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.

It is now well established that airways harbour a rich and diverse microbiome in healthy
controls. Respiratory tract invasion by pathogens rapidly causes a loss of microbiome
diversity and an impoverishment of host-microbiome interactions. These respiratory
microbiome alterations play an essential role in the development of lung inflammation
during pneumonia and reflect variation in baseline lung innate immunity. In published
studies of mechanically ventilated patients, it has been demonstrated that lung
microbiota are correlated with alveolar inflammation and that disruption of the gut
microbiome (via anti-anaerobic antibiotics) increases patients risk of prolonged
mechanical ventilation and mortality. These studies demonstrate the clinical significance
of the microbiome in recovery from lung injury. Alterations of the gut microbiome derived
metabolites also participate in the long-term immune reprogramming observed after sepsis.

In the healthy state, respiratory mucosal immunity actively controls the commensal
bacterial agents in the airways. Numerous studies have revealed profound immune
alterations in septic patients, considered immunocompetent" at the time of
hospitalization. Partner Nantes Université has demonstrated that pneumonia induces
prolonged immune reprogramming, characterized by the formation of paralyzed dendritic
cells (DCs) and low phagocytic alveolar macrophages (MAC), that lasts for months in
humans and is associated with prolonged susceptibility to bacterial and viral respiratory
infections. These results demonstrate that the required immune response to contain
respiratory pathogens and interact with the microbiome is rapidly dampened during
pneumonia and that this immune reprogramming lasts for years.

Critically ill patients are highly variable in their recovery from lung injury. Much of
this variation is attributable to the differential recovery of alveolar epithelial cell
integrity and function. An improved understanding of lung epithelial recovery will be
necessary to identify therapeutic targets for resolving lung injury and preventing CVRD
progression. Lung epithelial cells are subject to constant exposure to 1) microbiota
within the respiratory tract and 2) metabolites and translocated bacterial products from
the lower gut microbiome. Yet the role of the microbiome in alveolar epithelial recovery
is undetermined.

As a summary, we propose a reappraisal of the physiopathology of pneumonia based on the
concept of dysbiosis between a weakened microbiome and sepsis-induced immunosuppression,
which have the potential to explain the prolonged susceptibility to non-communicable
diseases, notably by sustaining epithelial injuries.

Role of host-microbiome interactions in CVRD progression Current pharmaceutical
interventions designed to slow the progression of atherosclerosis focus almost
exclusively on reducing plasma cholesterol levels. However, clinical and experimental
data support an additional critical role for inflammation in atherothrombosis. Notably,
inflammation inhibition targeting the central NLRP3 inflammasome to IL-1 to IL-6 pathway
of innate immunity is an emerging method for atherosclerosis treatment and prevention.
Macrophage accumulation within the vascular wall is a hallmark of atherosclerosis, and in
atherosclerotic lesions, macrophages respond to various environmental stimuli, such as
modified lipids and cytokines. We have demonstrated that trained immunity develops early
during pneumonia, correlates with the inflammatory response, and can help to predict
long-term outcomes after viral pneumonia.

This innate immune reprogramming, lasts for months after sepsis recovery and is
characterized by exacerbated inflammatory response and prolonged decrease phagocytic
activity of monocytes and macrophages during secondary immune stimulation. We thus
propose that the functional reprogramming of monocytes and macrophages observed after
pneumonia, can alter the control of atherosclerosis plaques, increasing the risk of major
CVD events. The gut microbiome has also emerged as a central factor affecting type 2
diabetes, obesity and the progression of atherosclerotic cardiovascular disease.

Integration of host-microbiome interactions to model the response to pneumonia and
identify patients at risk of unfavourable outcomes early Each patient likely responds
differently to therapeutic intervention and might recover differently after pneumonia.
Indeed, some subgroups of patients suffer rapid CVRD progression, and others return to
baseline conditions. Several biomarkers have been associated with pneumonia outcomes, but
none have reached the accuracy required for clinical implementation. This is mainly
because they are usually developed in small mono-centre cohorts and analyzed separately
in the microbiome and host status. So, pneumonia treatments and rehabilitation care are
"one-fits-all patients" approach leading to a large proportion of treatment failures and
CVRD progression.

There is a critical need for reliable biomarkers for the stratification of patients
predicting therapy success/failure and risk of CVRD progression/severe. The gold standard
to reach these objectives is to use large cohorts of patients, bar coding of the samples,
and high-throughput analysis followed by unbiased algorithm-guided analysis. In this
setting, the description that the integration of the host response and the microbiome
composition have a fair accuracy for the diagnosis of pneumonia demonstrates the
potential of protocols investigating the host/microbiome interactions for the development
of personalized treatment for respiratory infections.

The development and validation of endotypes to better understand the functional
mechanisms associated with CVRD progression will help clinicians to adapt treatment and
better prevent these conditions. The definition of phenotypes will also help identify
patients at risk early. We thus propose to combine host background (sex/gender, age,
ethnicity, medical history and genetic susceptibility, vaccination), CVRD risk factors
(dyslipidemia, diabetes, obesity), inflammation and soluble mediators (metabolome,
cytokines), immune status (epigenetic regulation) and microbiome composition during and
after pneumonia to capture the complexity of the hostmicrobiome interaction time course
and define endotypes and phenotypes associating pneumonia with CVRD.