multisystem inflammatory syndrome in children multisystem inflammatory syndrome in children multisystem inflammatory syndrome in children (mis-c), or paediatric inflammatory multisystem syndrome (pims / pims-ts), or systemic inflammatory syndrome in covid-19 (siscov), is a rare systemic illness involving persistent fever and extreme inflammation following exposure to sars-cov-2, the virus responsible for covid-19. mis-c has also been monitored as a potential, rare pediatric adverse event following covid-19 vaccination. it can rapidly lead to medical emergencies such as insufficient blood flow around the body (a condition known as shock). failure of one or more organs can occur. a warning sign is unexplained persistent fever with severe symptoms following exposure to covid-19. prompt referral to paediatric specialists is essential, and families need to seek urgent medical assistance. most affected children will need intensive care. paediatric multisystem inflammatory syndrome (pmis/pims/pims-ts)other names multisystem inflammatory syndrome in children (mis-c) multisystem inflammatory syndrome (mis) in children and adolescents temporally related to covid-19 paediatric inflammatory multisystem syndrome (pims), temporally associated with sars-cov-2 infection (pims-ts) kawa-covid-19 systemic inflammatory syndrome in covid-19 (siscov) tem image of sars-cov-2, the coronavirus responsible for covid-19: pmis / mis-c is thought to be caused by an unusual biological response to infection in certain childrenspecialtypaediatricssymptomsfever, abdominal pain, diarrhoea/vomiting, low blood pressure, insufficient blood supply (shock), pink eye, "strawberry tongue", rashes, large lymph nodes, swollen hands/feet, neurological disturbances, among otherscomplicationscardiac dysfunction; coronary artery abnormalities, including aneurysms; acute kidney injury; coagulopathyusual onsettypically 2–6 weeks after covid-19 exposurecausessevere acute respiratory syndrome coronavirus 2 (sars-cov-2)diagnostic methodclinical evaluation by specialistsdifferential diagnosisalternative infectious/non-infectious causes, kawasaki diseasetreatmentintravenous immunoglobulin (ivig); corticosteroids; oxygen, supportive careprognosisresponse to treatment, generally good; long-term prognosis, unclearfrequencyraredeaths<2% of reported cases all affected children have persistent fever. other clinical features vary. the first symptoms often include acute abdominal pain with diarrhoea or vomiting. muscle pain and general tiredness are frequent, and low blood pressure is also common. symptoms can also include pink eye, rashes, enlarged lymph nodes, swollen hands and feet, and "strawberry tongue". various mental disturbances are possible. a cytokine storm may take place, in which the child's innate immune system stages an excessive and uncontrolled inflammatory response. heart failure is common. clinical complications can include damage to the heart muscle, respiratory distress, acute kidney injury, and increased blood coagulation. coronary artery abnormalities can develop (ranging from dilatation to aneurysms). this life-threatening disease has proved fatal in under 2% of reported cases. early recognition and prompt specialist attention are essential. anti-inflammatory treatments have been used, with good responses being recorded for intravenous immunoglobulin (ivig), with or without corticosteroids. oxygen is often needed. supportive care is key for treating clinical complications. most children who receive expert hospital care survive. knowledge of this newly described syndrome is evolving rapidly. its 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. it can also show features of other serious inflammatory conditions of childhood, including toxic shock and macrophage activation syndromes. nevertheless, it appears to be a separate syndrome. older children tend to be affected. this emerging condition has been defined slightly differently (using different names), by the world health organization (who), the royal college of paediatrics and child health (rcpch), and the centers for disease control and prevention (cdc). although the condition is thought to follow sars-cov-2 viral infection, antigen or antibody tests are not always positive. exclusion of alternative causes, including bacterial and other infections, is essential for differential diagnosis. some general clinical guidance has been provided by the rcpch, the national institutes of health, the american college of rheumatology, and the american academy of pediatrics. clusters of new cases have been reported two to six weeks after local peaks in viral transmission. the disease is thought to be driven by a delayed biological mechanism in certain predisposed children. the european centre for disease prevention and control (ecdc) has rated risk to children in europe as being 'low' overall, based on a 'very low' likelihood of a child developing this 'high impact' disease. regarding ethnicity, the condition seems to affect more children of african, afro-caribbean, and hispanic descent, whereas kawasaki disease affects more of east asian ancestry. initial reports regarded children in various parts of europe and the united states, and it was unclear to what extent the condition had gone unrecognized elsewhere. reports have since emerged of cases in various other countries around the world. in adults, a similar condition has occasionally been reported, which has been called multisystem inflammatory syndrome in adults (mis-a). name the disorder has been called by various names, including: multisystem inflammatory syndrome in children (mis-c) multisystem inflammatory syndrome (mis) in children and adolescents temporally related to covid-19 paediatric inflammatory multisystem syndrome (pims) paediatric inflammatory multisystem syndrome, temporally associated with sars-cov-2 infection (pims-ts) paediatric multisystem inflammatory syndrome (pmis) kawa-covid-19 systemic inflammatory syndrome in covid-19 (siscov) background symptomatic cases of covid-19 in children have been relatively uncommon, possibly because they generally experience milder disease. early infection tends to be associated with mild or no symptoms, while the later pulmonary phase, which can be life-threatening in adults, is usually mild or absent. while cases of children with severe symptoms are exceptional, they can occasionally require intensive care. fatalities have been rare. in april 2020, a small group of children with evidence of sars-cov-2 infection or exposure to covid-19 were found to display clinical features corresponding to the diagnostic criteria of kawasaki disease, sometimes accompanied by shock. kawasaki disease is a rare syndrome which mainly affects young children (adult onset has occasionally been reported). it is a form of vasculitis, where blood vessels become inflamed throughout the body, and it results in a persistent fever. recovery typically occurs spontaneously, though some children later develop mid-sized or giant coronary artery aneurysms in the heart – a potentially fatal complication. symptoms of toxic shock (a syndrome caused by bacterial toxins) occasionally occur – an association sometimes referred to as 'kawasaki shock syndrome', which is characterized by systolic hypotension or signs of poor perfusion. while the exact cause of kawasaki disease is unknown, one plausible explanation is that it may stem from an infection triggering an autoimmune and/or autoinflammatory response in children who are genetically predisposed. no specific diagnostic test exists for kawasaki disease, and its recognition is based on various combinations of clinical and laboratory findings (including persistent fever, widespread rashes, enlarged lymph nodes, conjunctivitis, changes to the mucous membranes, and swollen hands and feet). characteristics mis-c / pims-ts is a systemic disorder involving persistent fever, extreme inflammation (hyperinflammation), and organ dysfunction, which is temporally associated with exposure to covid-19. onset may be delayed or contemporary with ongoing sars-cov-2 infection, which may pass without symptoms. the time the syndrome takes to appear following the initial viral infection is debated, though it may develop between the first and second week. epidemiological data suggest that recognition of the disease may typically be delayed by 2–6 weeks, and usually by 3–4 weeks. by the time of presention, children have often developed antibodies to sars-cov-2, but test negative for the virus at rt-pcr. the condition may match some or all of the diagnostic criteria for kawasaki disease (i.e. the 'complete' or 'incomplete'/'atypical' subtypes), or for kawasaki disease shock syndrome. it tends to affect all paediatric age groups, ranging from infancy to adolescence. it can also share clinical features with other paediatric inflammatory conditions, including toxic shock syndrome, and secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome. coinfections with other pathogens have been recorded. affected children always present with persistent fever. other clinical features at presentation vary. in contrast to acute covid-19, most children have gastrointestinal symptoms, such as diarrhoea, vomiting, and intense abdominal pain (sometimes severe enough to suggest appendicitis). muscle pain and feelings of tiredness and general physical weakness are also very common. some kawasaki-like symptoms that may be present (especially in children under the age of 5) include mucosal changes around the mouth ("strawberry tongue", cracked lips, etc.), 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. severe headache and altered mental state have been reported, along with various neurological disturbances. features of meningitis have been reported as well as septic encephalopathy, stroke, and guillain-barre syndrome. some patients present with very low blood pressure and shock, and they may require urgent admission to a paediatric intensive care unit. cardiovascular involvement is very frequent. acute heart failure is common in the form of left ventricular dysfunction, and a left ventricular ejection fraction under 60% is frequent. shock is often of myocardial – mainly left ventricular – origin. respiratory symptoms are less common, and are not usually a prominent feature. when present, breathing difficulties are often linked to shock, and are suggestive of heart failure. some children display features of a 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. some children have developed coronary artery aneurysms. electrocardiographic (ecg) abnormalities are common. other cardiological features sometimes include inflammation of the heart valves (valvulitis) and of the fibrous sac surrounding the heart (pericarditis). echocardiographic features of myocarditis (inflammation of the heart muscle) have been recorded. affected children consistently show laboratory evidence of hyperinflammation. pronounced biological markers of inflammation generally include strongly raised erythrocyte sedimentation rate (esr), c-reactive protein (crp), procalcitonin, ferritin, and il6. low platelet counts and impaired blood clotting (coagulopathy) are also common, with increased levels of d-dimer and fibrinogen. other haematological features include raised numbers of white blood cells (leukocytosis), characterized by high numbers of neutrophils, with many immature forms, and low numbers of lymphocytes (lymphopaenia). numbers of red blood cells and platelets may be either normal or decreased. acute kidney injury and low albumin levels in the blood (hypoalbuminaemia) are common. low blood sodium levels and raised liver enzymes have been reported. accumulations of fluid in the lungs (pleural effusion), around the heart (pericardial effusion), and in the abdomen (ascites) have also been reported, consistent with generalized inflammation. differences with respect to kawasaki disease include frequent presentation with gastrointestinal symptoms such as vomiting, diarrhoea, and abdominal pain. neurological involvement also appears to be relatively frequent. it often affects older children, whereas kawasaki disease usually occurs before the age of five. multiorgan disease appears to be more frequent. myocarditis and cardiogenic shock seem to be relatively common. myocarditis may be more evident in older children and adolescents. preschool children tend to display more kawasaki-like characteristics. features of macrophage activation syndrome appear to be more frequent than in kawasaki disease. characteristic laboratory findings that are not usually encountered in kawasaki disease include very high levels of ventricular natriuretic peptide (a marker of heart failure), as well as somewhat lower platelet counts, lower absolute lymphocyte counts, and higher crp levels. very high troponin levels (suggestive of myocardial damage) are also common. clinical course clinical course tends to be more severe than with kawasaki disease. a child's condition can deteriorate rapidly, even in the presence of reassuring laboratory findings. many children develop shock and heart failure. most require paediatric intensive care. supplemental oxygen is often needed, and mechanical ventilation is sometimes used. most children who receive expert multidisciplinary care survive. in addition to respiratory distress, major complications that may need aggressive supportive care can include myocardial damage, acute kidney injury, and coagulopathy (thrombophilia). in some cases, sustained cardiac arrhythmias have led to haemodynamic collapse and need for extracorporeal membrane oxygenation (ecmo). deaths have been recorded in a small minority (under 2%) of the cases reported. occasionally, fatalities have followed complications of ecmo. some children exposed to covid-19 also appear to have a less severe kawasaki-like disease. ventricular function often recovers before discharge from hospital (often after 6–10 days). coronary artery aneurysms can develop even in the absence of kawasaki-like features. their frequency and severity is uncertain. so far, they have been recorded in 7% of reported cases. long-term prognosis is unclear. diagnosis preliminary who case definition children and adolescents 0–19 years of age with fever >3 days and 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 (including echo findings or elevated