A Non-interventional, Prospective, Cross-sectional Study of Cardiovascular Disease Progression in Survivors of Community Acquired Pneumonia and Lung Infection by Sars-Cov-2

Post-acute pneumonia syndrome People believe that there is a "modern pandemic" beyond the pandemic. This is called the post-acute COVID syndrome (PACS), and it is a constellation of symptoms and medical entities which emerge after acute infection by the new coronavirus SARS-CoV-2 (COVID-19). However, in this definition, people are attracted by the apparent symptomatology and ignore that long-term complications may be even more severe. In this regard, it is reported that the incidence of type 2 diabetes mellitus (T2DM) is increasing almost 1.56-fold after acute COVID-19, which may happen without any symptoms. The increase in the incidence of T2DM is supported by two large-scale meta-analyses involving more than 4.2 million patients during the post-COVID-19 follow-up period.

Recent evidence from the Hellenic Sepsis Study group suggests that circulating monocytes of patients after the acute COVID- 19 illness have increased ability for the biosynthesis of interleukin (IL)-1β, many of them do not present symptoms of PACS.

Taking into consideration the importance of IL-1β for the pathogenesis of T2DM through the destruction of β-pancreatic cell islets, it is evident that increased cardiometabolic (CV) risk may also be a counterpart of PACS. In the CANTOS randomized clinical trial published several years ago, survivors of a first myocardial infarct were randomized to treatment with a placebo or canakinumab, one monoclonal antibody targeting IL-1β, for five years. Results showed that anti-IL-1 treatment decreased by 15% the incidence of secondary cardiovascular events outscoring excess IL-1β production as a driver of CV risk. Consequently, it is reasonable to hypothesize that COVID-19 survivors who over-produce IL-1β may present with long-term CV events.

Beyond state of the art: respiratory dysbiosis, a complete reappraisal of the physiopathology of pneumonia for innovative treatments Healthy distal airways have long been considered sterile, and pneumonia was thus supposed to be caused by the contamination of the lungs by exogenous virulent pathogens (for CAP) or during micro- aspirations of the digestive contents in comatose patients (for HAP). Based on this physiopathology, numerous strategies to rapidly eliminate pathogens are recommended and widely used in Europe and worldwide. However, the limits of CAP and HAP treatments which increase bacterial or viral clearance, are highlighted in almost all randomized trials evaluating antibiotics or antiviral drugs in which the rates of treatment failure commonly exceed 30%, and by the 30%-rate of patients presenting with prolonged symptoms after pathogen clearance. A reappraisal of the physiopathology of pneumonia seemed necessary to overcome the relative failure and improve patient outcomes.

We have demonstrated that pneumonia outcomes depend on pathogen clearance and restoring healthy interactions between a weakened microbiome and altered immunity. Since CVRD progression is associated with disruption of the host-microbiome interactions, we hypothesize that the dysbiosis induced by pneumonia participates in the CVRD progression reported after the infection recovery. We thus propose to perform i) a longitudinal follow-up of host-microbiome interactions in large cohorts of patients cured of pneumonia to demonstrate clinically meaningful associations between immune reprogramming, microbiome dysbiosis and CVRD progression, and ii) preclinical investigations in calibrated mice models to demonstrate causality between dysbiosis and CVRD progression.