Adolescents With COVID-19/MIS-C at HCFMUSP

Hospital das Clínicas da Faculdade de Medicina da USP, Fundação de Amparo à Pesquisa do Estado de São Paulo

This is a protocol aimed at children and adolescents contaminated with COVID, treated at the Hospital das Clínicas, University of Sao Paulo, Brazil (HCFMUSP), in the recovery phase. The study aims to evaluate the spectrum of pathogenic lesions of the virus not only in the respiratory system, but digestive, immunological, neurological and others. Clinical, evolutionary, laboratory and functional parameters will be used.

School-age children and adolescents COVID-19 survivors may have persistent inflammation, a chronic course of COVID-19, with isolated or concomitant aggressions of various organs and systems, making this disease a potential chronic condition, impacting aspects of quality of life related to health (HRQoL), physical and mental health. In addition, pediatric COVID-19 can induce autoimmunity (with the possibility of primary hypothyroidism and type I diabetes mellitus), delayed linear growth and delayed pubertal development, secondary immunodeficiency and present genetic polymorphisms in brain plasticity impacting rehabilitation. School-aged children and adolescents with COVID-19 could present muscle weakness, dysautonomy, asthenia and physical inactivity, so it is essential that safe and effective interventions are developed to maintain adequate levels of physical activity and that they can be implemented on a large scale. However, to date, there are no systematic longitudinal studies that have evaluated all these aspects in a pediatric population that survived COVID-19, particularly with chronic conditions and who were hospitalized in a tertiary service.

A 12 weeks parallel-group randomized controlled trial will be performed, in which covid-19 survivors adolescents will complete a telemonitored home-based exercise training program, 3 times per week. The training program will involve strength and aerobic exercises

The control group will receive all regular medical care and advice on healthy lifestyle including the promotion of recommended physical activity levels.

Online strength and aerobic home-based exercise training, 3 times per week, for 12 weeks. The exercise program is composed by 2 intensity-levels (starter and advanced).

Aims to investigate the mechanisms that lead to dyspnea and, consequently, intolerance to physical effort

It will also be assessed for school-age children (7-10 years old) and adolescents (11-18 years old) and by their primary caregiver

Patchy ground-glass opacities, crazy-paving pattern, and localization and pattern of large, confluent or small nodular lesions will be assessed

Conventional transthoracic echocardiogram with color Doppler to assess systolic and diastolic function

Conventional transthoracic echocardiogram with color Doppler to search for aspects of the coronary arteries

Echocardiogram with two-dimensional speckle-tracking technique to identify subclinical changes suggestive of ischemia or myocarditis

Baseline levels of cytokines IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-y, and IL-17A in serum samples will be tested by flow cytometry using the CBA technique (Cytometric bead array, BD Biosciences)

T cell lineages: CD3CD4, CD3CD8, naive cells (CD45RA+), memory cells (CD45RA-), effector cells (CD38+HLADR+)

B cell lineages: CD19, naive cells (CD27-), memory cells (CD27+), plasmablasts (CD27+CD38+CD138-), (plasmocytes CD27+CD38+CD138+)

The antipneumococcal antibody titer against 6 polysaccharides (serotypes 1, 5, 6B, 9V, 14, and 18C) will be analyzed by ELISA. The seroconversion criteria is IgG values > 1.3 mg/mL for each polysaccharide assessed

Evaluation of the thymus by the determination of TRECs (Thymic recent emigrant cells or T-cell receptor excision circles)

TRECs evaluate the peripheral function of the thymus from cells that have recently been released, using the RT-PCR technique

Changes in frequency of the anti-islet antibody of Langerhans will be assessed using indirect fluorescence

Diagnosis of type 1 diabetes mellitus will be assessed by the metabolic profile (fasting glucose, glycated hemoglobin and C peptide)

Linear growth will be assessed by using a standardized stadiometer, calculating standard deviation, growth curves, and growth speed

Development of puberty will be assessed according to the criteria of Tanner and Marshall in adolescents in the prepubertal age group

Bone biochemical and bone remodeling markers (calcium, phosphorus, 25OH alkaline phosphatase vitamin D, PTH, CTX, P1NP)

Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk used during the "timed up and go" test

Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk during the 6-minute walk test

Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk during the 10 meter gait test

Genetic Polymorphism Analysis will be assessed by salting out methodology followed by q-PCR (Real-time PCR) using the TaqMan assay using Step One Plus equipment

According to the gene sequence studied, the analysis will be performed using the Sanger sequencing technique with capillary electrophoresis in a 3130 automatic sequencer (Applied Biosystems). The genetic polymorphisms of the ABO system gene (rs505922), two polymorphisms of the OPRM1 gene (rs1799971 and rs1799972) and a polymorphism of the BDNF gene (rs6265) will be investigated, with possible contributions to the risk of impaired gait.

Mental health will be assessed by the "Strengths and Weaknesses of Attention-deficit/hyperactivity disorder (ADHD) symptoms and Normal behaviors"

This is an 18-item parent questionnaire for children and adolescents (18 years and younger). This rating scale includes positive "weaknesses" and negative "strengths" scoring, assessing symptoms of Attention-Deficit/Hyperactivity Disorder. Parents are asked to compare their child's behavior in a variety of settings over the past month to other children on a 7-point: 3-Far below, 2-Below, 1-Slightly below, 0-Average, -1-Slightly average, -2-Above, -3-Far above. Higher scores indicate greater symptomology

The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioural screening questionnaire, and includes 25 items on psychological attribute: emotional symptoms (5 items), conduct problems (5 items) hyperactivity/inattention (5 items), peer relationship problems (5 items), prosocial behaviour (5 items). Higher scores indicate greater difficulties

The Depression, Anxiety and Stress Scale - 21 Items (DASS-21) is a set of three self-report scales designed to measure the emotional states of depression, anxiety and stress (7 items each subscale). Patients are asked to score every item on a scale from 0 (did not apply to me at all) to 3 (applied to me very much). Sum scores for the total DASS-total scale range between 0 and 120. Scores ≥60 (for DASS-total) and ≥21 (for the depression subscale) are labeled as "high" or "severe".

24-hour recalls will be assessed on three non-consecutive days (two weekdays, and one weekend). Online Dietbox will be used.

Inclusion Criteria: school-age children and adolescents diagnosed with COVID-19 Exclusion Criteria: school-age children and adolescents with MIS-C, who present: myocardial dysfunction, refractory cardiac arrhythmias, coronary artery aneurysms with or without thrombi, electrocardiographic alterations suggestive of myocardial infarction or ischemia and clinical signs of heart failure; presence of any limitation or physical disability that prevents the practice of exercise; pregnancy.