Is multi-system inflammatory syndrome (MIS) a complication of COVID-19 (Coronavirus disease 2019)?

Multisystem Inflammatory Syndrome is a Recognized Complication of COVID-19

Yes, multisystem inflammatory syndrome (MIS) is definitively a complication of COVID-19, occurring in both children (MIS-C) and adults (MIS-A), typically manifesting 2-6 weeks after SARS-CoV-2 infection. 1

Understanding MIS as a COVID-19 Complication

MIS-C is temporally associated with SARS-CoV-2 infection and represents a rare but serious post-infectious hyperinflammatory syndrome. 1 The condition emerged in late April 2020 when reports from Italy and the United Kingdom described children with a syndrome resembling Kawasaki disease and toxic shock syndrome who had evidence of prior SARS-CoV-2 exposure. 1

Key Epidemiologic Features

• MIS-C remains a rare complication despite the vast majority of children with COVID-19 having mild symptoms and excellent outcomes. 1
• The syndrome shows increased incidence in patients of African, Afro-Caribbean, and Hispanic descent, with lower incidence in those of East Asian descent. 1, 2
• MIS-A affects young adults with a mean age of 32.9 years, and 70.4% of cases have no significant prior medical history. 3

Temporal Relationship to COVID-19

MIS typically occurs after a median of 4 weeks following SARS-CoV-2 infection, though it can manifest anywhere from immediately after acute infection to two months later. 3, 4 This delayed presentation is critical—patients may have negative PCR testing for active infection but positive serology indicating recent exposure. 4

Clinical Manifestations and Organ System Involvement

MIS-C Presentation

The most common features include fever, multiorgan dysfunction, and prominent gastrointestinal symptoms (abdominal pain, vomiting, diarrhea). 1, 2

Cardiac involvement is nearly universal and represents the most serious threat:

• Left ventricular dysfunction occurs in 20-55% of cases 1
• Coronary artery dilation or aneurysms develop in approximately 20% of patients 1
• Myocardial dysfunction, arrhythmias, and shock are more common than in classic Kawasaki disease 1, 2

Neurologic symptoms are prominent and include headache, altered mental status, encephalopathy, focal neurologic deficits, meningismus, and papilledema. 1, 2

Mucocutaneous findings include rash, bilateral conjunctivitis without exudate, oral mucosal changes (red/cracked lips, strawberry tongue), and extremity changes. 1

MIS-A Presentation

All but two reported adult cases presented with cardiac symptoms, making cardiac involvement the hallmark of MIS-A. 3 The most common secondary features are abdominal pain, vomiting, or diarrhea, followed by shock or hypotension. 3

Notably, MIS-A patients typically do not have severe respiratory illness, distinguishing it from acute COVID-19 pneumonia. 4

Diagnostic Criteria and Laboratory Findings

Laboratory Abnormalities

Patients demonstrate marked elevation of inflammatory markers including:

• C-reactive protein (CRP ≥10 mg/dl is considered marked elevation) 1
• Elevated ESR, ferritin, D-dimer, interleukin-6, and procalcitonin 1, 4
• Lymphopenia, neutrophilia, and thrombocytopenia (platelet count <150,000/μl) 1
• Elevated cardiac biomarkers (troponin T, BNP) 1

Evidence of SARS-CoV-2 Exposure

Diagnosis requires evidence of current or recent SARS-CoV-2 infection through positive PCR, positive serology, positive antigen test, or COVID-19 exposure within the prior 4 weeks. 1 Antibody testing may be necessary as PCR can be negative by the time MIS develops. 4

Morbidity and Mortality Considerations

Serious Complications

MIS carries significant morbidity with potential for:

• Coronary artery aneurysms requiring indefinite anticoagulation (z-score ≥10.0) 1
• Severe cardiac dysfunction with ejection fraction <35% requiring therapeutic anticoagulation 1
• Shock requiring ICU admission (more than half of MIS-A patients require ICU care) 3
• Acute kidney injury and multi-organ failure 3

Mortality Risk

While mortality occurs, it is relatively uncommon with appropriate treatment—only 4 deaths were reported among 71 MIS-A cases in systematic review. 3 However, untreated or delayed recognition can lead to irreversible complications, particularly cardiac sequelae. 1, 5

Critical Clinical Pitfalls

The most dangerous pitfall is failing to recognize MIS in patients presenting weeks after COVID-19 with negative PCR testing. 4 Always obtain serology in suspected cases. 1, 4

Myocardial dysfunction may present insidiously—all patients require electrocardiogram and echocardiogram even without overt cardiac symptoms. 1

Do not dismiss patients with mild symptoms—those with abnormal vital signs (tachycardia, tachypnea), respiratory distress, neurologic changes, renal or hepatic injury, marked inflammation (CRP >10 mg/dl), or abnormal cardiac findings require hospital admission. 1, 2

MIS-C can develop coronary artery aneurysms even without classic Kawasaki disease features, requiring serial echocardiographic monitoring at diagnosis, 7-14 days, and 4-6 weeks. 2

Treatment Implications

Management requires multidisciplinary involvement including pediatric rheumatology, cardiology, infectious disease, and hematology. 1, 2

Initial treatment involves intravenous immunoglobulin, consideration of corticosteroids, and anticoagulation based on cardiac involvement and thrombosis risk. 1, 5 Interleukin-1 or interleukin-6 blockade (anakinra or tocilizumab) may be needed for refractory cases. 1, 5

Low-dose aspirin (3-5 mg/kg/day; maximum 81 mg/day) should be used in patients with Kawasaki disease-like features and/or thrombocytosis (platelet count ≥450,000/μl) until platelet normalization and confirmed normal coronary arteries at ≥4 weeks. 1