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
A systemic disease is one that affects a number of organs and tissues, or affects the body as a whole.
Examples
* Mastocytosis, including mast cell activation syndrome and eosinophilic esophagitis
* Chronic fatigue syndrome
* Systemic va ...
involving persistent
fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
and extreme
inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
following exposure to
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, the virus responsible for
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
.
[ 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
Shock may refer to:
Common uses Collective noun
*Shock, a historic commercial term for a group of 60, see English numerals#Special names
* Stook, or shock of grain, stacked sheaves
Healthcare
* Shock (circulatory), circulatory medical emergen ...
).[ Failure of one or more organs can occur.][ A ]warning sign
A warning sign is a type of sign which indicates a potential hazard, obstacle, or condition requiring special attention. Some are traffic signs that indicate hazards on roads that may not be readily apparent to a driver.
While warning traffi ...
is unexplained persistent fever with severe symptoms following exposure to COVID-19. Prompt referral to paediatric
Pediatrics ( also spelled ''paediatrics'' or ''pædiatrics'') is the branch of medicine that involves the medical care of infants, children, adolescents, and young adults. In the United Kingdom, paediatrics covers many of their youth until the ...
specialists is essential, and families need to seek urgent medical assistance.[ Most affected children will need ]intensive care
Intensive care medicine, also called critical care medicine, is a medical specialty that deals with seriously or critically ill patients who have, are at risk of, or are recovering from conditions that may be life-threatening. It includes pro ...
.[
All affected children have persistent fever.][ Other clinical features vary.] The first symptoms often include acute abdominal pain with diarrhoea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
or vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
.[ ]Muscle pain
Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another like ...
and general tiredness are frequent,[ and ]low blood pressure
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
is also common.[ Symptoms can also include pink eye, ]rash
A rash is a change of the human skin which affects its color, appearance, or texture.
A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, c ...
es, enlarged lymph nodes
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In cl ...
, swollen hands and feet, and " strawberry tongue".[ Various mental disturbances are possible.][ A ]cytokine storm
A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Norm ...
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
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
, respiratory distress
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are c ...
, and increased blood coagulation.[ ]Coronary artery
The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ ...
abnormalities can develop (ranging from dilatation to aneurysm
An aneurysm is an outward bulging, likened to a bubble or balloon, caused by a localized, abnormal, weak spot on a blood vessel wall. Aneurysms may be a result of a hereditary condition or an acquired disease. Aneurysms can also be a nidus ( ...
s).[
This life-threatening disease has proved fatal in under 2% of reported cases.][ Early recognition and prompt specialist attention are essential.] Anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
treatments have been used, with good responses being recorded for intravenous immunoglobulin (IVIG), with or without corticosteroids.[ ]Oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as ...
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
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...
is evolving rapidly.[ Its clinical features may appear somewhat similar to ]Kawasaki disease
Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more th ...
, 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
Toxic shock syndrome (TSS) is a condition caused by bacterial toxins. Symptoms may include fever, rash, skin peeling, and low blood pressure. There may also be symptoms related to the specific underlying infection such as mastitis, osteomy ...
and macrophage activation
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cell ...
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
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
(WHO),[ the Royal College of Paediatrics and Child Health (RCPCH),] and the Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(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
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were amon ...
and other infections, is essential for differential diagnosis. Some general clinical guidance has been provided by the RCPCH,[ the ]National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
,[ the ]American College of Rheumatology The American College of Rheumatology (ACR; until 1985 called American Rheumatism Association) is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy ...
, 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
The European Centre for Disease Prevention and Control (ECDC) is an agency of the European Union (EU) whose mission is to strengthen Europe's defences against infectious diseases. It covers a wide spectrum of activities, such as: surveillance, ...
(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
The term ''Hispanic'' ( es, hispano) refers to people, cultures, or countries related to Spain, the Spanish language, or Hispanidad.
The term commonly applies to countries with a cultural and historical link to Spain and to viceroyalties forme ...
descent, whereas Kawasaki disease affects more of East Asia
East Asia is the eastern region of Asia, which is defined in both Geography, geographical and culture, ethno-cultural terms. The modern State (polity), states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. ...
n 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
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
infection (PIMS-TS)[
* Paediatric multisystem inflammatory syndrome (PMIS)][
* Kawa-COVID-19][
* Systemic inflammatory syndrome in COVID-19 (SISCoV)]
Background
Symptomatic cases of COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
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
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
infection or exposure to COVID-19 were found to display clinical features corresponding to the diagnostic criteria of Kawasaki disease
Kawasaki disease is a syndrome of unknown cause that results in a fever and mainly affects children under 5 years of age. It is a form of vasculitis, where blood vessels become inflamed throughout the body. The fever typically lasts for more th ...
, sometimes accompanied by shock.[ Kawasaki disease is a rare ]syndrome
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek language, Greek σύνδρομον, meaning "concurrence". When a sy ...
which mainly affects young children (adult onset has occasionally been reported). It is a form of vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...
, where blood vessels become inflamed throughout the body, and it results in a persistent fever
Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
. Recovery typically occurs spontaneously, though some children later develop mid-sized or giant coronary artery aneurysm
Coronary artery aneurysm is an abnormal dilatation of part of the coronary artery. This rare disorder occurs in about 0.3–4.9% of patients who undergo coronary angiography.
Signs and symptoms
Causes
Acquired causes include atherosclerosis in a ...
s in the heart – a potentially fatal complication. Symptoms of toxic shock
Toxic shock syndrome (TSS) is a condition caused by bacterial toxins. Symptoms may include fever, rash, skin peeling, and low blood pressure. There may also be symptoms related to the specific underlying infection such as mastitis, osteomy ...
(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
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
and/or autoinflammatory
Periodic fever syndromes are a set of disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Unlike autoimmune disorders such as systemic lupus erythematosus, in which the disease is caused by abnormalities of ...
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
Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In cl ...
, conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The ...
, changes to the mucous membranes
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
, and swollen hands and feet).
Characteristics
MIS-C / PIMS-TS is a systemic disorder involving persistent fever, extreme[ ]inflammation
Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
(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
Reverse transcription polymerase chain reaction (RT-PCR) is a laboratory technique combining reverse transcription of RNA into DNA (in this context called complementary DNA or cDNA) and amplification of specific DNA targets using polymerase ch ...
.[
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
Macrophage activation syndrome is a severe, potentially life-threatening, complication of several chronic rheumatic diseases of childhood. It occurs most commonly with systemic-onset juvenile idiopathic arthritis (SoJIA). In addition, MAS has be ...
.[ ]Coinfection
Coinfection is the simultaneous infection of a host by multiple pathogen species. In virology, coinfection includes simultaneous infection of a single cell by two or more virus particles. An example is the coinfection of liver cells with hepatiti ...
s with other pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
s 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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
symptoms, such as diarrhoea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenteri ...
, and intense abdominal pain (sometimes severe enough to suggest appendicitis
Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a ru ...
).[ ]Muscle pain
Myalgia (also called muscle pain and muscle ache in layman's terms) is the medical term for muscle pain. Myalgia is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another like ...
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
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It is ...
changes around the mouth (" strawberry tongue", cracked lips, etc.), red eyes (conjunctivitis
Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The ...
without pus
Pus is an exudate, typically white-yellow, yellow, or yellow-brown, formed at the site of inflammation during bacterial or fungal infection. An accumulation of pus in an enclosed tissue space is known as an abscess, whereas a visible collection ...
), 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
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
and shock
Shock may refer to:
Common uses Collective noun
*Shock, a historic commercial term for a group of 60, see English numerals#Special names
* Stook, or shock of grain, stacked sheaves
Healthcare
* Shock (circulatory), circulatory medical emergen ...
, and they may require urgent admission to a paediatric intensive care unit
A pediatric intensive care unit (also paediatric), usually abbreviated to PICU (), is an area within a hospital specializing in the care of critically ill infants, children, teenagers, and young adults aged 0-21. A PICU is typically directed by ...
.[
]Cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
involvement is very frequent.[ Acute heart failure is common in the form of ]left ventricular dysfunction
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, an ...
,[ and a left ventricular ejection fraction under 60% is frequent.][ Shock is often of ]myocardial
Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...
– 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
A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Norm ...
, including extremely high serum interleukin-6
Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene.
In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
(IL-6) levels,[ and need ]inotropic
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.
The term ''inotro ...
support to maintain cardiac output.[ ]Coronary artery
The coronary arteries are the arterial blood vessels of coronary circulation, which transport oxygenated blood to the heart muscle. The heart requires a continuous supply of oxygen to function and survive, much like any other tissue or organ ...
abnormalities, such as dilatation, are frequent.[ Some children have developed coronary artery aneurysms.] Electrocardiographic
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
(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
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of ...
(ESR), C-reactive protein
C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin- ...
(CRP), procalcitonin, ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
, and IL6.[ Low platelet counts and impaired ]blood clotting
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
( coagulopathy) are also common,[ with increased levels of ]D-dimer
D-dimer (or D dimer) is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cros ...
and fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
.[ Other haematological features include raised numbers of ]white blood cells
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
(leukocytosis
Leukocytosis is a condition in which the white cell (leukocyte count) is above the normal range in the blood. It is frequently a sign of an inflammatory response, most commonly the result of infection, but may also occur following certain parasi ...
), characterized by high numbers of neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s, with many immature forms, and low numbers of lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s ( lymphopaenia).[ Numbers of ]red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
s and platelets may be either normal or decreased.[ ]Acute kidney injury
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Causes of AKI are c ...
and low albumin levels in the blood (hypoalbuminaemia
Hypoalbuminemia (or hypoalbuminaemia) is a medical sign in which the level of albumin in the blood is low. This can be due to decreased production in the liver, increased loss in the gastrointestinal tract or kidneys, increased use in the body, o ...
) are common.[ Low blood sodium levels and raised ]liver enzyme
Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin tim ...
s have been reported.[ Accumulations of fluid in the lungs (]pleural effusion
A pleural effusion is accumulation of excessive fluid in the pleural space, the potential space that surrounds each lung.
Under normal conditions, pleural fluid is secreted by the parietal pleural capillaries at a rate of 0.6 millilitre per k ...
), around the heart (pericardial effusion
A pericardial effusion is an abnormal accumulation of fluid in the pericardial cavity. The pericardium is a two-part membrane surrounding the heart: the outer fibrous connective membrane and an inner two-layered serous membrane. The two layers of t ...
), and in the abdomen (ascites
Ascites is the abnormal build-up of fluid in the abdomen. Technically, it is more than 25 ml of fluid in the peritoneal cavity, although volumes greater than one liter may occur. Symptoms may include increased abdominal size, increased weight, a ...
) 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
image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL
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
Oxygen therapy, also known as supplemental oxygen, is the use of oxygen as medical treatment. Acute indications for therapy include hypoxemia (low blood oxygen levels), carbon monoxide toxicity and cluster headache. It may also be prophylactical ...
is often needed, and mechanical ventilation
Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move a ...
is sometimes used.[ Most children who receive expert multidisciplinary care survive.][ In addition to ]respiratory distress
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, 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
Diagnosis is by specialist clinical evaluation. Diagnostic suspicion may be raised by unexplained persistent fever and clinically concerning symptoms following exposure to COVID-19. Families need to seek immediate medical care, as the child's condition can deteriorate rapidly.[ Paediatricians' first involvement is often in the emergency department.][ Early recognition and multidisciplinary referral to paediatric specialists (in ]intensive care
Intensive care medicine, also called critical care medicine, is a medical specialty that deals with seriously or critically ill patients who have, are at risk of, or are recovering from conditions that may be life-threatening. It includes pro ...
, infectious diseases, cardiology, haematology
Hematology ( always spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood. It involves treating diseases that affect the produc ...
, rheumatology
Rheumatology (Greek ''ῥεῦμα'', ''rheûma'', flowing current) is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatolog ...
, etc.) is essential. Examinations may include blood tests, chest x-ray, heart ultrasound ( echocardiography), and abdominal ultrasound
Abdominal ultrasonography (also called abdominal ultrasound imaging or abdominal sonography) is a form of medical ultrasonography (medical application of ultrasound technology) to visualise abdominal anatomical structures. It uses transmission a ...
. Clinicians worldwide have been urged to consider this condition in children who display some or all the features of Kawasaki disease or toxic shock syndrome.[
]
Case definitions and guidance
A universally accepted case definition
In epidemiology, a clinical case definition, a clinical definition, or simply a case definition lists the clinical criteria by which public health professionals determine whether a person's illness is included as a ''case'' in an outbreak investiga ...
for this newly described syndrome has still not been agreed.[ In the meantime, different names and provisional case definitions are being used around the world.][ The initial case definitions released by the ]World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of ...
(WHO), the Royal College of Paediatrics and Child Health (RCPCH) and Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) all include involvement of more than one organ system, along with fever and elevated inflammatory markers. Criteria that vary among these three definitions include the ways in which involvement of different organs is defined, the duration of fever, and how exposure to COVID-19 is assessed.[
* The preliminary WHO case definition is for "multisystem inflammatory syndrome (MIS) in children and adolescents temporally related to COVID-19"][ (box).] The WHO has established a platform for standardized, anonymized clinical data, along with a dedicated case report form A case report form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The case report form is the tool used by the sponsor of the clinical trial to collect data from each participating patient. All data on ...
, and underlines the "urgent need for collection of standardized data describing clinical presentations, severity, outcomes, and epidemiology."[
* Diagnostic guidance by the RCPCH proposes a broader case definition (for PIMS-TS),][ which was also endorsed by an expert panel convened by the ]American College of Cardiology
The American College of Cardiology (ACC), based in Washington, D.C., is a nonprofit medical association established in 1949. It bestows credentials upon cardiovascular specialists who meet its qualifications. Education is a core component of the ...
. Key clinical criteria set out in the RCPHC case definition are: persistent fever, inflammation (indicated by neutrophilia
Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophils in the blood. Because neutrophils are the main type of granulocytes, mentions of granulocytosi ...
, high CRP levels and low lymphocyte count), and evidence of organ dysfunction (shock; cardiac, respiratory, renal
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; bloo ...
, gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
, or neurological
Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...
disorder), coupled with additional clinical features, including laboratory, imaging
Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image).
Imaging technology is the application of materials and methods to create, preserve, or duplicate images.
...
and ECG
Electrocardiography is the process of producing an electrocardiogram (ECG or EKG), a recording of the heart's electrical activity. It is an electrogram of the heart which is a graph of voltage versus time of the electrical activity of the hear ...
findings.[ Coronary artery abnormalities, such as dilatation, may be apparent at echocardiography and ECG (or ]contrast CT
Contrast CT, or contrast enhanced computed tomography (CECT), is X-ray computed tomography (CT) using radiocontrast. Radiocontrasts for X-ray CT are generally iodine-based types. This is useful to highlight structures such as blood vessels that ...
of the chest).[ ]Biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
s supporting the diagnosis include abnormal fibrinogen
Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood cl ...
levels, high D-dimer
D-dimer (or D dimer) is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cros ...
s (possible coagulopathy), high troponin
image:Troponin Ribbon Diagram.png, 400px, Ribbon representation of the human cardiac troponin core complex (52 kDa core) in the calcium-saturated form. Blue = troponin C; green = troponin I; magenta = troponin T.; ; rendered with PyMOL
Troponin, ...
, low albumin, and high ferritin
Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
. According to the RCPCH definition, the child may test positive or negative for SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, but other possible microbial causes need to be excluded.[
* The CDC case definition for MIS-C comprises individuals "aged <21 years presenting with fever, laboratory evidence of inflammation, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)."][ It also requires that there should either be a positive antigen/antibody SARS-CoV-2 test or COVID-19 exposure in the 4 weeks before onset of symptoms, along with exclusion of other plausible diagnoses.] This case definition is quite broad (it overlaps not only with Kawasaki disease, but also with juvenile rheumatoid arthritis
Juvenile may refer to:
*Juvenile status, or minor (law), prior to adulthood
*Juvenile (organism)
* Juvenile (rapper) (born 1975), American rapper
* ''Juvenile'' (2000 film), Japanese film
* ''Juvenile'' (2017 film)
*Juvenile (greyhounds), a greyh ...
, and various infectious/inflammatory conditions of childhood, including other viral diseases),[ but not as broad as the RCPCH definition.][ The CDC advises health providers in the United States to inform their public health authorities of suspected cases, even if they also meet full or partial criteria for Kawasaki disease, and to consider MIS-C after any childhood fatality in which there is evidence of SARS-CoV-2 infection.][
Further case definitions have been formulated by the British Paediatric Surveillance Unit (BPSU) and the Canadian Paediatric Surveillance Program (CPSP).] Some provisional diagnostic guidance has been provided by both the American College of Rheumatology The American College of Rheumatology (ACR; until 1985 called American Rheumatism Association) is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy ...
and the American Academy of Pediatrics. In the UK, consensus has been reached for diagnostic investigation of children with suspected PIMS-TS. A clinical pathway
A clinical pathway, also known as care pathway, integrated care pathway, critical pathway, or care map, is one of the main tools used to manage the quality in healthcare concerning the standardisation of care processes. It has been shown that the ...
for diagnostic evaluation of suspected MIS-C has also been proposed by the Children's Hospital of Philadelphia
The Children's Hospital of Philadelphia (CHOP) is a children's hospital in Philadelphia, Pennsylvania, with its primary campus located in the University City neighborhood of West Philadelphia in the campus of the University of Pennsylvania. The ...
. A set of guidelines proposed by Western New York
Western New York (WNY) is the westernmost region of the U.S. state of New York. The eastern boundary of the region is not consistently defined by state agencies or those who call themselves "Western New Yorkers". Almost all sources agree WNY i ...
recommends also evaluating children with clinical features that overlap with the MIS-C case definition, but who have been screened with mild illness and laboratory abnormalities, and who do not have an alternative diagnosis.
Differential diagnosis
It is essential to exclude alternative non-infectious and infectious causes of the inflammatory condition, including bacterial sepsis, staphylococcal
''Staphylococcus'' is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical ( cocci), and form in grape-like clusters. ''Staphylococcus'' species are facultati ...
and streptococcal
''Streptococcus'' is a genus of gram-positive ' (plural ) or spherical bacteria that belongs to the family Streptococcaceae, within the order Lactobacillales (lactic acid bacteria), in the phylum Bacillota. Cell division in streptococci occur ...
shock, and infections associated with myocarditis, such as enterovirus
''Enterovirus'' is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine ('enteric' meaning intestinal).
Serologic ...
. (Coinfection
Coinfection is the simultaneous infection of a host by multiple pathogen species. In virology, coinfection includes simultaneous infection of a single cell by two or more virus particles. An example is the coinfection of liver cells with hepatiti ...
with additional pathogens, including human metapneumovirus
''Human metapneumovirus'' (HMPV) is a negative-sense single-stranded RNA virus of the family ''Pneumoviridae'' and is closely related to the '' Avian metapneumovirus'' (AMPV) subgroup C. It was isolated for the first time in 2001 in the Netherla ...
and various other microbes, may sometimes occur.) Other potentially unrelated sources of abdominal pain include appendicitis
Appendicitis is inflammation of the appendix. Symptoms commonly include right lower abdominal pain, nausea, vomiting, and decreased appetite. However, approximately 40% of people do not have these typical symptoms. Severe complications of a ru ...
and mesenteric adenitis
Adenitis is a general term for an inflammation of a gland. Often it is used to refer to lymphadenitis which is the inflammation of a lymph node.
Classification
Lymph node adenitis
''Lymph adenitis'' or ''lymph node adenitis'' is caused by infec ...
.
Differential diagnosis with Kawasaki disease can be challenging, given the lack of a diagnostic test for either condition.[ It is not currently known whether the newly described condition is superimposable with Kawasaki disease shock syndrome.][ Since prompt diagnosis and timely treatment of actual Kawasaki disease is important to prevent complications, a call has been made to "Keep a high suspicion for Kawasaki disease in all children with prolonged fever, but especially in those younger than 1 year of age."][
]
Treatment
Due to the limited information available on this rare new diagnosis, clinical management has been largely based on expert opinion
An expert witness, particularly in common law countries such as the United Kingdom, Australia, and the United States, is a person whose opinion by virtue of education, training, certification, skills or experience, is accepted by the judge a ...
, including knowledge acquired from treating Kawasaki disease and other systemic inflammatory disorders of childhood, in addition to experience with COVID-19 in adults.[ Treatment is tailored for each individual child, with input from the various consulting specialists.][ Approaches vary.] The RCPCH initially outlined a provisional approach to clinical management, including guidance on early medical management, monitoring and some general principles of treatment;[ for the UK, consensus has since been reached regarding a recommended pathway for clinical management (including access to registered ]clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s).[ The ]National Institutes of Health
The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...
provides some general considerations.[ The American College of Rheumatology provides guidance for clinical management of MIS-C.] The American Academy of Pediatrics has also provided some interim guidance. Other proposals have also been made. RCPCH guidance recommends that all affected children should be treated as having suspected COVID-19.[
Little specific information is available regarding therapeutic effectiveness.][ Most children who have been treated as for Kawasaki disease have recovered.][ Supportive care is a mainstay of therapy,][ and for mild or moderate disease it may be sufficient.][ Major complications may respond well to more aggressive supportive care.][ Cardiac and respiratory support may benefit children who present predominantly with shock.][
Strategies for clinical management tend to be broadly based on ]anti-inflammatory
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as o ...
medications, treatment of shock, and prevention
Prevention may refer to:
Health and medicine
* Preventive healthcare, measures to prevent diseases or injuries rather than curing them or treating their symptoms
General safety
* Crime prevention, the attempt to reduce deter crime and crim ...
of thrombosis
Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (t ...
.[ Most children have received ]immunomodulatory
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
treatment with intravenous immunoglobulin (IVIG).[ IVIG has been reported target IL-1β+ neutrophils and their activation in the affected children. Other anti-inflammatory treatments have been used, including corticosteroids at various doses.][ Good responses have been recorded for IVIG, with or without corticosteroids.][ Cases requiring steroids due to resistance to IVIG may be more common than in Kawasaki disease.][ In a minority of cases,][ cytokine blockers have been used as a supplemental therapy to inhibit production of IL-6 (]tocilizumab
Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID19. It is a huma ...
) or IL-1 (anakinra
Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modif ...
); TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
-inhibitors (infliximab
Infliximab, a chimeric monoclonal antibody, sold under the brand name Remicade among others, is a medication used to treat a number of autoimmune diseases. This includes Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spon ...
) have also been used.[ ]Inotropic
An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.
The term ''inotro ...
or vasoactive agents are often used for children with cardiac dysfunction and hypotension.[ Anticoagulants have been used.][ Low-dose ]aspirin
Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...
has been used as an antiplatelet drug
An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effecti ...
.[
Treatment strategies are being considered to prevent serious long-term complications such as coronary artery aneurysms (the main complication of Kawasaki disease).] Close outpatient follow-up by a paediatric cardiology team has been recommended.
Causes
While it has been hypothesized that the condition is related to COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quickly ...
,[ it has also been emphasized that the potential link "is neither established nor well understood."] A temporal association between SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
infection and clinical presentation of the syndrome is plausible. A causality assessment found that 'temporality' was among the five (out of nine) Bradford Hill criteria The Bradford Hill criteria, otherwise known as Hill's criteria for causation, are a group of nine principles that can be useful in establishing epidemiologic evidence of a causal relationship between a presumed cause and an observed effect and have ...
that supported a causal relationship between SARS-CoV-2 infection and the development of the syndrome. Further characterization of the syndrome is essential to identify risk factor
In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection.
Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often ...
s and help understand causality.[ It is unclear to what extent this emerging syndrome has a similar ]aetiology
Etiology (pronounced ; alternatively: aetiology or ætiology) is the study of causation or origination. The word is derived from the Greek (''aitiología'') "giving a reason for" (, ''aitía'', "cause"); and ('' -logía''). More completely, e ...
to Kawasaki disease (a condition predating the emergence of SARS-CoV-2, which is currently thought to be triggered by a distinct viral agent).[ Although some cases resemble toxic shock syndrome, there is no evidence that staphylococcal or streptococcal toxins are involved.][ The role of ]comorbidities
In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
is unclear. Improved understanding will have potential implications for clinical management. Genome-wide association studies
In genomics, a genome-wide association study (GWA study, or GWAS), also known as whole genome association study (WGA study, or WGAS), is an observational study of a genome-wide set of genetic variants in different individuals to see if any varian ...
are expected to provide insights on susceptibility and potential biological mechanisms.[
]
Mechanism
The pathogenesis
Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
is not completely known and could implicate several factors. SARS-CoV-2 could have one of several roles; it could act as an environmental trigger
An environmental factor, ecological factor or eco factor is any factor, abiotic or biotic, that influences living organisms. Abiotic factors include ambient temperature, amount of sunlight, and pH of the water soil in which an organism lives. B ...
for the condition either directly or indirectly (by somehow paving the way for a different trigger).[
As with Kawasaki disease, ]antibody-dependent enhancement
Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its repl ...
, whereby development of antibodies could facilitate viral entry
Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variati ...
into host cells, has been proposed as a potential mechanism. Epidemiological considerations make a post-infectious mechanism seem likely, possibly coinciding with the development of acquired immune responses to the virus.[ It has been suggested that the condition may be caused by the cytokine storms induced by COVID-19.][ The characteristic ability of coronaviruses to block type I and type III interferon responses could help explain a delayed cytokine storm in children whose immune systems struggle to control SARS-CoV-2 viral replication, or are overwhelmed by a high initial ]viral load
Viral load, also known as viral burden, is a numerical expression of the quantity of virus in a given volume of fluid, including biological and environmental specimens. It is not to be confused with viral titre or viral titer, which depends on the ...
.[ One plausible chain of events leading up to a hyperimmune response could involve early viral triggering of macrophage activation, followed by ]T helper cell
The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are consider ...
stimulation, in turn leading to cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
release, stimulation of macrophages, neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s, and monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s, in conjunction with B cell and plasma cell activation, and autoantibody production.
It is unknown to what extent the pathophysiology resembles that of other paediatric inflammatory syndromes that share similar clinical features.[ Clinical overlaps with syndromes that have different causes (Kawasaki disease, toxic shock, macrophage activation syndrome, and secondary haemophagocytic lymphohistiocytosis) may be explained by immunological activation and dysregulation of similar inflammatory pathways.] In each of these syndromes, a cytokine storm leads to failure of multiple organs.[ They also share with MIS-C and severe cases of COVID-19 high levels both of ferritin (released by neutrophils) and of haemophagocytosis.][
The frequent gastrointestinal presentation and ]mesenteric
The mesentery is an organ that attaches the intestines to the posterior abdominal wall in humans and is formed by the double fold of peritoneum. It helps in storing fat and allowing blood vessels, lymphatics, and nerves to supply the intestine ...
lymph node inflammation are in keeping with the known liking of SARS-CoV-2 to replicate in enterocytes
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells which line the inner surface of the small and large intestines. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase it ...
.[ Association of Kawasaki-like disease with COVID-19 could support the view that SARS-CoV-2 can cause systemic vasculitis by targeting ]endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
tissue via angiotensin-converting enzyme 2
Angiotensin-converting enzyme 2 (ACE2) is an enzyme that can be found either attached to the membrane of cells (mACE2) in the intestines, kidney, testis, gallbladder, and heart or in a soluble form (sACE2). Both membrane bound and soluble ACE2 a ...
(ACE2), the protein which the virus uses to gain access to cells. While the initial infection is known to be capable of causing acute myocardial damage, occurrence of myocarditis could also plausibly be linked to systemic hyperinflammation triggered by a disorderly post-infectious immune response.[ It has been suggested that SARS-CoV-2 might lead to immune-mediated damage to the heart and coronary arteries via ]immune complex
An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. The bound antigen and antibody act as a unitary object, effectively an antigen o ...
es or increased T-cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
responses.[
Understanding the pathophysiology is a key research priority.] Questions regarding the underlying molecular mechanisms that lead to the disorder following exposure to SARS-CoV-2 include identification of: any genetic predisposition factors; any associations with particular viral variant/s; any molecular patterns capable of triggering the autoimmune/autoinflammatory responses.[ Another key question is whether the molecular mechanisms that trigger autoimmune/autoinflammatory responses in children with PMIS and adults with severe COVID-19 (including the induction of high concentrations of IL-6) are similar or distinct.][
A potential link with Kawasaki disease is under discussion.] It has been noted that a leading hypothesis for the pathogenesis of Kawasaki disease also involves a hyperinflammatory response to viral infection (such as by a novel RNA virus[) in some genetically predisposed children, and that SARS-CoV-2 is now "added to the list" of implicated viral triggers.][ Hopes have been expressed that study of the new condition may help understand the hidden mechanisms behind Kawasaki disease.][ But current evidence suggest that MIS-C and Kawasaki disease represent two distinct disease entities]
Proposed role of the STING pathway
A possible role of the stimulator of interferon genes known as STING has been proposed.[ SARS-CoV-2 is capable of upregulating the STING protein (encoded by TMEM173 transmembrane protein, and expressed in alveoli, endothelial cells, and the spleen), resulting in massive release of ]interferon-beta
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
and cytokines derived from activation of NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
and IRF-3.[ In MIS-C, such a scenario could lead to a clinical picture similar to STING-associated vasculopathy with onset in infancy (also known as SAVI) – a condition characterized by fever, lung injury, vascular inflammation, ]myositis
Myositis is a rare disease that involves inflammation of the muscles. This can present with a variety of symptoms such as skin involvement (i.e., rashes), muscle weakness, and other organ involvement. Systemic symptoms such as weight loss, fatigue ...
, skin lesions (occasionally acral necrosis), and arterial aneurysms.[ Variations in the presentation and severity of MIS-C might at least partially be explained by characteristic differences in polymorphisms of TMEM173 found in various populations.]
Epidemiology
Epidemiological information is limited, and clinical statistics currently derive from review of case series
A case series (also known as a clinical series) is a type of medical research study that tracks subjects with a known exposure, such as patients who have received a similar treatment, or examines their medical records for exposure and outcome. Cas ...
.[ This emerging condition is considered rare.] Its incidence is not known.[ Based on available reports, the ]fatality rate
In epidemiology, case fatality rate (CFR) – or sometimes more accurately case-fatality risk – is the proportion of people diagnosed with a certain disease, who end up dying of it. Unlike a disease's mortality rate, the CFR does not take int ...
among diagnosed cases appears to have been about 1.7% (notably higher than the rate of 0.07% recorded among children with Kawasaki disease in Japan).[ A rapid risk assessment conducted by the ]European Centre for Disease Prevention and Control
The European Centre for Disease Prevention and Control (ECDC) is an agency of the European Union (EU) whose mission is to strengthen Europe's defences against infectious diseases. It covers a wide spectrum of activities, such as: surveillance, ...
(ECDC) concluded that the overall risk to children in the European Union (EU), European Economic Area
The European Economic Area (EEA) was established via the ''Agreement on the European Economic Area'', an international agreement which enables the extension of the European Union's single market to member states of the European Free Trade As ...
(EEA) and the UK "is considered 'low', based on a 'very low' probability of he diseasein children and a 'high' impact of such disease."
Clusters of cases of the newly described condition have been recorded 3–4 weeks after peaks in SARS-CoV-2 viral transmission through various local communities.[ Such observations have been seen to support the concept that SARS-CoV-2 infection may be capable of triggering a severe form of a Kawasaki-like disease.] Frequent presentation without prominent respiratory symptoms in children who do not appear to have ongoing SARS-CoV-2 infection but who have already developed antibodies suggests that the disease may be driven by a delayed, post-infectious mechanism.[
The median age of onset appears to be at least 7 years (compared with 2 years for Kawasaki disease, which primarily affects children under the age of 5).][ Male children seem to be more frequently affected (broadly in line with Kawasaki disease, where the male to female ratio is about 1.5 to 1).] Many affected children appear not to have underlying health conditions, such as asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, co ...
or autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...
disorders, and there have been relatively few reports of known congenital heart disease
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
or preexisting cardiovascular disease.[ Over half (52%) the children with available information had no recorded underlying health condition, including being overweight or ]obese
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
(among those who did have some comorbidity, 51% were either overweight or obese).[
Regarding ethnicity, reports from France and the UK raised the possibility that children of Afro-Caribbean descent may be at greater risk, plausibly due to a genetic predisposition.][ In the US (as of mid-July), the majority of cases were classified as Hispanic/Latino (38%) or non-Hispanic ]Black
Black is a color which results from the absence or complete absorption of visible light. It is an achromatic color, without hue, like white and grey. It is often used symbolically or figuratively to represent darkness. Black and white ...
(33%) people.[ Based on reports confined to Europe and the US, the condition seems to affect more children of African, Afro-Caribbean, and ]Hispanic
The term ''Hispanic'' ( es, hispano) refers to people, cultures, or countries related to Spain, the Spanish language, or Hispanidad.
The term commonly applies to countries with a cultural and historical link to Spain and to viceroyalties forme ...
descent, whereas Kawasaki disease affects more of East Asian and Pacific Islander
Pacific Islanders, Pasifika, Pasefika, or rarely Pacificers are the peoples of the Pacific Islands. As an ethnic/racial term, it is used to describe the original peoples—inhabitants and diasporas—of any of the three major subregions of O ...
ancestry.[ The role of ]socioeconomic
Socioeconomics (also known as social economics) is the social science that studies how economic activity affects and is shaped by social processes. In general it analyzes how modern societies progress, stagnate, or regress because of their l ...
and other environmental factors in such discrepancies is unclear.
As regards geographical distribution, there has been uncertainty as to whether the initial reports of cases in Europe and North America reflected a true pattern, or whether the condition had gone unrecognized elsewhere.[ In Japan and other ]Southeast
The points of the compass are a set of horizontal, radially arrayed compass directions (or azimuths) used in navigation and cartography. A compass rose is primarily composed of four cardinal directions—north, east, south, and west—each sepa ...
and East Asian countries where Kawasaki disease is usually much more prevalent than in Europe, no case of Kawasaki-like disease linked to COVID-19 had been reported during the first wave of transmission. Reports of confirmed or suspected cases have since emerged in many different countries around the world.
None of the three main provisional case-definitions of the emerging entity is diagnostically specific
Specific may refer to:
* Specificity (disambiguation)
* Specific, a cure or therapy for a specific illness
Law
* Specific deterrence, focussed on an individual
* Specific finding, intermediate verdict used by a jury in determining the fina ...
.[ Concerns have been raised regarding the potential for missed or delayed diagnosis of Kawasaki disease due to heightened diagnostic suspicion for the new entity.] Misclassification of cases of Kawasaki disease and of other inflammatory and infectious diseases of childhood whose case definitions overlap with MIS-C could skew understanding of the new entity, such as the frequency of coronary artery aneurysms. Another concern is that clinically less severe cases of the new entity may be missed, and that the actual spectrum of disease severity could be broader, especially given the reliance on early observations of severe disease for provisional case definition.[ Some ]statistical modeling
A statistical model is a mathematical model that embodies a set of statistical assumptions concerning the generation of sample data (and similar data from a larger population). A statistical model represents, often in considerably idealized form, ...
has been used to explore possible subdivision of cases satisfying the CDC's case definition into three distinct subgroups based on underlying clinical similarities: ''Class 1'', characterized by pronounced multiorgan involvement, with little overlap with Kawasaki disease or acute COVID-19; ''Class 2'', more predominantly characterized by respiratory symptoms typical of acute COVID-19; ''Class 3'', a clinically less severe grouping, where rashes and mucosal symptoms are prevalent, with less multiorgan involvement, and generally greater overlap with Kawasaki disease. A suggestion that research into the biology of the disease might benefit from considering cases of Kawasaki disease and of the provisionally defined entity in conjunction is debated.
In adults
There has been uncertainty as to whether the condition is confined to children,[ and the appropriateness of excluding adults from case definitions has been questioned.] Sporadic reports exist of a similar life-threatening condition, denominated 'multisystem inflammatory syndrome in adults' (MIS-A), which also usually requires intensive care.
History
Cases of Kawasaki disease with concurrent SARS-CoV-2 infection have been recorded among children in Europe and in the United States since 7 April 2020, when a report was published by the American Academy of Pediatrics regarding a case of 'classic' Kawasaki disease in a six-month old girl who tested positive for COVID-19 in California. In this case, COVID-19 did not appear to have significant clinical implications.[
On 25 April, concerns were initially raised in the United Kingdom regarding a ]cluster
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of children of various ages presenting with a multisystem inflammatory state who required intensive care, and who all displayed "overlapping features of toxic shock syndrome and atypical Kawasaki disease with blood parameters consistent with severe COVID-19 in children." Details of the eight cases which helped trigger this alert (not all with confirmed exposure to COVID-19) were later reported in ''The Lancet
''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823.
The journal publishes original research articles, ...
'', where the authors summarized the clinical picture as "a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome." Accounts of analogous cases – including some that appeared less clinically severe – were also being informally shared among clinicians around Europe.[ The EU's ]Early Warning and Response System
The Early Warning and Response System (EWRS) for communicable diseases in the European Union was created by the European Commission to "ensure a rapid and effective response by the EU to events (including emergencies) related to communicable dis ...
flagged suspected cases in Austria, Germany
Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...
and Portugal
Portugal, officially the Portuguese Republic ( pt, República Portuguesa, links=yes ), is a country whose mainland is located on the Iberian Peninsula of Southwestern Europe, and whose territory also includes the Atlantic archipelagos of ...
that had tested positive for SARS-CoV-2. In Bergamo, at the heart of the COVID-19 epidemic in Lombardy, a cluster of 20 cases of Kawasaki disease appeared to be roughly equivalent to the number commonly recorded there over the course of three years.[ In France, the government reported on 29 April that around 15 children were in hospital in Paris with symptoms of Kawasaki disease,] an observation which prompted the organization of national surveillance programme for recent cases of Kawasaki-like disease.
On 1 May, the RCPCH published a preliminary case definition based on review of the characteristics of the cases identified in the UK, accompanied by some clinical guidance.[ Two weeks later, on 15 May, two further preliminary case definitions were published separately by the WHO][ and by the CDC,][ while the ECDC released a 'rapid risk assessment' of the condition on behalf of the European Union.] In the following weeks, further clinical guidance was released by other medical organizations, including the NIH,[ the American College of Rheumatology,] and the American Academy of Pediatrics. On 4 May, the New York City Department of Health and Mental Hygiene issued an alert to identify children with the condition in New York City hospitals, where 15 such cases were already being treated. On 9 May, the governor of New York, Andrew Cuomo
Andrew Mark Cuomo ( ; ; born December 6, 1957) is an American lawyer and politician who served as the 56th governor of New York from 2011 to 2021. A member of the Democratic Party, he was elected to the same position that his father, Mario Cu ...
announced a collaboration with the CDC to help develop national criteria for identifying and responding to the newly identified childhood disease.
By 12 May, some 230 suspected cases had been reported across the EU and EEA, and in the UK (in the following days, sources were reporting up to 100 in the UK, over 135 in France, 20 in the Netherlands, 10 in Switzerland and 10 in Germany). In the United States, more than 200 cases were suspected by mid-May, including some 145 in New York; 186 confirmed cases were eventually diagnosed between 15 March and 20 May in 26 US state
In the United States, a state is a constituent political entity, of which there are 50. Bound together in a political union, each state holds governmental jurisdiction over a separate and defined geographic territory where it shares its sove ...
s. As of 11 May 2020, five fatalities were reported (1 in France, 1 in the UK, 3 in the US). In peer-review
Peer review is the evaluation of work by one or more people with similar competencies as the producers of the work ( peers). It functions as a form of self-regulation by qualified members of a profession within the relevant field. Peer revie ...
ed medical journals, case series and related studies of the new condition were rapidly reported from countries including the UK; Italy;[ Spain;] France and Switzerland; France; and across the US, including New York. The emerging observations suggested somewhat greater variety in the severity of symptoms than was originally thought.[ The proposal of a new clinical entity during a pandemic also prompted scientific discussion about its possible distinction from Kawasaki disease, and the potential role of COVID-19.]