye syndrome caution; the genuine value of ongoing COVID-19 vaccination in reducing the risk of a future MIS-C episode; and, for any child found to have coronary or ventricular abnormalities, honest counselling about the follow-up and antithrombotic therapy that will be needed.^[6][1]
• Arrange psychological support for families navigating a frightening acute illness, often involving an ICU stay, and — where relevant — an ongoing cardiac diagnosis.

Shock and ICU-level MIS-C — the most important special population in this chapter

Most MIS-C patients develop some degree of hypoperfusion or shock, versus a small minority (Kawasaki disease shock syndrome) in classic Kawasaki disease.^[3] This group needs early critical-care involvement, high-dose IV pulse corticosteroid rather than the low-to-moderate dose, careful/judicious fluid resuscitation given the higher prevalence of myocardial dysfunction, and inotropic/vasopressor support.^[6][5]

Significant myocardial/ventricular dysfunction

Assess cardiac function and fluid status before the first IVIG infusion in every patient; consider the divided 1 g/kg/day-over-2-days IVIG regimen specifically in this group, monitor closely for volume overload after infusion, and be prepared to add diuresis once stabilized.^[5] The large majority of patients with MIS-C-associated ventricular dysfunction show meaningful improvement in ejection fraction within days to a few weeks of treatment, which is genuinely reassuring information to share with anxious families once the acute phase has stabilized.^[3][5]

Infants and very young children

MIS-C is less common in this age group than in the school-age/adolescent range where it predominates, and distinguishing it from classic Kawasaki disease can be especially difficult at younger ages; apply the CDC/CSTE exclusion criterion carefully (a documented Kawasaki disease diagnosis excludes MIS-C classification) and involve pediatric specialists early.^[2]

Adolescents

Adolescents fall within the CDC/CSTE case definition's under-21 age range and are old enough that COVID-19-vaccine-associated myocarditis becomes a relevant differential/coincident consideration; distinguish based on the multisystem/inflammatory-marker pattern and the fever/organ-involvement criteria that vaccine-associated myocarditis does not share (see Assessment & Diagnosis).^[2]

IgA deficiency

As with any IVIG indication, anaphylaxis is a recognized risk in patients with known IgA deficiency; screen where feasible and have the treating team plan accordingly.

Future COVID-19 vaccination after MIS-C

COVID-19 vaccination genuinely reduces the risk of a subsequent MIS-C episode, and current public health guidance supports vaccination after clinical recovery from MIS-C, including a return to baseline cardiac function; specific timing should follow current public health and specialist guidance rather than being initiated independently.^[1]

Renal and hepatic considerations

Use IVIG cautiously in renal impairment, favouring a non-sucrose formulation and adequate hydration where feasible. Aspirin should be used with attention to bleeding risk and GI tolerability in any child with a bleeding diathesis or significant hepatic impairment; there is no MIS-C-specific dose adjustment beyond standard pediatric practice.

Echocardiography and cardiac follow-up schedule

Obtain baseline echocardiogram, ECG, troponin, and BNP/NT-proBNP at diagnosis, without delaying IVIG/corticosteroid treatment. Repeat echocardiography at 7-14 days and again at 4-6 weeks after diagnosis — a schedule that parallels, but is not identical to, classic Kawasaki disease's 2-week/4-6-week convention.^[6] Arrange the first outpatient pediatric cardiology follow-up visit starting 2-3 weeks after discharge for every patient.^[1]

Long-term management, stratified by cardiac findings

• No coronary involvement and normalized ejection fraction confirmed on follow-up echocardiography: discontinue low-dose aspirin once the platelet count has normalized and the ≥4-week echocardiogram confirms normal coronary arteries.^[6]
• Coronary dilation or a small-to-medium aneurysm: continue low-dose aspirin long-term with periodic cardiology follow-up, using the same coronary-artery Z-score risk-stratification framework described in this platform's Kawasaki Disease chapter.^[3]
• Large/giant aneurysm, ejection fraction under 35%, or a documented thrombus: add therapeutic anticoagulation to antiplatelet therapy, with long-term specialized cardiology follow-up.^[5]

Ventricular function recovery

The large majority of patients with MIS-C-associated ventricular dysfunction show meaningful improvement in ejection fraction within days to a few weeks — genuinely reassuring information once the acute phase has stabilized, though re-check function at each follow-up rather than assuming recovery without confirming it.^[3][5]

Complications and honest evidence limitations

Coronary artery involvement, persistent ventricular dysfunction, and arrhythmia are the central cardiac complications to track. Because MIS-C is a comparatively recently described condition, long-term (multi-year) outcome data are still accumulating — be honest with families that some aspects of very-long-term prognosis remain under active study, even as short- and medium-term outcomes with prompt treatment are generally favourable.^[3]

1. Inadequate response to IVIG plus corticosteroid — persistent fever, ongoing systemic inflammation, or worsening organ dysfunction — requires prompt reassessment rather than a wait-and-see approach, mirroring the urgency of IVIG resistance in Kawasaki disease.^[5]
2. Do not reflexively repeat a full second dose of IVIG as the default escalation — the large infused volume carries a genuine risk of volume overload and hemolytic anemia, amplified by MIS-C's higher background rate of myocardial dysfunction.^[5]
3. Preferred escalation: intensify to (or add, if not already used) high-dose IV pulse methylprednisolone, or move to a biologic — anakinra (particularly with macrophage-activation-syndrome features) or infliximab (particularly for a more Kawasaki-like or GI-predominant phenotype) — specialist-directed.^[5]
4. Ongoing or worsening shock or myocardial dysfunction despite escalation: reassess for macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis, escalate ICU-level care, and involve rheumatology/critical care for further immunomodulation options.^[5]
5. New or worsening coronary findings on follow-up echocardiography: escalate the antithrombotic strategy (add or intensify anticoagulation) rather than continuing the prior aspirin-only plan unchanged.^[5]
6. Diagnostic uncertainty or an atypical course at any stage: reconsider alternative diagnoses (bacterial sepsis/toxic shock syndrome, a surgical abdomen, a documented Kawasaki disease, or another cause of macrophage activation syndrome/secondary HLH) rather than continuing to treat empirically as MIS-C indefinitely.^[2]

• Treating MIS-C as "just Kawasaki disease with a positive COVID test" — using Kawasaki disease's higher, anti-inflammatory acute aspirin dose rather than MIS-C's low, antithrombotic dosing, or skipping the SARS-CoV-2 evidence/exposure requirement that genuinely distinguishes the two conditions.^[6][2]
• Reflexively repeating a full second dose of IVIG in refractory MIS-C without considering the volume-overload/hemolytic-anemia risk, particularly in the depressed-ejection-fraction patient this disease disproportionately produces — favour corticosteroid intensification or a biologic instead.^[5]
• Underestimating shock risk, or not involving critical care early enough, given MIS-C's markedly higher shock rate than classic Kawasaki disease.^[3]
• Delaying IVIG/corticosteroid treatment while awaiting definitive SARS-CoV-2 laboratory confirmation in a clinically convincing, probable case — epidemiologic linkage alone is sufficient for a probable case, and treatment should not wait on confirmatory testing.^[2]
• Missing an alternative diagnosis — bacterial sepsis/toxic shock syndrome, a surgical abdomen given how prominent GI symptoms are in MIS-C, or a documented Kawasaki disease, which should specifically be excluded from MIS-C classification rather than treated as the same illness.^[2]
• Failing to arrange the full serial echocardiography schedule (7-14 days, 4-6 weeks) and the first outpatient cardiology visit at 2-3 weeks before discharge.^[6][1]
• Assuming a normal baseline echocardiogram rules out later coronary or ventricular involvement — MIS-C, like Kawasaki disease, can still evolve after the initial study, which is precisely why the serial schedule exists.^[6]
• Withholding aspirin out of a general Reye-syndrome-related reflex against pediatric aspirin use — this is a specific, deliberate, guideline-endorsed exception, not an oversight, and should be explained proactively.^[6]

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Disease-Modifying Acute Therapy — First-Line Combination

Give the corticosteroid together with IVIG from the outset for every confirmed or probable case — this upfront combination, not IVIG alone, is the current evidence-preferred approach.

Antiplatelet and Anticoagulant Therapy

Aspirin's role here is antithrombotic prophylaxis for the hypercoagulable state of MIS-C — a different rationale from Kawasaki disease's higher acute anti-inflammatory dosing, even though it is the same drug and the Reye-syndrome exception applies equally.

Second-Line Biologic Therapy for Refractory Disease

For inadequate response to IVIG plus corticosteroid. A full second IVIG dose is deliberately not the default escalation in MIS-C, given the volume-overload/hemolytic-anemia risk in a population already prone to myocardial dysfunction — escalate to one of these instead, specialist-directed.

Hemodynamic and Shock Support — ICU-Directed

Reflects MIS-C's substantially higher shock rate than classic Kawasaki disease. Included for pharmacist awareness of the full inpatient/ICU care pathway; dosing and agent selection are critical-care/specialist-directed.