Medium-Term Cardiac Outcomes in Young People with Multi-system Inflammatory Syndrome: The Era of COVID-19.

Multi-system inflammatory syndrome in children (MIS-C) causes widespread inflammation including a pancarditis in the weeks following a COVID infection. As we prepare for further coronavirus surges, understanding the medium-term cardiac impacts of this condition is important for allocating healthcare resources. A retrospective single-center study of 67 consecutive patients with MIS-C was performed evaluating echocardiographic and electrocardiographic (ECG) findings to determine the point of worst cardiac dysfunction during the admission, then at intervals of 6-8 weeks and 6-8 months. Worst cardiac function occurred 6.8 ± 2.4 days after the onset of fever with mean 3D left ventricle (LV) ejection fraction (EF) 50.5 ± 9.8%. A pancarditis was typically present: 46.3% had cardiac impairment; 31.3% had pericardial effusion; 26.8% demonstrated moderate (or worse) valvar regurgitation; and 26.8% had coronary dilatation. Cardiac function normalized in all patients by 6-8 weeks (mean 3D LV EF 61.3 ± 4.4%, p < 0.001 compared to presentation). Coronary dilatation resolved in all but one patient who initially developed large aneurysms at presentation, which persisted 6 months later. ECG changes predominantly featured T-wave changes resolving at follow-up. Adverse events included need for ECMO (n = 2), death as an ECMO-related complication (n = 1), LV thrombus formation (n = 1), and subendocardial infarction (n = 1). MIS-C causes a pancarditis. In the majority, discharge from long-term follow-up can be considered as full cardiac recovery is expected by 8 weeks. The exception includes patients with medium sized aneurysms or greater as these may persist and require on-going surveillance.

Post-COVID-19 paediatric inflammatory multisystem syndrome: association of ethnicity, key worker and socioeconomic status with risk and severity.

OBJECTIVES: Patients from ethnic minority groups and key workers are over-represented among adults hospitalised or dying from COVID-19. In this population-based retrospective cohort, we describe the association of ethnicity, socioeconomic and family key worker status with incidence and severity of Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS). SETTING: Evelina London Children's Hospital (ELCH), the tertiary paediatric hospital for the South Thames Retrieval Service (STRS) region. PARTICIPANTS: 70 children with PIMS-TS admitted 14 February 2020-2 June 2020. OUTCOME MEASURES: Incidence and crude ORs are presented, comparing ethnicity and socioeconomic status of our cohort and the catchment population, using census data and Index of Multiple Deprivation (IMD). Regression is used to estimate the association of ethnicity and IMD with admission duration and requirement for intensive care, inotropes and ventilation. RESULTS: Incidence was significantly higher in children from black (25.0 cases per 100 000 population), Asian (6.4/100 000) and other (17.8/100 000) ethnic groups, compared with 1.6/100 000 in white ethnic groups (ORs 15.7, 4.0 and 11.2, respectively). Incidence was higher in the three most deprived quintiles compared with the least deprived quintile (eg, 8.1/100 000 in quintile 1 vs 1.6/100 000 in quintile 5, OR 5.2). Proportions of families with key workers (50%) exceeded catchment proportions. Admission length of stay was 38% longer in children from black ethnic groups than white (95% CI 4% to 82%; median 8 days vs 6 days). 9/10 children requiring ventilation were from black ethnic groups. CONCLUSIONS: Children in ethnic minority groups, living in more deprived areas and in key worker families are over-represented. Children in black ethnic groups had longer admissions; ethnicity may be associated with ventilation requirement.This project was registered with the ELCH audit and service evaluation team, ref. no 11186.

Systemic Inflammation Is Associated With Neurologic Involvement in Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2.

OBJECTIVE: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS. METHODS: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms. RESULTS: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 µg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 µg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%). CONCLUSIONS: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully.

PIMS or not? Alternative diagnoses in the febrile child during the COVID-19 pandemic

BackgroundThe majority of children and young people affected by COVID-19 have remained asymptomatic or suffered mild illnesses. However throughout the pandemic patients with a novel rare but severe disease phenotype, Paediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-CoV-2 (PIMS-TS)1 continue to need hospital admission. The importance of considering the wider differential such as malignancies should be highlighted.ObjectivesTo establish the range of diagnoses of children admitted to a tertiary London children’s hospital presenting with a history of fever and high CRP, in whom PIMS-TS was considered as a diagnosis, during the COVID-19 pandemic.MethodsClinical records from 1st March 2020 to 30th June 2020 (inclusive) were retrospectively analysed to identify patients under the age of 18 years admitted to a tertiary London children’s hospital with a history of fever and CRP >60. Electronic notes were reviewed to determine final diagnosis.Results140 patients were admitted with a history of fever and CRP >60 during the study period. 58% (n=81) had PIMS-TS and 42% (n=59) had alternative diagnoses. Of those with an alternative diagnosis 81% (n=48) had infective diagnoses and of these 46% (n=22) had upper or lower respiratory tract infections;25% (n=12) had sepsis;13% (n=6) had urinary tract infections or pyelonephritis;10% (n=5) had gastroenteritis;4% (n=2) had lymphadenitis and 2% (n=1) had meningitis. 10% (n=5) had surgical diagnoses most commonly appendicitis (n=3). 5% (n=3) had inflammatory diagnoses;2 with an exacerbation of Crohn’s disease and 1 with vasculitis. 3% (n=2) had autoimmune diagnoses, 1 with juvenile idiopathic arthritis and 1 with Still’s disease who developed macrophage activation syndrome. 2% (n=1) had Burkitt leukaemia.ConclusionsIn the midst of a pandemic there is a high suspicion of PIMS-TS in unwell febrile children. The high numbers of patients with PIMS-TS admitted to this hospital reflects the regional referrals pathway for the PIMS-TS patients during the first wave of COVID-19. However infections remain a major cause of children presenting with fever and a high CRP. The range of alternative diagnoses outlined in our cohort is not surprising, when one considers that PIMS-TS is a disease with a subjective and broad case definition, with signs and symptoms overlapping with other serious diagnoses – infectious, surgical, inflammatory, autoimmune and malignant.The wider differential diagnoses should always be considered when children present with fever and a thorough history and examination is paramount. Alternative diagnoses may have indolent or more chronic symptoms. Our experience has shown that discussion within a multidisciplinary team has helped to ensure alternate diagnoses are not missed.ReferenceHealth Service Journal. National alert as ‘coronavirus-related condition may be emerging in children. April 2020. Available from: https://www.hsj.co.uk/acute-care/exclusive-national-alert-as-coronavirus-related-condition-may-be-emerging-in-children/7027496.article (Last accessed 5th March 2021).

Electrocardiographic Changes in Children with Multisystem Inflammation Associated with COVID-19: Associated with Coronavirus Disease 2019.

OBJECTIVE: To analyze findings and trends on serial electrocardiograms (ECGs) in multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease taken during the course of illness and at follow-up. STUDY DESIGN: We included all children presenting with MIS-C at a single center with 3 or more ECGs taken during the course of their illness. We measured ECG intervals (PR, QRSd, and QTc) and amplitudes (R-, S-, and T-waves) on each ECG and documented any arrhythmias and ST-segment changes. RESULTS: A majority of children (n = 42, 67%) showed ECG changes. The most common findings were low QRS amplitudes and transient T-wave inversion. ST changes were uncommon and included ST-segment elevation consistent with pericarditis in 1 child and acute coronary ischemia in 1 child. Arrhythmias were seen in 13 children (21%) but were benign with the exception of 1 child who was compromised by an atrial tachycardia requiring support with extracorporeal membrane oxygenation. No children were found to have high-grade atrioventricular block. CONCLUSIONS: MIS-C is associated with electrocardiographic changes over the course of the illness, with low amplitude ECGs on presentation, followed by transient T-wave inversion, particularly in the precordial leads. There was a low prevalence of ST-segment changes and tachyarrhythmias.

Acute Cardiovascular Manifestations in 286 Children With Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe.

BACKGROUND: The aim of the study was to document cardiovascular clinical findings, cardiac imaging, and laboratory markers in children presenting with the novel multisystem inflammatory syndrome associated with coronavirus disease 2019 (COVID-19) infection. METHODS: This real-time internet-based survey has been endorsed by the Association for European Paediatric and Congenital Cardiologists Working Groups for Cardiac Imaging and Cardiovascular Intensive Care. Children 0 to 18 years of age admitted to a hospital between February 1 and June 6, 2020, with a diagnosis of an inflammatory syndrome and acute cardiovascular complications were included. RESULTS: A total of 286 children from 55 centers in 17 European countries were included. The median age was 8.4 years (interquartile range, 3.8-12.4 years) and 67% were boys. The most common cardiovascular complications were shock, cardiac arrhythmias, pericardial effusion, and coronary artery dilatation. Reduced left ventricular ejection fraction was present in over half of the patients, and a vast majority of children had raised cardiac troponin when checked. The biochemical markers of inflammation were raised in most patients on admission: elevated C-reactive protein, serum ferritin, procalcitonin, N-terminal pro B-type natriuretic peptide, interleukin-6 level, and D-dimers. There was a statistically significant correlation between degree of elevation in cardiac and biochemical parameters and the need for intensive care support (P<0.05). Polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 was positive in 33.6%, whereas immunoglobulin M and immunoglobulin G antibodies were positive in 15.7% cases and immunoglobulin G in 43.6% cases, respectively, when checked. One child in the study cohort died. CONCLUSIONS: Cardiac involvement is common in children with multisystem inflammatory syndrome associated with the Covid-19 pandemic. The majority of children have significantly raised levels of N-terminal pro B-type natriuretic peptide, ferritin, D-dimers, and cardiac troponin in addition to high C-reactive protein and procalcitonin levels. In comparison with adults with COVID-19, mortality in children with multisystem inflammatory syndrome associated with COVID-19 is uncommon despite multisystem involvement, very elevated inflammatory markers, and the need for intensive care support.

Developing new models of care at speed: learning from healthcare redesign for children with COVID-related multisystem inflammation.

This article describes the rapid, system-wide reconfiguration of local and network services in response to the newly described paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) (also known as multisystem inflammatory syndrome in children). Developing the model of care for this novel disease, whose natural history, characteristics and treatment options were still unclear, presented distinct challenges.We analyse this redesign through the lens of healthcare management science, and outline transferable principles which may be of specific and urgent relevance for paediatricians yet to experience the full impact of the COVID-19 pandemic; and more generally, for those developing a new clinical service or healthcare operating model to manage the sudden emergence of any unanticipated clinical entity. Health service leaders in areas where COVID-19 is, or will soon be, in the ascendancy, and who are anticipating the imminent influx of PIMS-TS, should use these principles and recommendations to plan an agile, responsive and system-wide model of care for these children.

Multimodality cardiac evaluation in children and young adults with multisystem inflammation associated with COVID-19.

AIMS: Following the peak of the UK COVID-19 epidemic, a new multisystem inflammatory condition with significant cardiovascular effects emerged in young people. We utilized multimodality imaging to provide a detailed sequential description of the cardiac involvement. METHODS AND RESULTS: Twenty consecutive patients (mean age 10.6 ± 3.8 years) presenting to our institution underwent serial echocardiographic evaluation on admission (median day 5 of illness), the day coinciding with worst cardiac function (median day 7), and the day of discharge (median day 15). We performed cardiac computed tomography (CT) to assess coronary anatomy (median day 15) and cardiac magnetic resonance imaging (CMR) to assess dysfunction (median day 20). On admission, almost all patients displayed abnormal strain and tissue Doppler indices. Three-dimensional (3D) echocardiographic ejection fraction (EF) was <55% in half of the patients. Valvular regurgitation (75%) and small pericardial effusions (10%) were detected. Serial echocardiography demonstrated that the mean 3D EF deteriorated (54.7 ± 8.3% vs. 46.4 ± 8.6%, P = 0.017) before improving at discharge (P = 0.008). Left main coronary artery (LMCA) dimensions were significantly larger at discharge than at admission (Z score -0.11 ± 0.87 vs. 0.78 ± 1.23, P = 0.007). CT showed uniform coronary artery dilatation commonly affecting the LMCA (9/12). CMR detected abnormal strain in all patients with global dysfunction (EF <55%) in 35%, myocardial oedema in 50%, and subendocardial infarct in 5% (1/20) patients. CONCLUSIONS: Pancarditis with cardiac dysfunction is common and associated with myocardial oedema. Patients require close monitoring due to coronary artery dilatation and the risk of thrombotic myocardial infarction.

Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2.

Importance: In communities with high rates of coronavirus disease 2019, reports have emerged of children with an unusual syndrome of fever and inflammation. Objectives: To describe the clinical and laboratory characteristics of hospitalized children who met criteria for the pediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PIMS-TS) and compare these characteristics with other pediatric inflammatory disorders. Design, Setting, and Participants: Case series of 58 children from 8 hospitals in England admitted between March 23 and May 16, 2020, with persistent fever and laboratory evidence of inflammation meeting published definitions for PIMS-TS. The final date of follow-up was May 22, 2020. Clinical and laboratory characteristics were abstracted by medical record review, and were compared with clinical characteristics of patients with Kawasaki disease (KD) (n = 1132), KD shock syndrome (n = 45), and toxic shock syndrome (n = 37) who had been admitted to hospitals in Europe and the US from 2002 to 2019. Exposures: Signs and symptoms and laboratory and imaging findings of children who met definitional criteria for PIMS-TS from the UK, the US, and World Health Organization. Main Outcomes and Measures: Clinical, laboratory, and imaging characteristics of children meeting definitional criteria for PIMS-TS, and comparison with the characteristics of other pediatric inflammatory disorders. Results: Fifty-eight children (median age, 9 years [interquartile range {IQR}, 5.7-14]; 20 girls [34%]) were identified who met the criteria for PIMS-TS. Results from SARS-CoV-2 polymerase chain reaction tests were positive in 15 of 58 patients (26%) and SARS-CoV-2 IgG test results were positive in 40 of 46 (87%). In total, 45 of 58 patients (78%) had evidence of current or prior SARS-CoV-2 infection. All children presented with fever and nonspecific symptoms, including vomiting (26/58 [45%]), abdominal pain (31/58 [53%]), and diarrhea (30/58 [52%]). Rash was present in 30 of 58 (52%), and conjunctival injection in 26 of 58 (45%) cases. Laboratory evaluation was consistent with marked inflammation, for example, C-reactive protein (229 mg/L [IQR, 156-338], assessed in 58 of 58) and ferritin (610 µg/L [IQR, 359-1280], assessed in 53 of 58). Of the 58 children, 29 developed shock (with biochemical evidence of myocardial dysfunction) and required inotropic support and fluid resuscitation (including 23/29 [79%] who received mechanical ventilation); 13 met the American Heart Association definition of KD, and 23 had fever and inflammation without features of shock or KD. Eight patients (14%) developed coronary artery dilatation or aneurysm. Comparison of PIMS-TS with KD and with KD shock syndrome showed differences in clinical and laboratory features, including older age (median age, 9 years [IQR, 5.7-14] vs 2.7 years [IQR, 1.4-4.7] and 3.8 years [IQR, 0.2-18], respectively), and greater elevation of inflammatory markers such as C-reactive protein (median, 229 mg/L [IQR 156-338] vs 67 mg/L [IQR, 40-150 mg/L] and 193 mg/L [IQR, 83-237], respectively). Conclusions and Relevance: In this case series of hospitalized children who met criteria for PIMS-TS, there was a wide spectrum of presenting signs and symptoms and disease severity, ranging from fever and inflammation to myocardial injury, shock, and development of coronary artery aneurysms. The comparison with patients with KD and KD shock syndrome provides insights into this syndrome, and suggests this disorder differs from other pediatric inflammatory entities.