Remdesivir, Sinus Bradycardia and Therapeutic Drug Monitoring in Children With Severe COVID-19

To the Editors:

We would like to thank Eleftheriou et al¹ for their observation of sinus bradycardia in children treated with remdesivir (RDV) for COVID-19 and report similar findings in 3 of 4 children with severe COVID-19 who received RDV on our pediatric intensive care unit. We treated 2 boys with underlying chronic conditions (11 years with advanced neuronal ceroid lipofuscinoses type 2 and 13 years with primordial dwarfism) with RDV suffering from COVID-19 pneumonia, progressive demand for oxygen and high SARS-CoV-2 RNA copy number in nasopharyngeal swaps. The first patient developed episodes of sinus bradycardia on day 3 and day 4 on RDV (heart rate dropped to 59 bpm from 90 to 100 baseline), the second on day 5 (56 bpm from >100 baselines) when catecholamines were also withdrawn. Both patients survived but suffer from residual lung damage aggravating their chronic disease. In addition, significant sinus bradycardia (38 bpm from >100 baseline) also occurred on day 5 of RDV treatment in the first of 2 girls (7 years with dystrophy, mild microcephaly and hypothyroidism and 4 years with adipositas) who developed critical COVID-19 disease. In this girl, however, severe myocarditis leading to the need for extracorporeal life support (ECLS), hemofiltration, catecholamine-dosing and multiple other drugs could also have led to bradycardia.² Notably, in this patient, levels of RDV on day 5 and day 6 (2531 and 1938 ng/ml 1 h post-infusion, respectively) and its metabolite GS-441524 (trough level 239.5 and 291 ng/ml, respectively) were confirmed to be within target levels during ECLS and hemofiltration by the UHPLC-MS/MS method.³ Sadly, both girls on ECLS finally succumbed due to fulminant COVID-19 despite multi-disciplinary intensive care. All children received 5 mg/kg RDV on the first day, followed by 2.5 mg/kg as considered to be safe and effective for compassionate use in children with severe COVID-19.⁴

We agree with Eleftheriou et al that physicians should be aware of potential cardiovascular adverse effects of RDV and use continuous cardiac monitoring and therapeutic drug monitoring in selected cases when treating children, especially in those with pre-existing cardiac conditions. Notably, catecholamine treatment and withdrawal can either mask or lead to bradycardia itself.

To the best of our knowledge, there are currently no other antiviral drugs (including monoclonal antibodies) to fight SARS-CoV-2 with at least some clinical experience in children and none are expected to receive marked authorization in the near future as clinical trials focus on participants 12 years and older. Hence, we are left with the blanket statement that children are spared from severe COVID-19, an argument that is currently being used in many European countries, including the UK and Germany, to not vaccinate adolescents. Although few children become severely ill from SARS-CoV-2 infection compared with adults, the increasing number of delta variant infections will most likely result in preventable morbidity and mortality in this age group. Therefore, we call not only for pediatric clinical trials of antiviral drugs but, more importantly, for universal access to COVID-19 immunization for children and adolescents as safe and effective vaccines become licensed and available.⁵