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.