DOI: 10.25934/pr00008450
title:  The effect of Body Mass Index (BMI) and Age on Baricitinib efficacy in Covid-19 patients 

description: Since the beginning of the pandemics, the Covid-19 infection has killed millions of people worldwide. The mortality in Covid-19 patients has been linked to both alveolar damage and immunothrombosis in the pulmonary capillary network. Alveolar damage is described as specific changes that occur to the structure of the lungs during injury or disease, while immunothrombosis refers to the formation of blood coagulation and platelet aggregation which may result in lack of blood flow through the circulatory system, resulting in depletion of oxygen that may cause irreversible damage. The Sars-Cov-2 virus leads to virally mediated inflammation in the alveolus which can lead to destruction of type 2 pneumocytes with subsequent fibrosis causing alveolar damage. The pulmonary arterial three ultimately divides into a network of billions of capillaries that ensheath the alveoli and mediates gas exchange. Immunothrombosis in these sites prevents this happening. It has been widely described in severe covid-19 patients (Bonaventura et al., 2021).

Baricitinib is a reversible Janus-Kinase (JAK) inhibitor drug with selectivity for JAK1 and JAK2. JAK proteins are associated to receptors for many inflammatory molecules and essential for their action. Baricitinib was licensed initially for the treatment of Rheumatoid Arthritis and works by the combinatorial inhibition of key cytokines, including interleukin-6 (IL-6), and also the modulation of lymphocyte function (Assadiasl et al., 2021). 

Most recently, Baricitinib was proven to reduce mortality and need for mechanical ventilation among hospitalized Covid-19 patients (Selvaraj et al., 2022), being effective especially in subjects with severe Covid-19 that require supplemental oxygen. Other immunomodulatory agents including corticosteroids and il-6 blockers have also been proven to be effective for severe Covid-19 (Abani et al., 2021; Horby et al., 2021)
 
We believe that the benefit of JAK inhibition in Covid-19 relates to the ability of these drugs to mitigate against immunothrombosis in COVID-19 pneumonia.  We also think that poorer clinical outcomes in COVID-19 in obese subjects, older subjects with ischemic heart disease, i.e, atherosclerotic coronary artery disease, that typically manifests as myocardial infarction, angina pectoris or heart failure, and other cardiovascular risk factors relate to the immunothrombosis.  

We want to analyze closer the COV BARRIER data (a Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Phase 3 Study of Baricitinib in Patients With COVID-19 Infection) (Marconi et al., 2021) and evaluate possible links between survival and Body Mass Index (BMI)—a surrogate marker for the determination of the degree of obesity – and age across the BMI and age spectrum.  

We expect that younger subjects with normal BMI and COVID-19 pneumonia may benefit less from the Baricitinib treatment as the immunothrombosis, which we believe is beneficially modulated, is more severe in older subjects that have higher BMI. Thrombosis is general commoner with older age. This is multifaceted and linked to factors such as “immunesenescence”, where there is generally a greater reliance on innate immune cells for immune responses and we theorize this may be a factor in Covid-19 severity.

This will help the medical community to understand better how Baricitinib works in Covid-19 and which patients would benefit the most from it.