Immunomodulatory adjuvant therapy in severe community-acquired pneumonia

Abstract

Severe pneumonia has a high mortality (38.2%) despite evidence-based therapy. Rising rates of antimicrobial resistance increase the urgency to develop new treatment strategies. Multiple adjuvant therapies for pneumonia have been investigated but none are currently licensed. Profound immune dysregulation occurs in patients with severe infection. An initial hyper-inflammatory response is followed by a secondary hypo-inflammatory response with ‘immune-paralysis’. There is focus on the development of immunostimulatory agents to improve host ability to combat primary infection and reduce secondary infections. Successful treatments must be targeted to immune response; promising biomarkers exist but have not yet reached common bedside practice. We explore evidence for adjuvant therapies in community-acquired pneumonia. We highlight novel potential treatment strategies using a broad-based search strategy to include publications in pneumonia and severe sepsis. We explore reasons for the failure to develop effective adjuvant therapies and highlight the need for targeted therapy specific to immune activity.

Keywords::

• augmented passive immunotherapy
• critical care
• GM-CSF
• IFN-γ
• IL-7
• macrolides
• statin
• thymosin-α1

Financial & competing interests disclosure

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.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Severe community-acquired pneumonia is a major international public health problem causing high mortality and significant long-term morbidity. Effective evidence-based treatment is limited to antibiotics, organ support and source control. There is an immediate need for more effective therapies, and the rising spectre of antimicrobial resistance makes this an urgent priority.

• Multiple immunosuppressive adjuvant agents (e.g. glucocorticoids, drotrecogin alfa and eritoran) have been trialed for severe pneumonia without success.

• The immunomodulatory actions of established agents such as statins and macrolide antibiotics may reduce the incidence and severity of pneumonia, but the magnitude of effect is small. There is little evidence for the use of statins as an intervention in patients who present with pneumonia. Differentiation between the immunomodulatory and antimicrobial actions of macrolides for the treatment of pneumonia is difficult.

• Recognition of the secondary hypoinflammatory phase in infection has prompted clinical trials using immunostimulatory agents for the treatment of severe sepsis (e.g. granulocyte macrophage colony-stimulating factor, IFN-γ and Thymosin-α1) with some promising findings, but as yet, no conclusive evidence of benefit is available.

• Augmented passive immunotherapy is the combination of specific antibodies against infection with an agent (e.g. P4 peptide) to stimulate phagocyte activity. There are very promising results in murine pneumonia models and ex vivo human alveolar macrophages and neutrophils using this potential treatment strategy.

• Given the highly heterogenic nature of host response to infection, future successful treatments must be targeted to individual immune response. However, at present, tests developed to measure immune function are not widely available to clinicians. The next 5 years should see the development of promising markers of immune function such as monocyte human leukocyte antigen-DR expression to guide developing therapies.