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.

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

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