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As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development. For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.

Sepsis remains a major global cause of morbidity and death. This investigation from Australia and New Zealand ICUs challenges the utility of the two criteria of the systemic inflammatory response syndrome as a key element in defining severe sepsis. Severe sepsis is a major cause of admission to the intensive care unit (ICU) and death. 1 , 2 The criteria according to the systemic inflammatory response syndrome (SIRS) were described 23 years ago as a clinical expression of the host response to inflammation. 3 In this context and in the presence of symptoms meeting two or more SIRS criteria, severe sepsis was seen as evolving from infection to sepsis, severe sepsis, and septic shock, in order of increasing severity. This approach was codified by the consensus statement of the American College of Chest Physicians and Society of Critical Care Medicine in 1992 . . .

An observational cohort study evaluated immunomodulatory therapy of multisystem inflammatory syndrome in children by comparing IVIG, IVIG plus glucocorticoids, or glucocorticoids alone. The investigators found no evidence of the superiority of any of the three therapies, although significant differences may emerge as more data accrue.

An analysis of surveillance data on inpatients younger than 21 years of age who had multisystem inflammatory syndrome in children and were hospitalized between March 15 and October 31, 2020, showed that initial treatment with IVIG plus glucocorticoids was associated with a lower risk of cardiovascular dysfunction and a lower incidence of adjunctive therapy use than IVIG alone.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

Recent reports highlight a new clinical syndrome in children related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 —multisystem inflammatory syndrome in children (MIS-C)—which comprises multiorgan dysfunction and systemic inflammation 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 – 13 . We performed peripheral leukocyte phenotyping in 25 children with MIS-C, in the acute ( n  = 23; worst illness within 72 h of admission), resolution ( n  = 14; clinical improvement) and convalescent ( n  = 10; first outpatient visit) phases of the illness and used samples from seven age-matched healthy controls for comparisons. Among the MIS-C cohort, 17 (68%) children were SARS-CoV-2 seropositive, suggesting previous SARS-CoV-2 infections 14 , 15 , and these children had more severe disease. In the acute phase of MIS-C, we observed high levels of interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, interferon-γ and differential T and B cell subset lymphopenia. High CD64 expression on neutrophils and monocytes, and high HLA-DR expression on γδ and CD4 + CCR7 + T cells in the acute phase, suggested that these immune cell populations were activated. Antigen-presenting cells had low HLA-DR and CD86 expression, potentially indicative of impaired antigen presentation. These features normalized over the resolution and convalescence phases. Overall, MIS-C presents as an immunopathogenic illness 1 and appears distinct from Kawasaki disease. Characterization of a cohort of children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection provides insights into the immunopathogenic features of the disease.

[...]some degree of host response is actually inherent to the infection; indeed, this is an important component of the difference between infection and mere colonisation. [...]the 1991 criteria for sepsis continue to be used.

Early recognition of sepsis is critical for timely initiation of treatment. The first objective of this study was to assess the timeliness of diagnostic procedures for recognizing sepsis in emergency departments. We define diagnostic procedures as tests used to help diagnose the condition of patients. The second objective was to estimate associations between diagnostic procedures and time to antibiotic treatment, and to estimate associations between time to antibiotic treatment and mortality. This observational study from 24 emergency departments in Norway included 1559 patients with infection and at least two systemic inflammatory response syndrome criteria. We estimated associations using linear and logistic regression analyses. Of the study patients, 72.9% (CI 70.7-75.1) had documented triage within 15 minutes of presentation to the emergency departments, 44.9% (42.4-47.4) were examined by a physician in accordance with the triage priority, 44.4% (41.4-46.9) were adequately observed through continual monitoring of signs while in the emergency department, and 25.4% (23.2-27.7) received antibiotics within 1 hour. Delay or non-completion of these key diagnostic procedures predicted a delay of more than 2.5 hours to antibiotic treatment. Patients who received antibiotics within 1 hour had an observed 30-day all-cause mortality of 13.6% (10.1-17.1), in the timespan 2 to 3 hours after admission 5.9% (2.8-9.1), and 4 hours or later after admission 10.5% (5.7-15.3). Key procedures for recognizing sepsis were delayed or not completed in a substantial proportion of patients admitted to the emergency department with sepsis. Delay or non-completion of key diagnostic procedures was associated with prolonged time to treatment with antibiotics. This suggests a need for systematic improvement in the initial management of patients admitted to emergency departments with sepsis.

This report describes the epidemiology and clinical course of patients younger than 21 years of age from 26 states who had multisystem inflammatory syndrome. Many were infected with SARS-CoV-2 at least 1 to 2 weeks before syndrome onset. The median age of the patients was 8.3 years, and 73% were previously healthy.

A multisystem inflammatory syndrome in children is associated with Covid-19. This report from New York State presents a descriptive analysis that summarizes the clinical presentation, complications, and outcomes of 99 pediatric patients meeting the New York State Department of Health definition of this syndrome.