Multisystem Inflammatory Syndrome: Symptoms, Types, Causes and Treatment

Multisystem Inflammatory Syndrome (MIS) is a rare but serious condition that typically appears after infection with SARS-CoV-2, the virus responsible for COVID-19. First recognized in children (MIS-C), and later in adults (MIS-A) and neonates (MIS-N), this syndrome triggers widespread inflammation involving multiple organs and can mimic or overlap with other inflammatory diseases. Understanding the symptoms, types, causes, and treatment of MIS is crucial for timely recognition and effective management, which can be life-saving.

Symptoms of Multisystem Inflammatory Syndrome

Recognizing the symptoms of Multisystem Inflammatory Syndrome is essential for prompt diagnosis and intervention. The syndrome is marked by a hyperinflammatory state that can affect nearly every organ system. While the symptom profile overlaps with other conditions like Kawasaki disease and toxic shock syndrome, certain clinical features and laboratory markers distinguish MIS.

Symptom	Description	Frequency/Severity	Source(s)
Fever	Persistent high fever	Nearly 100%	1 2 3 4
GI Symptoms	Abdominal pain, diarrhea, vomiting	70–87%	1 2 4 5
Rash	Red or bumpy skin rash	60–73%	1 4 5
Conjunctivitis	Red eyes (non-purulent)	56–73%	1 4 3
Cardiac Signs	Myocarditis, shock, chest pain	53–71%	1 2 3 4 5
Mucosal Changes	Cracked lips, red tongue	27%	1
Neurologic	Headache, confusion, seizures	10–20%	3 5
Laboratory	Elevated CRP, D-dimer, troponin, IL-6	Nearly all patients	1 2 3 4

Table 1: Key Symptoms of Multisystem Inflammatory Syndrome

Common Presenting Symptoms

The most consistent and universal symptom is persistent fever, often accompanied by gastrointestinal complaints such as abdominal pain, vomiting, and diarrhea. These symptoms tend to appear suddenly, typically 2–6 weeks after SARS-CoV-2 infection or exposure, sometimes even if the initial infection was mild or asymptomatic 1 2 3 4.

Dermatologic and Mucocutaneous Manifestations

• Rash is very common, often appearing as a red, patchy, or bumpy eruption.
• Conjunctival injection (red eyes without discharge) and mucosal changes (cracked lips, swollen tongue) are reminiscent of Kawasaki disease, especially in children 1 4.

Cardiovascular Involvement

Cardiac symptoms are particularly concerning, including:

• Myocarditis (inflammation of the heart muscle)
• Depressed heart function (seen on echocardiogram)
• Circulatory shock requiring ICU admission or vasopressors in severe cases 1 2 3 4 5

Other Systemic Symptoms

• Neurological symptoms such as headache, confusion, or even seizures may occur, especially in severe cases 3 5.
• Respiratory symptoms are less common and, if present, usually reflect cardiac dysfunction rather than primary lung disease 1 5.

Laboratory Findings

Laboratory tests almost always reveal:

• Elevated inflammatory markers (CRP, ferritin, D-dimer, IL-6)
• Cardiac biomarkers (troponin, BNP) indicating heart stress or injury
• Abnormal blood counts (low platelets or lymphocytes) These laboratory abnormalities help confirm the diagnosis and assess severity 1 2 3 4.

Types of Multisystem Inflammatory Syndrome

Multisystem Inflammatory Syndrome is not exclusive to children. Since its initial description, three main types have emerged, each affecting a different age group with unique features.

Type	Population	Distinct Features	Source(s)
MIS-C	Children/adolescents	GI, mucocutaneous, cardiac, shock	1 2 4 8
MIS-A	Adults	Cardiovascular, GI, neuro, less respiratory	5 6
MIS-N	Neonates	Cardiac, GI, respiratory, after maternal SARS-CoV-2	11

Table 2: Types of Multisystem Inflammatory Syndrome

MIS-C: Multisystem Inflammatory Syndrome in Children

• Typically affects children and adolescents under 21 years.
• Presents 2–6 weeks after SARS-CoV-2 exposure or infection.
• Most common features: fever, GI symptoms, mucocutaneous signs, and significant cardiac involvement, sometimes progressing to shock 1 2 4 8.
• Laboratory findings: high inflammatory and cardiac markers.

MIS-A: Multisystem Inflammatory Syndrome in Adults

• Recognized in adults, usually presenting about 4 weeks post-COVID-19 infection 5 6.
• Features: prominent cardiovascular and gastrointestinal involvement, elevated inflammatory markers, and often neurological symptoms.
• Unlike severe COVID-19, respiratory symptoms are not dominant.
• Diagnosis may require antibody testing, as PCR may be negative 5.

MIS-N: Multisystem Inflammatory Syndrome in Neonates

• Reported in newborns whose mothers had COVID-19 during pregnancy 11.
• Presents with cardiac abnormalities, respiratory distress, GI symptoms, and elevated inflammatory markers in the first few days after birth.
• Likely related to maternal antibody transfer rather than direct infection.
• Cardiac involvement is especially prominent (QTc prolongation, AV block, shock) 11.

Overlapping and Atypical Presentations

• There are reports of atypical cases and overlap with Kawasaki disease, toxic shock syndrome, and other hyperinflammatory conditions, which can complicate diagnosis 1 4 8.
• The spectrum of organ involvement may vary with age and genetic predisposition.

Causes of Multisystem Inflammatory Syndrome

Understanding what causes MIS is key to both prevention and management. While the syndrome's precise mechanisms are still under investigation, evidence points to a dysregulated immune response following SARS-CoV-2 infection.

Cause	Mechanism/Description	Evidence Level	Source(s)
SARS-CoV-2	Post-infectious immune response	Strong	1 2 3 4 8
Immune Dysregulation	Hyperinflammation, cytokine storm	Strong	3 4 8
Genetic Factors	Variants affecting immune regulation (e.g., SOCS1)	Emerging evidence	10
Maternal Antibodies (MIS-N)	Passive transfer to neonates causing inflammation	Moderate	11

Table 3: Key Causes of Multisystem Inflammatory Syndrome

Role of SARS-CoV-2

• MIS-C, MIS-A, and MIS-N all occur after SARS-CoV-2 infection or exposure. The syndrome typically appears several weeks later, after the acute infectious phase has resolved 1 2 3 4 8.
• Many patients are PCR-negative but antibody-positive, supporting a post-infectious process 4 5 6.

Immune Dysregulation and Hyperinflammation

• MIS is believed to result from an abnormal, exaggerated immune response rather than direct viral injury.
• This involves a cytokine storm—excessive release of inflammatory molecules such as IL-6, CRP, and ferritin—which then damages multiple organ systems 3 4 8.
• The immune system's overreaction may be triggered by molecular mimicry, autoantibody production, or persistent viral antigen stimulation.

Genetic Susceptibility

• Some children may have underlying genetic variants that predispose them to immune dysregulation, such as mutations in the SOCS1 gene, which normally helps control inflammation 10.
• Research is ongoing to identify other potential genetic risk factors.

Maternal Antibody Transfer in MIS-N

• In neonates, the syndrome seems linked not to direct infection but to the transplacental transfer of maternal antibodies against SARS-CoV-2, which may inadvertently trigger hyperinflammation in the newborn 11.

Other Potential Factors

• The reason why only a small fraction of those exposed to SARS-CoV-2 develop MIS remains unclear.
• Age, sex, ethnicity (higher rates in Black and Hispanic populations), and pre-existing conditions like obesity may increase risk 1 3.

Treatment of Multisystem Inflammatory Syndrome

Treatment of MIS is evolving as more evidence emerges. The primary aim is to dampen hyperinflammation, support affected organs, and prevent complications, especially in the heart.

Treatment	Description	Indication/Notes	Source(s)
IVIG	Immunomodulation (IV immune globulin)	First-line, nearly all cases	12 13 14 15
Corticosteroids	Reduce inflammation	Adjunct to IVIG or alone	12 13 14 15
Biologics	Anakinra, infliximab (target cytokines)	Severe/refractory cases	14 15
Antiplatelets	Aspirin	Mild cases, coronary protection	15
Anticoagulants	Heparin, LMWH	Severe, high clot risk	15
Supportive Care	ICU, vasopressors, oxygen, ventilation	As needed for organ support	1 2 3 4 5
Cardiology f/u	Ongoing heart monitoring	All cases	15

Table 4: Key Treatments for Multisystem Inflammatory Syndrome

Immunomodulatory Therapy

Intravenous Immunoglobulin (IVIG)

• IVIG is considered the cornerstone of MIS treatment, recommended in nearly all protocols 12 13 14 15.
• It works by modulating the immune response and has been shown to reduce the risk of cardiovascular dysfunction when combined with corticosteroids 12.

Corticosteroids

• Steroids (e.g., methylprednisolone) are commonly added to IVIG, especially in moderate to severe cases 12 13 14 15.
• Combination therapy (IVIG + steroids) appears more effective than IVIG alone in preventing ongoing heart dysfunction 12.

Biologic Agents

• For severe or refractory cases, biologic drugs targeting specific cytokines such as IL-1 (anakinra) or TNF-alpha (infliximab) may be used 14 15.
• Their use is less common and typically reserved for those not responding to initial therapy.

Antiplatelet and Anticoagulation Therapy

• Aspirin is often prescribed, especially if there is coronary artery involvement or as a preventive measure 15.
• In severe cases, or where there is a risk of blood clots, anticoagulation with heparin or low molecular weight heparin may be indicated 15.

Supportive Care

• Many patients require intensive care support, including fluids, vasopressors for shock, respiratory support, and careful monitoring of organ function 1 2 3 4 5.
• Cardiac monitoring and follow-up are essential, given the risk of lingering heart involvement 15.

Protocol Variability and Outcomes

• While IVIG and steroids are nearly universal, the choice, dosing, and sequence of therapies may vary by institution and severity 14 15.
• Most children and adults recover well with prompt treatment, though rare fatalities have occurred 2 12 13.
• Long-term outcomes, especially for heart health, are still being studied.

Conclusion

Multisystem Inflammatory Syndrome is a complex, post-infectious condition that can affect children, adults, and neonates. Its severity and multi-organ involvement make early recognition and prompt, evidence-based treatment vital. Here are the key points from this article:

• Symptoms: Persistent fever, GI symptoms, rash, mucocutaneous signs, and cardiac involvement are the hallmark features.
• Types: MIS occurs in children (MIS-C), adults (MIS-A), and neonates (MIS-N), with overlapping but distinct presentations.
• Causes: The syndrome is triggered by an abnormal immune response to SARS-CoV-2, sometimes influenced by genetic and maternal factors.
• Treatment: Immunomodulatory therapy (IVIG and corticosteroids), supportive care, and close cardiac monitoring are central to management, with biologics and anticoagulation used as needed.

Early diagnosis and individualized treatment protocols are crucial to reducing complications and improving outcomes in this rare but serious syndrome.