Current and emerging evidence for immunomodulatory therapy in community-acquired pneumonia

Community-acquired pneumonia (CAP) is the most common infectious disease related cause of death worldwide despite the use of effective antimicrobials. Much of the morbidity and mortality seen in CAP patients at high risk of death has been attributed to exaggerated host responses that result in bystander tissue damage and organ failure. Therefore there is great need to further understand the effect of hyperinflammatory phenotypes on CAP outcomes and develop adjuvant therapy that can attenuate excessive inflammatory responses without compromising host defense. Furthermore, there is growing concern regarding the development of antimicrobial resistance and recent research aims to modulate immune mechanisms that boost pathogen killing and clearance. In this review we summarize the growing body of evidence for the use of adjuvant immunomodulators in the treatment of CAP and highlight emerging immunomodulators that have been tested in pre-clinical studies, which need to be evaluated and developed for clinical trials. In summary, current evidence supports the use of macrolide combination antibiotic therapy and unless contraindicated continuation of pre-admission statin and antiplatelet therapy. Corticosteroids are beneficial in the context of septic shock and critical illness related adrenal insufficiency and may be of benefit to individuals with severe CAP and a hyperinflammatory phenotype given the potential for improving patient-centered and economic outcomes with negligible adverse effects. Despite much promise in pre-clinical work, many clinical trials of drugs targeting the coagulation pathways have unfortunately failed to demonstrate clinical benefits in humans. Results of trials evaluating aspirin, intravenous immunoglobulin (IVIg) and thrombomodulin are awaited and may yet influence practice, whilst further identification of inflammatory phenotypes will in the future allow personalized approaches and identify subgroups of patients that may respond to adjuvants that have previously not demonstrated favorable outcomes when used in heterogeneous cohorts.