Role of the inflammatory response in community-acquired pneumonia: clinical implications

ABSTRACT

Introduction

Despite adequate antibiotic coverage, community-acquired pneumonia (CAP) remains a leading cause of hospitalization and mortality worldwide. It induces both a local pulmonary and a systemic inflammatory response, particularly significant in severe cases. The intensity of the dysregulated host response varies from patient to patient and has a negative impact on survival and other outcomes.

Areas covered

This comprehensive review summarizes the pathophysiological aspects of the inflammatory response in CAP, briefly discusses the usefulness of biomarkers, and assesses the clinical evidence for modulating the inflammatory pathways. We searched PubMed for the most relevant studies, reviews, and meta-analysis until August 2020.

Expert opinion

Notable efforts have been made to identify biomarkers that can accurately differentiate between viral and bacterial etiology, and indeed, to enhance risk stratification in CAP. However, none has proven ideal and no recommended biomarker-guided algorithms exist. Biomarker signatures from proteomic and metabolomic studies could be more useful for such assessments. To date, most studies have produced contradictory results concerning the role of immunomodulatory agents (e.g. corticosteroids, macrolides, and statins) in CAP. Adequately identifying the population who may benefit most from effective modulation of the inflammatory response remains a challenge.

KEYWORDS:

• Biomarkers
• community-acquired pneumonia
• corticosteroids
• immunoglobulins
• immunomodulation
• inflammatory response
• influenza
• macrolides
• metabolomics
• statins

Article highlights

• The pathophysiology of the immunological response in community-acquired pneumonia (CAP) has been extensively studied. It is known that the lung microbiota is critical to CAP susceptibility and that the intensity of the inflammatory response, which varies from host to host, affects outcomes.

• Our understanding of the mechanisms of the immune response, its dynamic nature and association with pathogen’s virulence factors remains incomplete

• Biomarkers have been investigated for the purposes of diagnosis, etiology, predicting treatment failure, and guiding antibiotic therapy, but none is ideal. Proteomic and metabolomic studies of biomarker signatures have shown encouraging preliminary results.

• Once promising compounds have failed to show clinical benefit, including tifacogin (a recombinant tissue factor pathway inhibitor), drotrecogin alfa (a recombinant form of activated protein C), and trimodulin (a novel polyclonal antibody preparation). Studies on molecules that sequester bacterial exotoxins are currently in their early stages.

• Studies on the use of corticosteroids have produced contradictory results and may even increase mortality in cases of pneumonia caused by influenza. Moreover, the routine use of corticosteroids for CAP is not recommended in the latest guidelines of the American Thoracic Society and the Infectious Diseases Society of America.

• Statins and macrolides have a range of immunomodulatory effects. Studies of macrolides suggest a potential benefit in severe CAP. However, the results from two randomized clinical trials have been contradictory.

• Adequately identifying the target population who could benefit most from effective modulation of the inflammatory pathways remains a challenge.

Acknowledgments

The authors are supported by research grants from the Instituto de Salud Carlos III, Spanish Ministry of Science, Innovation and Universities, through the 2018 call of pre-doctoral contract for training in health research (PFIS contract FI18/00183), with additional help from the European Social Fund (programming period 2014-2020) “The European Social Funds invests in your future”. The authors are also supported by Plan Nacional de I+D+i 2013‐2016 378 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0005) ‐ co‐financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 382 2014‐2020. The authors are also supported by a grant resulting from the 201808-10 project, funded by La Marató de TV3. We also thank CERCA Programme/Generalitat de Catalunya for their institutional support.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed grant funding from Merck; Medical Titan Group. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.