COVID-19 in a tertiary paediatric centre in Portugal: a single-centre retrospective study.

OBJECTIVE: To describe the demographic, clinical, laboratory and imaging features of the first 300 SARS-CoV-2-infected children presenting to a tertiary paediatric centre in Portugal. DESIGN: Single-centre, retrospective, descriptive study of paediatric patients who had a confirmed SARS-CoV-2 infection from 7 March to 20 September 2020. SETTING: Tertiary paediatric referral centre (Hospital Dona Estefânia, Lisbon, Portugal). PATIENTS: 18 years or younger. MAIN OUTCOME MEASURES: Incidence, mortality, age of infection, clinical characteristics, treatment prescribed and outcome. RESULTS: Three hundred patients with confirmed COVID-19 presented to the centre. One hundred and seventeen (39%) patients were admitted to the hospital: 69 with COVID-19 and 48 for other reasons. The most common symptoms in children admitted with COVID-19 were fever (49) and cough (38). Six patients required intensive care. Two children died and seven reported short-term sequelae. CONCLUSIONS: COVID-19 is usually a mild disease in children, but a small proportion of patients develop severe and critical disease. Fatal outcomes were rare and only occurred in children with severe previous medical conditions.

Saliva molecular testing bypassing RNA extraction is suitable for monitoring and diagnosing SARS-CoV-2 infection in children.

BACKGROUND: Adults are being vaccinated against SARS-CoV-2 worldwide, but the longitudinal protection of these vaccines is uncertain, given the ongoing appearance of SARS-CoV-2 variants. Children remain largely unvaccinated and are susceptible to infection, with studies reporting that they actively transmit the virus even when asymptomatic, thus affecting the community. METHODS: We investigated if saliva is an effective sample for detecting SARS-CoV-2 RNA and antibodies in children, and associated viral RNA levels to infectivity. For that, we used a saliva-based SARS-CoV-2 RT-qPCR test, preceded or not by RNA extraction, in 85 children aged 10 years and under, admitted to the hospital regardless of COVID-19 symptomatology. Amongst these, 29 (63.0%) presented at least one COVID-19 symptom, 46 (54.1%) were positive for SARS-CoV-2 infection, 28 (32.9%) were under the age of 1, and the mean (SD) age was 3.8 (3.4) years. Saliva samples were collected up to 48 h after a nasopharyngeal swab-RT-qPCR test. RESULTS: In children aged 10 years and under, the sensitivity, specificity, and accuracy of saliva-RT-qPCR tests compared to NP swab-RT-qPCR were, respectively, 84.8% (71.8%-92.4%), 100% (91.0%-100%), and 91.8% (84.0%-96.6%) with RNA extraction, and 81.8% (68.0%-90.5%), 100% (91.0%-100%), and 90.4% (82.1%-95.0%) without RNA extraction. Rescue of infectious particles from saliva was limited to CT values below 26. In addition, we found significant IgM positive responses to SARS-CoV-2 in children positive for SARS-CoV-2 by NP swab and negative by saliva compared to other groups, indicating late infection onset (>7-10 days). CONCLUSIONS: Saliva is a suitable sample type for diagnosing children aged 10 years and under, including infants aged <1 year, even bypassing RNA extraction methods. Importantly, the detected viral RNA levels were significantly above the infectivity threshold in several samples. Further investigation is required to correlate SARS-CoV-2 RNA levels to viral transmission.

Multisystem Inflammatory Syndrome in Children Associated with COVID-19 in a Tertiary Level Hospital in Portugal.

INTRODUCTION: Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe manifestation of coronavirus disease 2019 (COVID-19). The aim of this study was to describe the characteristics of children with MIS-C admitted to a pediatric tertiary hospital in Portugal. MATERIAL AND METHODS: Observational descriptive study of MIS-C patients admitted between April 2020 and April 2021. Demographic and clinical characteristics, diagnostic tests, and treatment data were collected. The diagnosis of MIS-C was based on the World Health Organization and Centers for Disease Control and Prevention criteria. RESULTS: We reported 45 children with MIS-C. The median age was seven years (IQR 4 - 10 years) and 60.0% were previously healthy. SARS-CoV-2 infection was confirmed in 77.8% by RT-PCR or antibody testing for SARS-CoV-2, and in 73.3%, an epidemiological link was confirmed. All the patients had a fever and organ system involvement: hematologic (100%), cardiovascular (97.8%), gastrointestinal (97.8%), mucocutaneous (86.7%), respiratory (26.7%), neurologic (15.6%), and renal (13.3%) system. Neurological (p = 0.035) and respiratory (p = 0.035) involvement were observed in patients with a more severe presentation. There was a significant difference of medians when comparing disease severity groups, namely in the values of hemoglobin (p = 0.015), lymphocytes (p = 0.030), D-dimer (p = 0.019), albumin (p < 0.001), NT-proBNP (p = 0.005), ferritin (p = 0.048), CRP (p = 0.006), procalcitonin (p = 0.005) and IL-6 (p = 0.002). From the total number of children, 93.3% received intravenous immunoglobulin, 91.1% methylprednisolone, and one patient (2.2%) received anakinra. Thirteen patients (28.8%) required intensive care and there were no deaths. Of the 21 patients evaluated, 90.4% had reduction of exercise capacity and of the 15 patients who underwent cardiac magnetic resonance, 53.3% had sequelae of cardiac injury. CONCLUSION: We observed a large spectrum of disease presentation in a group of patients where most were previously healthy. A small percentage of patients (28.9%) had a severe presentation of the disease. MIS-C is a challenge in current clinical practice and its diagnosis requires a high level of clinical suspicion as the timely initiation of therapy is essential to prevent complications. However, there is no scientific consensus on the treatment and follow-up of these patients.

Introdução: A síndrome inflamatória multissistémica em crianças (MIS-C) é uma manifestação rara, mas grave da doença por coronavírus 2019 (COVID-19). Este estudo teve como objetivo descrever as características de crianças com MIS-C internadas num hospital pediátrico terciário em Portugal. Material e Métodos: Estudo observacional e descritivo de doentes com MIS-C internados de abril de 2020 a abril de 2021. Analisaram-se dados demográficos, clínicos, exames de diagnóstico e terapêutica. O diagnóstico baseou-se nos critérios da Organização Mundial de Saúde e Centers for Disease Control and Prevention. Resultados: Foram identificadas 45 crianças, com mediana de idades de sete anos (AIQ 4 - 10 anos) sendo 60,0% previamente saudáveis. A infeção por SARS-CoV-2 foi confirmada por RT-PCR ou serologia em 77,8% dos doentes e 73,3% tinham link epidemiológico. Todos os casos cursaram com febre e envolvimento multiorgânico: hematológico (100%), cardiovascular (97,8%), gastrointestinal (97,8%), mucocutâneo (86,7%), respiratório (26,7%), neurológico (15,6%) e renal (13,3%). O envolvimento neurológico (p = 0,035) e respiratório (p = 0,035) ocorreu nos doentes mais graves. Houve uma diferença significativa das medianas quando comparados grupos de gravidade da doença, nomeadamente nos valores de hemoglobina (p = 0,015), linfócitos (p = 0,030), D-dímeros (p = 0,019), albumina (p < 0,001), NT-proBNP (p = 0,005), ferritina (p = 0,048), pCr (p = 0,006), procalcitonina (p = 0,005) e IL-6 (p = 0,002). Destas crianças, 93,3% realizaram imunoglobulina intravenosa, 91% metilprednisolona e um (2,2%) realizou anakinra. Treze doentes (28,8%) necessitaram de cuidados intensivos e não se registaram óbitos. Dos 21 doentes avaliados seis meses após a alta, 90,4% apresentaram diminuição da tolerância ao esforço e 8/15 (53,3%) lesão cardíaca persistente. Conclusão: Observámos um amplo espectro de apresentação da doença num grupo de doentes previamente saudável, na sua maioria. Uma pequena percentagem de pacientes (28,9%) teve uma apresentação grave da doença. O diagnóstico da MIS-C é um desafio na prática clínica atual e requer um elevado nível de suspeição pois o início atempado de terapêutica é fundamental para prevenir complicações. No entanto, não existe ainda consenso científico sobre a melhor terapêutica e seguimento destes doentes.

Protocol-based cardiotoxicity monitoring in hydroxychloroquine medicated COVID-19 pediatric patients.

INTRODUCTION/OBJECTIVES: By May 2020, SARS-CoV-2 had caused more than 400 000 deaths worldwide. Initially, hydroxychloroquine was a treatment option for COVID-19. More recent studies have questioned its safety and efficacy and, until stronger evidence is available, it was suspended from therapy protocols. We describe our experience treating COVID-19 Portuguese pediatric patients with hydroxychloroquine, having applied a protocol for monitoring cardiac toxicity. METHODS: An observational retrospective study of COVID-19 pediatric patients, admitted from March to April 2020 and treated with hydroxychloroquine. Cardiotoxicity was assessed using ECG recordings and corrected QT-time (QTc). Patients were classified into risk-groups depending on QTc value: normal, slightly elevated or severely elevated (>500 ms). RESULTS: Total of 14 patients, with a median age of 10 years [four months; 17 years], treated with hydroxychloroquine for a median of five days. Hydroxychloroquine was used in monotherapy in six patients (mainly mild disease with comorbidities), and in association with lopinavir/ritonavir (3) and azithromycin (5) in moderate to severe disease. Other QT-prolonging therapies were used in five patients: oseltamivir (3), omeprazole (1), morphine (1) and ketamine (1). At 48 hours of treatment, two patients temporarily suspended hydroxychloroquine due to QTc prolongation (>500 ms). All patients completed the whole treatment. No other side effects or deaths occurred. CONCLUSION: Clinical trials are evolving to define hydroxychloroquine effectivity and safety. Our considerable pediatric population supports the need for cardiotoxicity monitoring during therapy but suggest its use seems to be safe in COVID-19 pediatric patients, even in association with other QT-prolonging therapies.

INTRODUÇÃO/OBJETIVO: A hidroxicloroquina foi inicialmente uma das opções terapêuticas na Covid-19. Descreve-se o tratamento com hidroxicloroquina em doentes Covid-19 pediátricos, tendo aplicado um protocolo de monitoração cardíaca pelo seu potencial arritmogénico. MÉTODOS: Estudo observacional retrospetivo de doentes pediátricos com Covid-19, internados de março a abril 2020, medicados com hidroxicloroquina. A monitoração cardíaca foi realizada por eletrocardiogramas regulares e cálculo do intervalo QT corrigido durante o tratamento. Os doentes foram classificados consoante o valor de QTc: normal, moderadamente aumentado ou muito aumentado (>500 msg). RESULTADOS: Total de 14 doentes, com mediana de 10 anos [4 meses; 17 anos], medicados com HCQ durante uma mediana de 5 dias em doentes com pneumonia ou comorbilidades. A monoterapia foi realizada em 6 doentes, 4 com fatores de risco, e em associação com lopinavir/ritonavir (3) e azitromicina (5) na doença grave e moderada. Foram ainda usados fármacos capazes de prolongar o intervalo QT: oseltamivir (3), omeprazol (1), cetamina e morfina (1) em 5 doentes. Após 48 horas de terapêutica, dois doentes apresentaram intervalo QTc muito aumentado, condicionando suspensão temporária do fármaco. Todos os doentes concluíram o tratamento sem outros efeitos adversos. CONCLUSÃO: A HCQ permanece em ensaios clínicos para avaliação da sua efetividade e segurança. A nossa amostra considerável em doentes pediátricos apoia a necessidade de monitoração de toxicidade cardíaca, mas sugere na população estudada, mesmo na associação com outros fármacos que prolongam o intervalo QT, a segurança de sua utilização.

Clinical and Therapeutic Approach to Hospitalized COVID-19 Patients: A Pediatric Cohort in Portugal.

INTRODUCTION: Coronavirus disease 2019, or COVID-19, in children is usually a mild disease, but severe illness has been reported. Currently, the therapy benefits of antiviral experimental drugs are still uncertain. The main aim of this study is to describe the experience of a level III hospital regarding therapeutic management of hospitalized children with COVID-19 and to characterize clinical features and evolution. MATERIAL AND METHODS: This is a descriptive study of patients with COVID-19 in a level III pediatric hospital in Portugal between March and June 2020. Experimental drugs were administered according to the best scientific evidence at the time as 'off-label use'. RESULTS: Among 200 children with SARS-CoV-2 infection, 37 were admitted due to COVID-19. Median age was one year (23 days - 18 years), 43% had comorbidities and 20/37 (54%) received antiviral therapy. Hydroxychloroquine was administered in 13 patients, in monotherapy or combined with lopinavir/ritonavir or azithromycin. Lopinavir/ritonavir was administered in eight patients and three children were treated with remdesivir. The patients who were treated had pneumonia (14), multisystem inflammatory syndrome in children (2), sepsis (2), myocarditis (1), acute respiratory distress syndrome (1), and mild illness with comorbidities (3). Other therapies included methylprednisolone and immunoglobulin (3), enoxaparin (2), antibiotics (16), oxygen (7), corticosteroids, and other inhaled therapy (16). DISCUSSION: Several treatment approaches have been proposed for severe COVID-19, even though none of them had been proven effective or approved for small children. Currently, remdesivir is approved for children aged above 12 years-old. Although 54% of our patients were treated with antivirals, it is important to understand that the favorable clinical evolution could be related with the natural course of the disease. CONCLUSION: A significant proportion of our population presented severe and critical disease, was hospitalized and received treatment according to the most recent data, although most patients had mild disease. COVID-19 treatment in children is a clinical challenge and clinical trials are urgently needed.

Introdução: A infeção SARS-CoV-2 em idade pediátrica cursa maioritariamente com doença ligeira. No entanto, pode ocorrer doença grave, ainda que com menor frequência. Atualmente, os benefícios das terapêuticas antivirais experimentais ainda são incertos. O objetivo deste estudo consiste em descrever a experiência de um hospital terciário no tratamento de crianças internadas por COVID-19 e caracterizar a clínica e evolução. Material e Métodos: Estudo descritivo em doentes até aos 18 anos de idade, internados com COVID-19 num hospital pediátrico de nível III em Portugal, de março a junho de 2020. Os fármacos antivirais foram administrados em regime de off-label. Resultados: Identificaram-se 200 casos de infeção SARS-CoV-2, dos quais 37 foram internados com COVID-19. A idade mediana foi de um ano (23 dias - 18 anos), 43% apresentavam comorbilidades e 20/37 (54%) receberam terapêutica antiviral. A hidroxicloroquina foi administrada em 13 doentes em monoterapia ou associada a lopinavir/ritonavir ou azitromicina. O lopinavir/ritonavir foi utilizado em oito doentes e três doentes receberam remdesivir. O tratamento antiviral foi aplicado a doentes com pneumonia (14), sépsis (2), síndrome inflamatório multisistémico pediátrico (2), síndrome dificuldade respiratória aguda (1), miocardite (1) e crianças com doença ligeira e comorbilidades (3). Realizaram-se também outras terapêuticas que incluíram metilprednisolona e imunoglobulina (3), enoxaparina (2), antibióticos (16), oxigenoterapia (7) e broncodilatadores e corticoides inalados (16). Discussão: Diversas abordagens terapêuticas têm sido sugeridas para casos graves de COVID-19, embora nenhuma seja até à data considerada eficaz, ou esteja aprovada em crianças pequenas. Atualmente, o remdesivir está aprovado para idades superiores a 12 anos. Apesar de 54% dos nossos doentes terem sido tratados com antivirais, é importante compreender que a evolução favorável poderá ter estado associada à evolução natural da doença. Conclusão: Uma percentagem significativa da população apresentou doença grave a crítica, com necessidade de internamento e tratamento, este último definido com base nas recomendações da comunidade científica à data, embora a maioria apresentasse doença ligeira. O tratamento da COVID-19 em idade pediátrica é um desafio, sendo urgente realizar ensaios clínicos relativos a esta matéria.