Introduction: coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory
syndrome coronavirus 2 is currently a major public health challenge. COVID-19 infection
results in diverse symptoms and morbidity. In severe cases, COVID-19 pathophysiology includes
destruction of lung epithelial cells, thrombosis, and vascular leak leading to acute
respiratory distress syndrome (ARDS) and subsequent pulmonary fibrosis. Clinical
manifestations of COVID-19 can include cardiac involvement with complications, such as
myocarditis (including fulminant cases), arrhythmias and rapid-onset heart failure. In
children, severe acute infection is less common than in adults. Another COVID-19 related
entity is a delayed life-threatening syndrome mimicking incomplete Kawasaki disease (KD) and
toxic shock syndrome now designated as pediatric inflammatory multisystem syndrome (PIMS-TS)
or MIS-C. Although rare, this syndrome remains an important source of pediatric COVID-19
related morbidity and mortality. The cardiovascular system is one of the major systems
affected by this syndrome, manifesting mainly as myocarditis and/or coronary vasculitis.
Endothelial dysfunction (ED) is a frequent long-term complication in patients after KD,
manifesting as diminished production or availability of nitric oxide (NO) and an imbalance in
the relative contribution of endothelium-derived relaxing and contracting factors. Little is
known regarding ED post COVID-19 in the pediatric population but there is some evidence that
endothelial injury might play a role in the pathogenesis of the disease. Patients who recover
from acute COVID-19 infection or post-COVID-19 syndrome can have diverse complaints and
symptoms such as chest pain, palpitations, weakness, myalgia and dyspnea. Several "return to
play" guidelines exist for athletes, adults and children, due to concerns about long term
cardiovascular and respiratory complications. Cardiopulmonary exercise testing (CPET) has
become an important clinical tool to evaluate exercise capacity and predict outcome in
patients with heart failure and other cardiac conditions. It provides assessment of
integrative exercise responses involving the pulmonary, cardiovascular, and skeletal muscle
systems, which are not adequately reflected through the measurement of individual organ
system function. CPET is increasingly being used in a wide spectrum of clinical applications
for evaluation of undiagnosed exercise intolerance and for objective determination of
functional capacity and impairment. Few reports are available regarding CPET in post- COVID
-19 infection adult patients, most of them after severe acute illness. Those reports
demonstrated decreased aerobic capacity, not related to pulmonary limitation.
Peripheral Arterial Tonography (EndoPAT™) is a non-invasive and operator independent
assessment of endothelial dysfunction. It evaluates the change in the volume of the pulse,
using a volume sensor that is placed on the second fingertip both on the hand that is under
evaluation and the free hand, measuring the reactive hyperemia mediated by NO release in
response to local ischemia. EndoPAT™ has been in clinical research use for evaluation of
endothelial changes in vasculitis, and has been deemed feasible and reproducible in the
pediatric population. EndoPAT™, has been validated as a good evaluation tool for various
blood-vessel related functions including arterial stiffness. In children, EndoPAT™
feasibility has been demonstrated in various conditions including inflammatory bowel disease
(IBD) and Type I diabetes mellitus. We will therefore use this method to evaluate possible
endothelial dysfunction in patients who suffered from PIMS. Endothelial dysfunction was
previously evaluated by serum levels of endothelin, endothelin is a vasoconstricting
substances that was previously used to evaluate endothelial dysfunction and high levels of
endothelin were previously proved to be associated with coronary vasoconstriction. We aim to
evaluate children, adolescents and adults, who had infection with COVID-19 or were diagnosed
with PIMS and compare them to healthy controls, using pulmonary function tests,
echocardiography, 6-min walk test (6MWT), CPET ,EndoPAT™ and serum levels of endothelin in
order to identify long term cardiac or pulmonary residual function/limitation which might
explain the symptoms or the long-term cardiopulmonary sequela of COVID-19 infection. Study
design: Pediatric and adult patients recovering from COVID-19 with or without complaints or
followed at the PIMS outpatient clinic or referred to the CPET clinic at Rambam Medical
Center will be enrolled in the study. Data will be collected retrospectively/ prospectively,
approximately 3 months after acute infection or post- COVID PIMS. CPET will be performed as
part of the clinical evaluation recommended by the following physician. EndoPAT assesment- as
part of the research. and blood endothelin levels- as part of the research. Participants will
undergo all or part of the evaluation, and possibly repeated evaluations if needed. For CPET
results each patient will be age- and sex-matched with an historical control from our CPET
research database containing records of 200 healthy patients. For EndoPAT results- patient
recovering from COVID-19 without PIMS will be evaluated as controls and the data will be
compared to normal known values for age.