Home-Based Exercise Training in the Recovery of Multisystem Inflammatory Syndrome in Children: A Case Series Study.

OBJECTIVE: To assess the potential therapeutic role of exercise on health-related quality of life, assessed by the Pediatric Outcomes Data Collection Instrument (PODCI), coronary flow reserve (CFR), cardiac function, cardiorespiratory fitness, and inflammatory and cardiac blood markers in multisystemic inflammatory syndrome in children (MIS-C) patients. METHODS: This is a case series study of a 12-wk, home-based exercise intervention in children and adolescents after MIS-C diagnosis. From 16 MIS-C patients followed at our clinic, 6 were included (age: 7-16 years; 3 females). Three of them withdrew before the intervention and served as controls. The primary outcome was health-related quality of life, assessed PODCI. Secondary outcomes were CFR assessed by 13N-ammonia PET-CT imaging, cardiac function by echocardiography, cardiorespiratory fitness, and inflammatory and cardiac blood markers. RESULTS: In general, patients showed poor health-related quality of life, which seemed to be improved with exercise. Additionally, exercised patients showed improvements in coronary flow reserve, cardiac function, and aerobic conditioning. Non-exercised patients exhibited a slower pattern of recovery, particularly in relation to health-related quality of life and aerobic conditioning. CONCLUSIONS: Our results suggest that exercise may play a therapeutic role in the treatment of post-discharge MIS-C patients. As our design does not allow inferring causality, randomized controlled trials are necessary to confirm these preliminary findings.

Technical performance of a lateral flow immunoassay for detection of anti-SARS-CoV-2 IgG in the outpatient follow-up of non-severe cases and at different times after vaccination: comparison with enzyme and chemiluminescent immunoassays.

This study assessed the technical performance of a rapid lateral flow immunochromatographic assay (LFIA) for the detection of anti-SARS-CoV-2 IgG and compared LFIA results with chemiluminescent immunoassay (CLIA) results and an in-house enzyme immunoassay (EIA). To this end, a total of 216 whole blood or serum samples from three groups were analyzed: the first group was composed of 68 true negative cases corresponding to blood bank donors, healthy young volunteers, and eight pediatric patients diagnosed with other coronavirus infections. The serum samples from these participants were obtained and stored in a pre-COVID-19 period, thus they were not expected to have COVID-19. In the second group of true positive cases, we chose to replace natural cases of COVID-19 by 96 participants who were expected to have produced anti-SARS-CoV-2 IgG antibodies 30-60 days after the vaccine booster dose. The serum samples were collected on the same day that LFIA were tested either by EIA or CLIA. The third study group was composed of 52 participants (12 adults and 40 children) who did or did not have anti-SARS-CoV-2 IgG antibodies due to specific clinical scenarios. The 12 adults had been vaccinated more than seven months before LFIA testing, and the 40 children had non-severe COVID-19 diagnosed using RT-PCR during the acute phase of infection. They were referred for outpatient follow-up and during this period the serum samples were collected and tested by CLIA and LFIA. All tests were performed by the same healthcare operator and there was no variation of LFIA results when tests were performed on finger prick whole blood or serum samples, so that results were grouped for analysis. LFIA's sensitivity in detecting anti-SARS-CoV-2 IgG antibodies was 90%, specificity 97.6%, efficiency 93%, PPV 98.3%, NPV 86.6%, and likelihood ratio for a positive or a negative result were 37.5 and 0.01 respectively. There was a good agreement (Kappa index of 0.677) between LFIA results and serological (EIA or CLIA) results. In conclusion, LFIA analyzed in this study showed a good technical performance and agreement with reference serological assays (EIA or CLIA), therefore it can be recommended for use in the outpatient follow-up of non-severe cases of COVID-19 and to assess anti-SARS-CoV-2 IgG antibody production induced by vaccination and the antibodies decrease over time. However, LFIAs should be confirmed by using reference serological assays whenever possible.

SARS-CoV-2 and rhinovirus infections: are there differences in clinical presentation, laboratory abnormalities, and outcomes in the pediatric population?

This study aims to assess COVID-19 and other respiratory viruses in pediatric patients. Between April 17 and September 30, 2020, we collected 1,566 respiratory samples from 1,044 symptomatic patients who were younger than 18 years old to assess SARS-CoV-2 infection. Of these, 919 were analyzed for other respiratory pathogens (ORP). Patients with laboratory-confirmed COVID-19 or ORP were included. We evaluated 76 pediatric COVID-19 infections and 157 other respiratory virus infections. Rhinovirus occurred in 132/157 (84%). COVID-19 patients who were significantly older, had more fevers, headaches and pneumonia than those with ORP. The median white blood cell count was lower in patients with SARS-CoV-2 than in those with ORP (6,470 versus 8,170; p=0.02). COVID-19 patients had significantly worse symptoms than those with ORP.

In-depth cardiovascular and pulmonary assessments in children with multisystem inflammatory syndrome after SARS-CoV-2 infection: A case series study.

We assessed PET-CT myocardial blood flow (MBF) using N-13 ammonia, brachial flow-mediated dilation, and cardiopulmonary exercise test in five post-discarged MIS-C survivors. None of the patients (median age: 9, range: 7-18 years; 3 females; 2 males) had preexisting pediatric chronic conditions. At the follow-up visit, two patients exhibited severe perfusion defect developed in the left ventricular cavity, suggesting extensive myocardial ischemia (MBF <2.0) and one patient showed persistent mild pericardial effusion. Others two patients demonstrated endothelial dysfunction. Nevertheless, all patients had lower predicted values in the VO2peak , VO2VAT , OUES, and O2 Pulse (range: 35.2%-64.5%; 15.6%-38.2%; 1.0-1.3 L/min; 4-7 ml/beat), respectively. Our d suggested that previously health MIS-C patients had impaired MBF, endothelial dysfunction and lower cardiopulmonary capacity at follow-up analysis. Multidisciplinary further investigations should be conducted to reinforce these findings.

Segmental cardiac strain assessment by two-dimensional speckle-tracking echocardiography in surviving MIS-c patients: Correlations with myocardial flow reserve (MFR) by 13 N-ammonia PET-CT.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-c) is associated with severe cardiovascular impairment and eventually death. Pathophysiological mechanisms involved in myocardial injury were scarcely investigated, and cardiovascular outcomes are uncertain. Autopsy studies suggested that microvascular dysfunction may be relevant to LV impairment. OBJECTIVE: We aimed to evaluate segmental LV longitudinal strain by 2DST echocardiography and myocardial flow reserve (MFR) by 13 N-ammonia PET-CT, in six surviving MIS-c patients. METHODS: Each patient generated 34 LV segments for combined 2DST and MRF analysis. MFR was considered abnormal when <2, borderline when between 2 and 2.5 and normal when >2.5. RESULTS: From July 2020 to February 2021, six patients were admitted with MIS-c: three males, aged 9.3 (6.6-15.7) years. Time from admission to the follow-up visit was 6.05 (2-10.3) months. Although all patients were asymptomatic and LV EF was ≥55%, 43/102 (42.1%) LV segments showed MFR <2.5. There was a modest positive correlation between segmental peak systolic longitudinal strain and MFR: r = .36, p = .03 for basal segments; r = .41, p = .022 for mid segments; r = .42, p = .021 for apical segments. Median peak systolic longitudinal strain was different among MRF categories: 18% (12%-24%) for abnormal, 18.5% (11%-35%) for borderline, and 21% (12%-32%) for normal MFR (p = .006). CONCLUSION: We provided preliminary evidence that surviving MIS-c patients may present subclinical impairment of myocardial microcirculation. Segmental cardiac strain assessment 2DST seems useful for MIS-c cardiovascular follow-up, given its good correlation with 13 N-ammonia PET-CT derived MFR.

Differences in children and adolescents with SARS-CoV-2 infection: a cohort study in a Brazilian tertiary referral hospital.

OBJECTIVES: To compare demographic/clinical/laboratory/treatments and outcomes among children and adolescents with laboratory-confirmed coronavirus disease 2019 (COVID-19). METHODS: This was a cross-sectional study that included patients diagnosed with pediatric COVID-19 (aged <18 years) between April 11, 2020 and April 22, 2021. During this period, 102/5,951 (1.7%) of all admissions occurred in neonates, children, and adolescents. Furthermore, 3,962 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection samples were processed in patients aged <18 years, and laboratory-confirmed COVID-19 occurred in 155 (4%) inpatients and outpatients. Six/155 pediatric patients were excluded from the study. Therefore, the final group included 149 children and adolescents (n=97 inpatients and 52 outpatients) with positive SARS-CoV-2 results. RESULTS: The frequencies of sore throat, anosmia, dysgeusia, headache, myalgia, nausea, lymphopenia, pre-existing chronic conditions, immunosuppressive conditions, and autoimmune diseases were significantly reduced in children and adolescents (p<0.05). Likewise, the frequencies of enoxaparin use (p=0.037), current immunosuppressant use (p=0.008), vasoactive agents (p=0.045), arterial hypotension (p<0.001), and shock (p=0.024) were significantly lower in children than in adolescents. Logistic regression analysis showed that adolescents with laboratory-confirmed COVID-19 had increased odds ratios (ORs) for sore throat (OR 13.054; 95% confidence interval [CI] 2.750-61.977; p=0.001), nausea (OR 8.875; 95% CI 1.660-47.446; p=0.011), and lymphopenia (OR 3.575; 95% CI 1.355-9.430; p=0.010), but also had less hospitalizations (OR 0.355; 95% CI 0.138-0.916; p=0.032). The additional logistic regression analysis on patients with preexisting chronic conditions (n=108) showed that death as an outcome was significantly associated with pediatric severe acute respiratory syndrome (SARS) (OR 22.300; 95% CI 2.341-212.421; p=0.007) and multisystem inflammatory syndrome in children (MIS-C) (OR 11.261; 95% CI 1.189-106. 581; p=0.035). CONCLUSIONS: Half of the laboratory-confirmed COVID-19 cases occurred in adolescents. Individuals belonging to this age group had an acute systemic involvement of SARS-CoV-2 infection. Pediatric SARS and MIS-C were the most important factors associated with the mortality rate in pediatric chronic conditions with COVID-19.

The Heart of Pediatric Patients with COVID-19: New Insights from a Systematic Echocardiographic Study in a Tertiary Hospital in Brazil. / O Coração de Pacientes Pediátricos com COVID-19: Novos Insights a Partir de um Estudo Ecocardiográfico Sistemático em um Hospital Terciário no Brasil.

BACKGROUND: COVID-19 pandemic represents a huge burden to the health system in the world. Although pediatric COVID-19 patients have been relatively spared compared with adults, recent reports showed an increasing number of critically ill patients with multisystemic inflammatory syndrome in children (MIS-c), with marked cardiovascular impairment. Nevertheless, little is known about the relationship between cardiac abnormalities and inflammatory and coagulation biomarkers. OBJECTIVES: to investigate echocardiographic abnormalities in pediatric patients with COVID-19 admitted to tertiary hospital. METHODS: this was a retrospective longitudinal study, based on the review of medical records and echocardiograms of patients (0-19 years) admitted to a tertiary hospital between March 30 and June 30, 2020. For statistical analysis, the significance level was set at 5% (p < 0.05). RESULTS: Forty-eight patients were enrolled, 73% with preexisting diseases, 20 (41.7%) with MIS-c. Median age was 7.5 (0-18.6) years; 27 (56.2%) were male. Median duration of hospitalization was 15.4 (2-92) days and seven (14.6%) patients died. A total of 70 echocardiograms were performed; 66.7% patients were scanned only once and 33.3% multiple times. Twenty-three (48%) patients showed echocardiographic abnormalities: eight (16.6%) left ventricle (LV) systolic dysfunction, six (12.5%) right ventricle (RV) systolic dysfunction and 12 (25%) coronary dilatation (Z-score>+2.5). Echocardiographic abnormalities were significantly associated with MIS-c, admission to the pediatric intensive care unit, multiple organ dysfunction, ventilatory/vasoactive support, and death (p<0.05). Significantly higher d-dimer (ng/mL) levels were detected in patients with LV dysfunction [16733(4157-115668) vs. 2406.5(190-95040)], RV dysfunction [25769(3422-115668) vs. 2803.5(190-95040)] and coronary artery dilation [9652.5(921-115668) vs. 2724(190- 95040)] (p<0.05). CONCLUSION: Echocardiographic abnormalities in COVID-19 pediatric patients were frequent and associated with worse clinical outcomes. Exacerbation of the inflammation and coagulation pathways may play an important role in cardiovascular injury in those patients.

FUNDAMENTO: A pandemia da COVID-19 representa uma enorme carga para o sistema de saúde do mundo. Apesar de pacientes pediátricos terem sido relativamente poupados em comparação a adultos, estudos recentes mostraram um número crescente de pacientes críticos com Síndrome Inflamatória Multisistêmica Pediátrica (SIM-P) com disfunção cardiovascular importante. No entanto, pouco se conhece a respeito da relação entre anormalidades cardíacas e biomarcadores inflamatórios e de coagulação. OBJETIVOS: Investigar anormalidades ecocardiográficas em pacientes pediátricos com COVID-19 admitidos em um hospital terciário. MÉTODOS: Este foi um estudo longitudinal retrospectivo, baseado na revisão de prontuários médicos e ecocardiogramas de pacientes (0-19 anos) admitidos em um hospital terciário entre 30 de março e 30 de junho de 2020. Para a análise estatística, o nível de significância foi estabelecido em 5% (p<0,05). RESULTADOS: Foram incluídos 48 pacientes, 73% com doenças pré-existentes, 20 (41,7%) com SIM-P. A idade mediana foi 7,5 (0-18,6) anos; 27 (56,2%) eram do sexo masculino. A duração mediana de internação foi 15,4 (2-92) dias e sete (14,6%) pacientes morreram. Um total de 70 ecocardiografias foram realizadas, 66,7% submeteram-se ao exame somente uma vez, e 33,3% várias vezes. Vinte e três (48%) pacientes apresentaram anormalidades no ecocardiograma: oito (16.6%) disfunção sistólica do ventrículo esquerdo, seis (12.5%) disfunção sistólica do ventrículo direito, e 12 (25%) dilatação da artéria coronária (Z-score>+2,5). Anormalidades ecocardiográficas foram significativamente associadas com SIM-P, admissão na unidade de terapia intensiva pediátrica, suporte ventilatório/vasoativo, e morte ( p <0,05). Níveis significativamente mais altos de d-dímero (ng/mL) foram detectados em pacientes com disfunção ventricular esquerda [16733(4157-115668) vs. 2406.5(190-95040)], disfunção ventricular direita [25769(3422-115668) vs. 2803.5(190-95040)] e dilatação da artéria coronária [9652.5(921-115668) vs. 2724(190- 95040)] (p<0,05). CONCLUSÃO: Anormalidades ecocardiográficas eram frequentes nos pacientes pediátricos com COVID-19 e associadas com piores desfechos clínicos. Exacerbação das vias de inflamação e coagulação pode exercer um importante papel na lesão cardiovascular nesses pacientes.

An autopsy study of the spectrum of severe COVID-19 in children: From SARS to different phenotypes of MIS-C.

BACKGROUND: COVID-19 in children is usually mild or asymptomatic, but severe and fatal paediatric cases have been described. The pathology of COVID-19 in children is not known; the proposed pathogenesis for severe cases includes immune-mediated mechanisms or the direct effect of SARS-CoV-2 on tissues. We describe the autopsy findings in five cases of paediatric COVID-19 and provide mechanistic insight into the mechanisms involved in the pathogenesis of the disease. METHODS: Children and adolescents who died with COVID-19 between March 18 and August 15, 2020 were autopsied with a minimally invasive method. Tissue samples from all vital organs were analysed by histology, electron microscopy (EM), reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). FINDINGS: Five patients were included, one male and four female, aged 7 months to 15 years. Two patients had severe diseases before SARS-CoV-2 infection: adrenal carcinoma and Edwards syndrome. Three patients were previously healthy and had multisystem inflammatory syndrome in children (MIS-C) with distinct clinical presentations: myocarditis, colitis, and acute encephalopathy with status epilepticus. Autopsy findings varied amongst patients and included mild to severe COVID-19 pneumonia, pulmonary microthrombosis, cerebral oedema with reactive gliosis, myocarditis, intestinal inflammation, and haemophagocytosis. SARS-CoV-2 was detected in all patients in lungs, heart and kidneys by at least one method (RT-PCR, IHC or EM), and in endothelial cells from heart and brain in two patients with MIS-C (IHC). In addition, we show for the first time the presence of SARS-CoV-2 in the brain tissue of a child with MIS-C with acute encephalopathy, and in the intestinal tissue of a child with acute colitis. Interpretation: SARS-CoV-2 can infect several cell and tissue types in paediatric patients, and the target organ for the clinical manifestation varies amongst individuals. Two major patterns of severe COVID-19 were observed: a primarily pulmonary disease, with severe acute respiratory disease and diffuse alveolar damage, or a multisystem inflammatory syndrome with the involvement of several organs. The presence of SARS-CoV-2 in several organs, associated with cellular ultrastructural changes, reinforces the hypothesis that a direct effect of SARS-CoV-2 on tissues is involved in the pathogenesis of MIS-C. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Bill and Melinda Gates Foundation.

Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome

OBJECTIVES: To assess the outcomes of pediatric patients with laboratory-confirmed coronavirus disease (COVID-19) with or without multisystem inflammatory syndrome in children (MIS-C). METHODS: This cross-sectional study included 471 samples collected from 371 patients (age&lt;18 years) suspected of having severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study group comprised 66/371 (18%) laboratory-confirmed pediatric COVID-19 patients: 61 (92.5%) patients tested positive on real-time reverse transcription-polymerase chain reaction tests for SARS-CoV-2, and 5 (7.5%) patients tested positive on serological tests. MIS-C was diagnosed according to the criteria of the Center for Disease Control. RESULTS: MIS-C was diagnosed in 6/66 (9%) patients. The frequencies of diarrhea, vomiting, and/or abdominal pain (67% vs. 22%, p=0.034);pediatric SARS (67% vs. 13%, p=0.008);hypoxemia (83% vs. 23%, p=0.006);and arterial hypotension (50% vs. 3%, p=0.004) were significantly higher in patients with MIS-C than in those without MIS-C. The frequencies of C-reactive protein levels &gt;50 mg/L (83% vs. 25%, p=0.008) and D-dimer levels &gt;1000 ng/mL (100% vs. 40%, p=0.007) and the median D-dimer, troponin T, and ferritin levels (p&lt;0.05) were significantly higher in patients with MIS-C. The frequencies of pediatric intensive care unit admission (100% vs. 60%, p=0.003), mechanical ventilation (83% vs. 7%, p&lt;0.001), vasoactive agent use (83% vs. 3%, p&lt;0.001), shock (83% vs. 5%, p&lt;0.001), cardiac abnormalities (100% vs. 2%, p&lt;0.001), and death (67% vs. 3%, p&lt;0.001) were also significantly higher in patients with MIS-C. Similarly, the frequencies of oxygen therapy (100% vs. 33%, p=0.003), intravenous immunoglobulin therapy (67% vs. 2%, p&lt;0.001), aspirin therapy (50% vs. 0%, p&lt;0.001), and current acute renal replacement therapy (50% vs. 2%, p=0.002) were also significantly higher in patients with MIS-C. Logistic regression analysis showed that the presence of MIS-C was significantly associated with gastrointestinal manifestations [odds ratio (OR)=10.98;95%CI (95% confidence interval)=1.20-100.86;p=0.034] and hypoxemia [OR=16.85;95%CI=1.34-211.80;p=0.029]. Further univariate analysis showed a positive association between MIS-C and death [OR=58.00;95%CI=6.39-526.79;p&lt;0.0001]. CONCLUSIONS: Pediatric patients with laboratory-confirmed COVID-19 with MIS-C had a severe clinical spectrum with a high mortality rate. Our study emphasizes the importance of investigating MIS-C in pediatric patients with COVID-19 presenting with gastrointestinal involvement and hypoxemia.

Severe clinical spectrum with high mortality in pediatric patients with COVID-19 and multisystem inflammatory syndrome.

OBJECTIVES: To assess the outcomes of pediatric patients with laboratory-confirmed coronavirus disease (COVID-19) with or without multisystem inflammatory syndrome in children (MIS-C). METHODS: This cross-sectional study included 471 samples collected from 371 patients (age<18 years) suspected of having severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The study group comprised 66/371 (18%) laboratory-confirmed pediatric COVID-19 patients: 61 (92.5%) patients tested positive on real-time reverse transcription-polymerase chain reaction tests for SARS-CoV-2, and 5 (7.5%) patients tested positive on serological tests. MIS-C was diagnosed according to the criteria of the Center for Disease Control. RESULTS: MIS-C was diagnosed in 6/66 (9%) patients. The frequencies of diarrhea, vomiting, and/or abdominal pain (67% vs. 22%, p=0.034); pediatric SARS (67% vs. 13%, p=0.008); hypoxemia (83% vs. 23%, p=0.006); and arterial hypotension (50% vs. 3%, p=0.004) were significantly higher in patients with MIS-C than in those without MIS-C. The frequencies of C-reactive protein levels >50 mg/L (83% vs. 25%, p=0.008) and D-dimer levels >1000 ng/mL (100% vs. 40%, p=0.007) and the median D-dimer, troponin T, and ferritin levels (p<0.05) were significantly higher in patients with MIS-C. The frequencies of pediatric intensive care unit admission (100% vs. 60%, p=0.003), mechanical ventilation (83% vs. 7%, p<0.001), vasoactive agent use (83% vs. 3%, p<0.001), shock (83% vs. 5%, p<0.001), cardiac abnormalities (100% vs. 2%, p<0.001), and death (67% vs. 3%, p<0.001) were also significantly higher in patients with MIS-C. Similarly, the frequencies of oxygen therapy (100% vs. 33%, p=0.003), intravenous immunoglobulin therapy (67% vs. 2%, p<0.001), aspirin therapy (50% vs. 0%, p<0.001), and current acute renal replacement therapy (50% vs. 2%, p=0.002) were also significantly higher in patients with MIS-C. Logistic regression analysis showed that the presence of MIS-C was significantly associated with gastrointestinal manifestations [odds ratio (OR)=10.98; 95%CI (95% confidence interval)=1.20-100.86; p=0.034] and hypoxemia [OR=16.85; 95%CI=1.34-211.80; p=0.029]. Further univariate analysis showed a positive association between MIS-C and death [OR=58.00; 95%CI=6.39-526.79; p<0.0001]. CONCLUSIONS: Pediatric patients with laboratory-confirmed COVID-19 with MIS-C had a severe clinical spectrum with a high mortality rate. Our study emphasizes the importance of investigating MIS-C in pediatric patients with COVID-19 presenting with gastrointestinal involvement and hypoxemia.