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<unk>  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 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."
Multisystem inflammatory syndrome in children
Kawasaki disease
Cutaneous manifestations of COVID-19
Systemic inflammatory response syndrome
Chest pain in children
complications of Typhus
Multiple organ dysfunction syndrome
complications of Sepsis