Multisystem inflammatory syndrome in children (MIS-C), or pediatric inflammatory multisystem syndrome is a rare systemic illness involving persistent fever and extreme inflammation following exposure to SARS-CoV-2, the virus responsible for COVID-19.
Its pathogenesis is unknown.
It can rapidly lead to medical emergencies such as shock.
Children account for only 1-2% of hospitalizations in patients with Covid-19.
It affects all paediatric age groups, ranging from infancy to adolescence.p
Patients have a severe systemic hyperinflammatory disease occurring 2-6 weeks after severe acute respiratory syndrome Covid-19.
It is associated with a wide range of clinical manifestations including: persistent fever, digestive symptoms, diarrhea, vomiting, abdominal pain, rash, bilateral nonpurulent conjunctivitis, mucocutaneous inflammatory signs, and frequent cardiovascular involvement.
Muscle pains, tiredness and general physical weakness are also very common.
Affected children always present with persistent fever.
MIS-C is often associated with hemodynamic failure, with acute dysfunction requiring hemodynamic support in 60-75% of cases, and is it sometimes associated with death.
MIS-C is thought to be caused by an unusual biological response to infection in certain children.
MIS-C manifests with fever, abdominal pain, diarrhea/vomiting, hypotension, shock, pink eye, rashes, muscle pain and general tiredness are frequent, and low blood pressure is also common, lymphadenopathy, swollen hands/feet, and neurological disturbances.
Conjunctival injection and rash resembling Kawasakiâ€˜s disease occurs in a high percentage of children with this condition.
The first symptoms often include acute abdominal pain with diarrhea or vomiting.
Complications of MIS-C:
Cardiac dysfunction; coronary artery abnormalities, aneurysms; acute kidney injury; coagulopathy.
Usual onset of MIS-C is typically 2â€“6 weeks after COVID-19 exposure.
Severely affected children have been reported with multi organ failure in shock that requires inotropic support.
Causes include severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Laboratory tests show intense inflammation with elevated CRP, ferritin, troponin, and N+terminal pro-B type natriuretic peptide and reduced levels of hemoglobin, platelets and lymphocytes.
Differential diagnosis of MIS-C
Alternative infectious/non-infectious causes
Treatment of MIS-C includes:
Intravenous immunoglobulin (IVIG); corticosteroids; oxygen, and supportive care.
The response to treatment is generally good, but long-term prognosis is unknown.
Deaths from MIS-C are rare, with <2% of reported cases.
Other findings include: pink eye, rashes, enlarged lymph nodes, swollen hands and feet, and “strawberry tongue”, and mental disturbances.
A cytokine storm in which the child’s innate immune system stages an excessive and uncontrolled inflammatory response may occur.
Heart failure is a common complication, and can cytokine storm include damage to the heart muscle, respiratory distress, acute kidney injury, increased blood coagulation, coronary artery abnormalities can develop, ranging from dilatation to aneurysms.
Treatment with anti-inflammatory agents have been used, with good responses being recorded for intravenous immunoglobulin (IVIG), with or without corticosteroids.
Supportive care is key for treating clinical complications.
Some studies suggest the addition of glucocorticoids to IV IgG is associated with lower risk of new or persistent cardiovascular dysfunction.
Clinical features may appear somewhat similar to Kawasaki disease, a rare disease of unknown origin that typically affects young children, in which blood vessels become inflamed throughout the body.
MIS-C can have features of other serious inflammatory conditions of childhood, including toxic shock and macrophage activation syndromes.
Older children tend to be affected.
The condition is thought to follow SARS-CoV-2 viral infection, but the antigen or antibody tests are not always positive.
Exclusion of alternative causes, including bacterial and other infections, is essential for differential diagnosis.
It is suspected MIS-C is driven by a delayed biological mechanism in certain predisposed children.
The condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent, whereas Kawasaki disease affects more of East Asian ancestry.
Occasionally adults, have a similar condition called multisystem inflammatory syndrome in adults (MIS-A).
Symptomatic COVID-19 in children have been relatively uncommon, due to milder disease.
The later pulmonary phase, which can be life-threatening in adults, is usually mild or absent in children.
Cases of children with severe symptoms are exceptional.
Occasionally children require intensive care, and fatalities have been rare.
MIS-C is a systemic disorder involving persistent fever, extreme inflammation
and organ dysfunction, which is temporally associated with exposure to COVID-19.
Onset may be delayed or contemporary with ongoing SARS-CoV-2 infection.
Following the initial viral infection is
it may develop between the first and second week.
Recognition of the disease may typically be delayed by 2â€“6 weeks.
By the time of disease presentation , children have often developed antibodies to SARS-CoV-2, but test negative for the virus at RT-PCR.
It shares clinical features with other pediatric inflammatory conditions: toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome.
Some Kawasaki-like symptoms that may be present: include mucosal changes around the mouth, strawberry tongue, cracked lips, red eyes, conjunctivitis without pus, widespread rash
consistent with leukocytoclastic vasculitis, red or swollen hands and feet, and enlarged lymph nodes.
Chest or neck pain may also be present, and headache and altered mental state have been reported, along with various neurological disturbances.
Meningitis, encephalopathy, stroke and Guillain-Barre Syndrome have been reported.
Some patients present with low blood pressure and shock, and may require urgent admission to a pediatric intensive care unit.
Cardiovascular involvement is very frequent: Acute heart failure is common and a left ventricular ejection fraction under 60% is frequent, shock is often left ventricular in origin.
Some children display cytokine storm,including extremely high serum interleukin-6 (IL-6) levels, and need inotropic support to maintain cardiac output.
Coronary artery abnormalities, such as dilatation, are frequent manifestations of MIS-C, as are electrocardiographic (ECG) abnormalities
Some children have developed coronary artery aneurysms, inflammation of the heart valves (valvulitis), pericarditis, and myocarditis.
Affected children consistently show hyperinflammation: raised erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), procalcitonin, ferritin, low platelet counts and impaired blood clotting (coagulopathy) are also common, with increased levels of D-dimer and fibrinogen, leukocytosis, characterized by high numbers of neutrophils, with many immature forms, and lymphopenia.
Numbers of red blood cells and platelets may be either normal or decreased in MIS-C.
Acute kidney injury and hypoalbuminaemia are common.
Low blood sodium levels and raised liver enzymes have been reported.
Pleural effusion, pericardial effusion and ascites have also been reported, consistent with generalized inï¬‚ammation.
Unlike Kawasaki disease there is frequent presentation with gastrointestinal symptoms such as vomiting, diarrhea, and abdominal pain.
Neurological involvement also appears to be relatively frequent.
MIS-C often affects older children., whereas Kawasaki disease usually occurs before the age of five.
Myocarditis and cardiogenic shock are relatively common, and may be more evident in older children and adolescents.
Preschool children tend to display more Kawasaki-like characteristics.
The macrophage activation syndrome appears to be more frequent than in Kawasaki disease.
Laboratory findings in MIS-C include: high levels of ventricular natriuretic peptide, as well as somewhat lower platelet counts, lower absolute lymphocyte counts, higher CRP levels, and high troponin levels.
Clinical course tends to be more severe than with Kawasaki disease.
Many children develop shock and heart failure, and require intensive care,
supplemental oxygen and mechanical ventilation.
Most children survive.
Death has occurred in about 2% of the cases reported.
Coronary artery aneurysms can develop even in the absence of Kawasaki-like features: recorded in 7% of reported cases.
Children and adolescents
0â€“19 years of age with fever >3 days
Two of the following:
Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs
(oral, hands or feet)
Hypotension or shock
Features of myocardial dysfunction, pericarditis, Valvulitis, or coronary abnormalities.
Coagulation abnormalities by PT, PTT, elevated d-Dimer.
Acute gastrointestinal problems:
diarrhea, vomiting, or abdominal pain
Elevated markers of inflammation
such as ESR, C-reactive protein, or procalcitonin
No other obvious microbial cause of inflammation, including bacterial sepsis,
staphylococcal or streptococcal shock syndromes.
Evidence of COVID-19
Likely contact with patients with COVID-19
Early recognition and multidisciplinary pediatric specialists in intensive care, infectious diseases, cardiology, haematology, rheumatology, is essential.
Alternative non-infectious and infectious causes of the inflammatory condition including bacterial sepsis, staphylococcal and streptococcal shock, and infections associated with myocarditis, such as enterovirus, abdominal pain include appendicitis and mesenteric adenitis, Kawasaki disease
Most children who have been treated as for Kawasaki disease have recovered.
Supportive care is a mainstay of therapy.
Management includes anti-inflammatory medications, treatment of shock, and prevention of thrombosis.
Most children have received immunomodulatory treatment with intravenous immunoglobulin (IVIG) or
In a minority of cases, cytokine blockers have been used as a supplemental therapy to inhibit production of IL-6 (tocilizumab) or IL-1 (anakinra); TNF-Î±-inhibitors (infliximab) have also been used.
Inotropic or vasoactive agents are often used for children with cardiac dysfunction and hypotension.
Anticoagulants and low-dose aspirin has been used.
It has been hypothesized that the condition is related to COVID-19.
The frequent gastrointestinal symptoms and mesenteric lymph node inflammation are related to SARS-CoV-2 ability to replicate in enterocytes.
Angiotensin-converting enzyme 2 (ACE2), is the protein which the virus uses to gain access to cells.
The fatality rate among diagnosed cases appears to have been about 1.7%.
The median age of onset appears to be at least 7 years.
Kawasaki disease, which primarily affects children under the age of 5
Male children seem to be more frequently affected?
Many affected children appear not to have underlying health conditions such as: asthma, autoimmune disorders, heart disease or preexisting cardiovascular disease.
Over half the children with available information had no recorded underlying health condition.
The condition seems to affect more children of African, Afro-Caribbean, and Hispanic descent.
Kawasaki disease affects more of East Asian and Pacific Islander ancestry.
Treatment with IV I G/ methylprednisone versus IV IG alone was associated with the most favorable fever course.