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Host-targeted Approaches for the Prevention and the treatment of Hospital-Acquired Pneumonia

Periodic Reporting for period 1 - HAP2 (Host-targeted Approaches for the Prevention and the treatment of Hospital-Acquired Pneumonia)

Reporting period: 2020-01-01 to 2021-06-30

The “HAP2” project is a 5-year project involving 10 partners from 6 countries, aiming to develop host-directed drugs and biomarkers to enhance the prevention and the treatment of hospital-acquired pneumonia (HAP) 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 notably: i) prolonged hospitalisation (equivalent to 7 extra days of intensive care unit), ii) altered quality of life after the infection, and iii) an attributable mortality of 10%. The burden for society is high with an average cost for each episode of HAP of 40,000 euros.

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. Notably, we are proposing that HAP does not result from the lung contamination by oro-digestive bacteria but is the consequence of a loss of control of the respiratory microbiome by mucosal immunity (a so-called state of dysbiosis). Host-targeted approaches aiming to restore the immune control of the microbiome have the potential to reduce the rate of treatment failure and to 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: first the development of host-targeted drugs for the prevention and treatment of HAP; second the development of a precision medicine based on the investigation of the host-pathogens interactions.
Main results achieved so far include:
WP1: setting up the project governance structure and procedures
WP2: initiating the first clinical trial (PREV-HAP)
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 hospitalized in intensive care units and healthy controls)
WP4: combining pre-existing clinical data and the first “omics” data generated from WP3 to identify attributes of high predictive values
WP5: designing the methodological developments (i.e. 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
WP6: developing the project’s core dissemination and communication tools (logo, brochure and website) and setting up a data management strategy and data sharing infrastructure for the project (the “data hub”)
WP7: managing the 'ethics requirements' that the project must comply with (submitted as deliverables)
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 targeted on the taxa with the greater relative abundance found in the culture of lower respiratory fluids, mostly because of the clinical interpretation of the results of bacterial cultures to assign pathogenic role.
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 thus 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 (Figure 6) . 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 thus demonstrate for the first time 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 in a given individual. Several biomarkers have been associated with HAP in critically ill patients, but none has been widely implemented in clinical practice . Notably, the investigation of the host, or of the microbiome, fails to diagnose pneumonia when they are conducted separately . We therefore propose to combine host background, host response to hospitalization and pathogen response to hospitalization to develop clinico-biological scores with high accuracy (Area Under the Curve >0.9) 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 such as those developed by HAP2 are becoming increasingly relevant to better tackle and manage infectious diseases and, importantly, reduce the disease burden on patients effectively: thanks to a better understanding of the physiopathology of the diseases and a more personalised management of patients. The project outcomes will therefore undoubtedly contribute to a better ability and preparedness to manage future epidemic outbreaks.
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