Ignite Creation Date:
2024-10-25 @ 7:59 PM
Last Modification Date:
2024-10-26 @ 3:40 PM
Study NCT ID:
NCT06601998
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-09-16
Brief Title:
Cardiovascular Disease Progression in Survivors of Community Acquired Pneumonia and Lung Infection by Covid-19
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Non-interventional Prospective Cross-sectional Study of Cardiovascular Disease Progression in Survivors of Community Acquired Pneumonia and Lung Infection by Sars-Cov-2
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
HOMI-LUNG CAP
Brief Summary:
Pneumonia which can be acquired in the community including influenza and COVID-19 is a leading cause of mortality The risk of severe cardiovascular diseases events stroke myocardial infarction pulmonary embolism increases after infections but causal mechanisms are not understood yet There is an essential need for improved understanding of the relationship between pneumonia and cardiovascular diseases and early identification of patients at risk of cardiovascular events to develop tailored therapies
The overall concept underpinning Homi-lung is to investigate the time course of host-microbiome interactions during ampampamp after pneumonia to i understand the causal relationship between trained immunity microbiome dysbiosis and cardiovascular and respiratory diseases CVRD progressions ii define endotypes of pneumonia associated with response to treatment ampampamp CVRD history iii develop biomarkers to predict the individual response to the treatment ampampamp CVRD progression and iv preclinically validate therapeutical approaches for CVRD during ampampamp after pneumonia
The overall concept underpinning Homi-lung is to investigate the time course of host-microbiome interactions during ampampamp after pneumonia to i understand the causal relationship between trained immunity microbiome dysbiosis and cardiovascular and respiratory diseases CVRD progressions ii define endotypes of pneumonia associated with response to treatment ampampamp CVRD history iii develop biomarkers to predict the individual response to the treatment ampampamp CVRD progression and iv preclinically validate therapeutical approaches for CVRD during ampampamp after pneumonia
Detailed Description:
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 156-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 42 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 successfailure and risk of CVRD progressionsevere 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 hostmicrobiome 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 sexgender 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
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 successfailure and risk of CVRD progressionsevere 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 hostmicrobiome 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 sexgender 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None