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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
100
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).
Hospital das Clinicas Faculdade de Medicina USP
São Paulo, São Paulo, Brazil
Quality of Life assessed by the Pediatric Quality of Life Inventory (Peds-QoL)
The instrument was translated and validated for the Brazilian population
Time frame: Change from Baseline at 3 months
Quality of Life assessed by the Pediatric Quality of Life Inventory (Peds-QoL)
The instrument was translated and validated for the Brazilian population
Time frame: Change from Baseline at 6 months
Flow-volume loop assessed by spirometry
Aims to investigate the mechanisms that lead to dyspnea and, consequently, intolerance to physical effort
Time frame: Baseline, 3 months, 6 months
Health-related quality of life assessed by the Pediatric Outcomes Data Collection Instrument
It will also be assessed for school-age children (7-10 years old) and adolescents (11-18 years old) and by their primary caregiver
Time frame: Baseline, 3 months, 6 months, 12 months
Complete blood count (hemoglobin, leukocyte, lymphocyte and platelet count)
Time frame: Baseline, 3 months, 6 months, 12 months
Inflammatory markers (C-reactive protein, fibrinogen, D-dimer and ferritin);
Time frame: Baseline, 3 months, 6 months,12 months
Lactate dehydrogenase
Time frame: Baseline, 3 months, 6 months, 12 months
Aspartate and alanine aminotransferase
Time frame: Baseline, 3 months, 6 months, 12 months
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Serum urea and creatinine
Time frame: Baseline, 3 months, 6 months, 12 months
Triglycerides
Time frame: Baseline, 3 months, 6 months, 12 months
Creatinine phosphokinase (CK)
Time frame: Baseline, 3 months, 6 months, 12 months
Amilase
Time frame: Baseline, 3 months, 6 months, 12 months
Lipase
Time frame: Baseline, 3 months, 6 months, 12 months
Troponin T
Time frame: Baseline, 3 months, 6 months, 12 months
Pro-BNP
Time frame: Baseline, 3 months, 6 months, 12 months
Lung abnormalities will be assessed by pulmonary computed tomography
Patchy ground-glass opacities, crazy-paving pattern, and localization and pattern of large, confluent or small nodular lesions will be assessed
Time frame: Baseline, 3 months, 6 months, 12 months
Systolic and diastolic function will be assessed by echocardiogram
Conventional transthoracic echocardiogram with color Doppler to assess systolic and diastolic function
Time frame: Baseline, 3 months, 6 months, 12 months
Valve dysfunction will be assessed by echocardiogram
Conventional transthoracic echocardiogram with color Doppler to search for valve dysfunction
Time frame: Baseline, 3 months, 6 months, 12 months
Pericardial effusion will be assessed by echocardiogram
Conventional transthoracic echocardiogram with color Doppler to search for pericardial effusion
Time frame: Baseline, 3 months, 6 months, 12 months
Coronary arteries will be assessed by echocardiogram
Conventional transthoracic echocardiogram with color Doppler to search for aspects of the coronary arteries
Time frame: Baseline, 3 months, 6 months, 12 months
Ischemia will be assessed by echocardiogram
Echocardiogram with two-dimensional speckle-tracking technique to identify subclinical changes suggestive of ischemia or myocarditis
Time frame: Baseline, 3 months, 6 months, 12 months
Immunocompetence, including thymic function
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)
Time frame: Baseline, 3 months, 6 months, 12 months
Leukogram will be assessed by leukocyte and lymphocyte counts
Time frame: Baseline, 3 months, 6 months,, 12 months
Immunophenotyping of lymphocytes T cell lineages will be evaluated by flow cytometry
T cell lineages: CD3CD4, CD3CD8, naive cells (CD45RA+), memory cells (CD45RA-), effector cells (CD38+HLADR+)
Time frame: Baseline, 3 months, 6 months, 12 months
Immunophenotyping of lymphocytes B cell lineages will be evaluated by flow cytometry
B cell lineages: CD19, naive cells (CD27-), memory cells (CD27+), plasmablasts (CD27+CD38+CD138-), (plasmocytes CD27+CD38+CD138+)
Time frame: Baseline, 3 months, 6 months, 12 months
Immunophenotyping of lymphocytes NK cells will be evaluated by flow cytometry
NK cells: (CD3-CD16+CD56+), degranulated: CD107a+
Time frame: Baseline, 3 months, 6 months, 12 months
Serum levels of anti-Streptococcus pneumoniae IgG antibodies
Time frame: Baseline, 3 months, 6 months, 12 months
Anti-pneumococcal vaccine response will be assessed by ELISA
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
Time frame: Baseline, 3 months, 6 months, 12 months
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
Time frame: Baseline, 3 months, 6 months, 12 months
Changes in frequency of the autoantibodies of the thyroid gland
(anti-thyroperoxidase antibodies, anti-thyroglobulin)
Time frame: Baseline, 3 months, 6 months, 12 months
Changes in frequency of the anti-GAD antibody will be assessed using immunoprecipitation
Time frame: Baseline, 3 months, 6 months, 12 months
Changes in frequency of the anti-islet antibody of Langerhans will be assessed using indirect fluorescence
Time frame: Baseline, 3 months, 6 months, 12 months
Changes in frequency of the anti-insulin antibody will be assessed by radioimmunoassay
Time frame: Baseline, 3 months, 6 months, 12 months
Diagnosis of thyroid dysfunction will be assessed by thyroid profile (TSH, free T4 and T3)
Time frame: Baseline, 3 months, 6 months, 12 months
Diagnosis of type 1 diabetes mellitus will be assessed by the metabolic profile (fasting glucose, glycated hemoglobin and C peptide)
Time frame: Baseline, 3 months, 6 months,, 12 months
Linear growth will be assessed by using a standardized stadiometer, calculating standard deviation, growth curves, and growth speed
Time frame: Baseline, 3 months, 6 months, 12 months
Development of puberty will be assessed according to the criteria of Tanner and Marshall in adolescents in the prepubertal age group
Time frame: Baseline, 3 months, 6 months, 12 months
Bone age will be assessed using non-dominant hand and wrist radiography
Time frame: Baseline, 12 months
Bone mineral density will be assessed by Bone densitometry (DXA) in the region of the lumbar spine
Time frame: Baseline, 3 months, 6 months, 12 months
Bone mineral content will be assessed by Bone densitometry (DXA) in the region of the lumbar spine
Time frame: Baseline, 3 months, 6 months, 12 months
Bone mineral density will be assessed by Bone densitometry (DXA) in the proximal femur
Time frame: Baseline, 3 months, 6 months, 12 months
Bone mineral content will be assessed by Bone densitometry (DXA) in the proximal femur
Time frame: Baseline, 3 months, 6 months, 12 months
Bone mineral density will be assessed by Bone densitometry (DXA) in the whole body
Time frame: Baseline, 3 months, 6 months, 12 months
Bone mineral content will be assessed by Bone densitometry (DXA) in the whole body
Time frame: Baseline, 3 months, 6 months, 12 months
Body composition (visceral adipose tissue) will be assessed by Bone densitometry
Time frame: Baseline, 3 months, 6 months, 12 months
Body composition (lean mass) will be assessed by Bone densitometry
Time frame: Baseline, 3 months, 6 months, 12 months
Body composition (fat mass) will be assessed by Bone densitometry
Time frame: Baseline, 3 months, 6 months, 12 months
Bone biochemical and bone remodeling markers (calcium, phosphorus, 25OH alkaline phosphatase vitamin D, PTH, CTX, P1NP)
Time frame: Baseline, 3 months, 6 months, 12 months
Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk used during the "timed up and go" test
Time frame: Baseline, 3 months, 6 months, 12 months
Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk during the 6-minute walk test
Time frame: Baseline, 3 months, 6 months, 12 months
Pediatric gait assessment will be assessed by an Actigraph (3D accelerometer) model G-Walk during the 10 meter gait test
Time frame: Baseline, 3 months, 6 months, 12 months
Pediatric gait assessment will be assessed by musculoskeletal ultrasound
Time frame: Baseline, 3 months, 6 months, 12 months
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.
Time frame: Baseline, 3 months, 6 months, 12 months
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
Time frame: Baseline, 3 months, 6 months, 12 months
Mental health will be assessed by the "Strengths and Difficulties Questionnaire"
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
Time frame: Baseline, 3 months, 6 months, 12 months
Mental health will be assessed by the "Depression, Anxiety and Stress Scale"
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".
Time frame: Baseline, 3 months, 6 months, 12 months
Physical activity levels assessed by ActivPAL
ActivPAL will be used for 7 days for at least 10 hours/day
Time frame: Baseline, 3 months, 6 months, 12 months
Food consumption levels assessed by food records
24-hour recalls will be assessed on three non-consecutive days (two weekdays, and one weekend). Online Dietbox will be used.
Time frame: Baseline, 3 months, 6 months, 12 months
Blood flow will be assessed using a Doppler Ultrasound
Baseline blood flow measurements will be assessed in the brachial artery
Time frame: Baseline, 3 months, 6 months, 12 months
Endothelial function will be assessed using a Doppler Ultrasound
Flow-mediated vasodilation (VMF) will be assessed in the brachial artery
Time frame: Baseline, 3 months, 6 months, 12 months