Periodic Reporting for period 3 - HAP2 (Host-targeted Approaches for the Prevention and the treatment of Hospital-Acquired Pneumonia)
Reporting period: 2023-01-01 to 2024-06-30
The HAP2 project is a 7-year project aiming to develop host-directed drugs and biomarkers to enhance the prevention and the treatment of hospital-acquired pneumonia and develop precision medicine in infectious diseases.
HAP is a major health concern worldwide and the most frequent cause of hospital-acquired infections, with 500,000 episodes of HAP being treated every year in Europe. HAP has dramatic medical consequences: prolonged hospitalisation, altered quality of life after the infection, and an attributable mortality of 10%. The burden for society is high with an average cost for each episode of HAP of 40,000EUR.
HAP is moreover frequently induced by drug-resistant pathogens, and is responsible of 33% of the antimicrobial use in European hospitals.
The HAP2 project proposes a complete reappraisal of the physiopathology of HAP based on the concept of respiratory dysbiosis. We are proposing that HAP does not result from the lung contamination by oro-digestive bacteria but is the consequence of a control loss of the respiratory microbiome by mucosal immunity (so-called state of dysbiosis). Host-targeted approaches aiming to restore the immune control of the microbiome could reduce the rate of treatment failure and improve outcomes of patients with HAP. The restoration of immune-competence of critically ill patients will also enhance the prevention of HAP and enable a significant reduction in the use of antibiotics in European hospitals, tackling the problem of bacterial resistance.
The HAP2 project will reach two ground-breaking objectives in the field of bacterial infections: the development of 1.host-targeted drugs for the prevention and treatment of HAP; 2.precision medicine based on the investigation of the host-pathogens interactions.
HAP is a major health concern worldwide and the most frequent cause of hospital-acquired infections, with 500,000 episodes of HAP being treated every year in Europe. HAP has dramatic medical consequences: prolonged hospitalisation, altered quality of life after the infection, and an attributable mortality of 10%. The burden for society is high with an average cost for each episode of HAP of 40,000EUR.
HAP is moreover frequently induced by drug-resistant pathogens, and is responsible of 33% of the antimicrobial use in European hospitals.
The HAP2 project proposes a complete reappraisal of the physiopathology of HAP based on the concept of respiratory dysbiosis. We are proposing that HAP does not result from the lung contamination by oro-digestive bacteria but is the consequence of a control loss of the respiratory microbiome by mucosal immunity (so-called state of dysbiosis). Host-targeted approaches aiming to restore the immune control of the microbiome could reduce the rate of treatment failure and improve outcomes of patients with HAP. The restoration of immune-competence of critically ill patients will also enhance the prevention of HAP and enable a significant reduction in the use of antibiotics in European hospitals, tackling the problem of bacterial resistance.
The HAP2 project will reach two ground-breaking objectives in the field of bacterial infections: the development of 1.host-targeted drugs for the prevention and treatment of HAP; 2.precision medicine based on the investigation of the host-pathogens interactions.
WP1 setting up the project governance structure and procedures
WP2 Promoting and completing the first clinical trial (PREV-HAP): 109 patients have been included and the dataset has been analysed, the manuscript has been published in an international journal. The protocol of the second clinical trial (HAP-DEX trial) has been submitted to the European Agency for authorisation, first patients have been included since May 2024, and new centres in Spain, Greece and Belgium will be opened soon.
WP3 investigating HAP-specific signatures likely to influence susceptibility and severity of the disease (based on pre-existing respiratory fluids, PBMCs and plasma samples of patients from intensive care units and healthy controls) in both a pre-existing biobank and samples collected during the PREV-HAP study. During this trial, we defined a cluster of patients whose inflammatory response to IFN-g was specific and related to respiratory complications. We defined and validated a respiratory microbiome signature associated with HAP and patient unfavourable outcomes. We identified heterogeneity in the metabolomic response to critical illness related to the risk of severe HAP and a favourable response to IFN-gamma treatment.
WP4 combining pre-existing clinical data and the first “omics” data generated from WP3 to identify attributes of high predictive values. We have developed a multi-omic score for predicting HAP (early vs late and severe vs non-severe) and are in the process of external validation in the PREV-HAP cohort. We also identified groups of bacteria associated with specific immune responses and risk of HAP. Finally, we defined a clinico-biological score in HAP patients, associated with the respiratory microbiome composition, the blood cytokine landscape and the risk of treatment failure. We also found that this score can help adapt antimicrobial treatment in HAP patients
WP5 designing the methodological developments (psychometric and economic models) required to investigate the suitability, acceptability and adaptability of host-targeted treatment for HAP treatment and prevention in different population groups. We have validated this approach in the PREV-HAP cohort and demonstrated the importance of the responder in estimating the quality of life. We also demonstrated that immune therapy with IFN gamma-1b in critically ill patients is cost-effective with a 90-day perspective.
WP6 developing the project’s core dissemination and communication tools and setting up a data management strategy and data sharing infrastructure.
WP7 managing the 'ethics requirements' compliance. Based on safety regular monitoring, the PREV-HAP study was early discontinued to guarantee patient safety. We revised the benefit/risk ratio of the TREAT-HAP trial and revised the protocol based on meetings with DSMB and French regulatory agency.
WP2 Promoting and completing the first clinical trial (PREV-HAP): 109 patients have been included and the dataset has been analysed, the manuscript has been published in an international journal. The protocol of the second clinical trial (HAP-DEX trial) has been submitted to the European Agency for authorisation, first patients have been included since May 2024, and new centres in Spain, Greece and Belgium will be opened soon.
WP3 investigating HAP-specific signatures likely to influence susceptibility and severity of the disease (based on pre-existing respiratory fluids, PBMCs and plasma samples of patients from intensive care units and healthy controls) in both a pre-existing biobank and samples collected during the PREV-HAP study. During this trial, we defined a cluster of patients whose inflammatory response to IFN-g was specific and related to respiratory complications. We defined and validated a respiratory microbiome signature associated with HAP and patient unfavourable outcomes. We identified heterogeneity in the metabolomic response to critical illness related to the risk of severe HAP and a favourable response to IFN-gamma treatment.
WP4 combining pre-existing clinical data and the first “omics” data generated from WP3 to identify attributes of high predictive values. We have developed a multi-omic score for predicting HAP (early vs late and severe vs non-severe) and are in the process of external validation in the PREV-HAP cohort. We also identified groups of bacteria associated with specific immune responses and risk of HAP. Finally, we defined a clinico-biological score in HAP patients, associated with the respiratory microbiome composition, the blood cytokine landscape and the risk of treatment failure. We also found that this score can help adapt antimicrobial treatment in HAP patients
WP5 designing the methodological developments (psychometric and economic models) required to investigate the suitability, acceptability and adaptability of host-targeted treatment for HAP treatment and prevention in different population groups. We have validated this approach in the PREV-HAP cohort and demonstrated the importance of the responder in estimating the quality of life. We also demonstrated that immune therapy with IFN gamma-1b in critically ill patients is cost-effective with a 90-day perspective.
WP6 developing the project’s core dissemination and communication tools and setting up a data management strategy and data sharing infrastructure.
WP7 managing the 'ethics requirements' compliance. Based on safety regular monitoring, the PREV-HAP study was early discontinued to guarantee patient safety. We revised the benefit/risk ratio of the TREAT-HAP trial and revised the protocol based on meetings with DSMB and French regulatory agency.
The ambition of HAP2 is to revolutionize the management of HAP by building on the novel concept of critical-illness related immunosuppression altering the host-pathogens interactions.
Currently, the treatments of HAP are all targeting the taxa with the greater relative abundance found in the culture of lower respiratory fluids. The frequent treatment failures observed with antimicrobial therapy can thus be explained by a further reduction of bacterial diversity and of metabolic functions within antibiotic treatment. We have proposed that the prevention and the treatment of HAP should aim to restore mucosal immunity and respect the diversity of the microbiome, rather than to sterilize airways with antibiotics. The development and validation of such strategies able to restore the mucosal immunity will probably minimize, or even replace, antibiotics - which are currently the sole therapies to date - for the management of HAP. This project will demonstrate the clinical proof-of-concept of tailored immunotherapy for HAP.
Current treatment of HAP targets the dominant pathogen in the respiratory fluid but this “one-fits all patients” approach leads to a large proportion of treatment failures. Although each individual patient likely responds differently to therapeutic intervention, there are currently no reliable biomarkers for the stratification of patients predicting therapy success/failure. Several biomarkers have been associated with HAP in critically ill patients, but none has been widely implemented in clinical practice. The investigation of the host or of the microbiome fails to diagnose pneumonia when they are conducted separately. We propose to combine host background, host response to hospitalization and pathogen response to hospitalization to develop clinico-biological scores with high accuracy for the stratification of patients and the development of a precision medicine (theranostic).
Overall, HAP² will open new opportunities for science and technology to cure patients with HAP and be a game-changer when caring for bacterial infections. The development of host-targeted approaches for the treatment of bacterial infection will also be the first alternative treatment to antibiotics for HAP, therefore contributing to solve the worldwide medical concern of resistant bacteria. Moreover, the COVID-19 pandemic has demonstrated that infectious diseases remain a major threat to EU and global health. Host-targeted approaches are becoming increasingly relevant to better tackle and manage infectious diseases and reduce the disease burden on patients effectively: thanks to a better understanding of the physiopathology of the diseases and more personalised management of patients. The project outcomes will therefore contribute to a better ability and preparedness to manage future epidemic outbreaks.
Currently, the treatments of HAP are all targeting the taxa with the greater relative abundance found in the culture of lower respiratory fluids. The frequent treatment failures observed with antimicrobial therapy can thus be explained by a further reduction of bacterial diversity and of metabolic functions within antibiotic treatment. We have proposed that the prevention and the treatment of HAP should aim to restore mucosal immunity and respect the diversity of the microbiome, rather than to sterilize airways with antibiotics. The development and validation of such strategies able to restore the mucosal immunity will probably minimize, or even replace, antibiotics - which are currently the sole therapies to date - for the management of HAP. This project will demonstrate the clinical proof-of-concept of tailored immunotherapy for HAP.
Current treatment of HAP targets the dominant pathogen in the respiratory fluid but this “one-fits all patients” approach leads to a large proportion of treatment failures. Although each individual patient likely responds differently to therapeutic intervention, there are currently no reliable biomarkers for the stratification of patients predicting therapy success/failure. Several biomarkers have been associated with HAP in critically ill patients, but none has been widely implemented in clinical practice. The investigation of the host or of the microbiome fails to diagnose pneumonia when they are conducted separately. We propose to combine host background, host response to hospitalization and pathogen response to hospitalization to develop clinico-biological scores with high accuracy for the stratification of patients and the development of a precision medicine (theranostic).
Overall, HAP² will open new opportunities for science and technology to cure patients with HAP and be a game-changer when caring for bacterial infections. The development of host-targeted approaches for the treatment of bacterial infection will also be the first alternative treatment to antibiotics for HAP, therefore contributing to solve the worldwide medical concern of resistant bacteria. Moreover, the COVID-19 pandemic has demonstrated that infectious diseases remain a major threat to EU and global health. Host-targeted approaches are becoming increasingly relevant to better tackle and manage infectious diseases and reduce the disease burden on patients effectively: thanks to a better understanding of the physiopathology of the diseases and more personalised management of patients. The project outcomes will therefore contribute to a better ability and preparedness to manage future epidemic outbreaks.