troponin/nt-probnp) evidence of coagulopathy (by pt, ptt, elevated d-dimers) acute gastrointestinal problems (diarrhoea, vomiting, or abdominal pain) and elevated markers of inflammation such as esr, c-reactive protein, or procalcitonin and no other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes and evidence of covid-19 (rt-pcr, antigen test or serology positive), or likely contact with patients with covid-19 (note: consider this syndrome in children with features of typical or atypical kawasaki disease or toxic shock syndrome.) 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, infectious diseases, cardiology, haematology, rheumatology, etc.) is essential. examinations may include blood tests, chest x-ray, heart ultrasound (echocardiography), and abdominal ultrasound. 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 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 (who), the royal college of paediatrics and child health (rcpch) and centers for disease control and prevention (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, 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. key clinical criteria set out in the rcphc case definition are: persistent fever, inflammation (indicated by neutrophilia, high crp levels and low lymphocyte count), and evidence of organ dysfunction (shock; cardiac, respiratory, renal, gastrointestinal, or neurological disorder), coupled with additional clinical features, including laboratory, imaging and ecg findings. coronary artery abnormalities, such as dilatation, may be apparent at echocardiography and ecg (or contrast ct of the chest). biomarkers supporting the diagnosis include abnormal fibrinogen levels, high d-dimers (possible coagulopathy), high troponin, low albumin, and high ferritin. according to the rcpch definition, the child may test positive or negative for sars-cov-2, 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, 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 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 for diagnostic evaluation of suspected mis-c has also been proposed by the children's hospital of philadelphia. a set of guidelines proposed by western new york 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 and streptococcal shock, and infections associated with myocarditis, such as enterovirus. (coinfection with additional pathogens, including human metapneumovirus and various other microbes, may sometimes occur.) other potentially unrelated sources of abdominal pain include appendicitis and mesenteric adenitis. 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, 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 trials). the national institutes of health 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 medications, treatment of shock, and prevention of thrombosis. most children have received immunomodulatory 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) or il-1 (anakinra); tnf-α-inhibitors (infliximab) have also been used. inotropic or vasoactive agents are often used for children with cardiac dysfunction and hypotension. anticoagulants have been used. low-dose aspirin has been used as an antiplatelet drug. 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, it has also been emphasized that the potential link "is neither established nor well understood." a temporal association between sars-cov-2 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 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 factors and help understand causality. it is unclear to what extent this emerging syndrome has a similar aetiology 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 is unclear. improved understanding will have potential implications for clinical management. genome-wide association studies are expected to provide insights on susceptibility and potential biological mechanisms. mechanism the pathogenesis 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 for the condition either directly or indirectly (by somehow paving the way for a different trigger). as with kawasaki disease, antibody-dependent enhancement, whereby development of antibodies could facilitate viral entry 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. one plausible chain of events leading up to a hyperimmune response could involve early viral triggering of macrophage activation, followed by t helper cell stimulation, in turn leading to cytokine release, stimulation of macrophages, neutrophils, and monocytes, 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 lymph node inflammation are in keeping with the known liking of sars-cov-2 to replicate in enterocytes. association of kawasaki-like disease with covid-19 could support the view that sars-cov-2 can cause systemic vasculitis by targeting endothelial tissue via angiotensin-converting enzyme 2 (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 complexes or increased t-cell 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 and