The immunomodulatory effects of statins in community-acquired pneumonia: A systematic review

Summary

Objective

To evaluate the potential immunomodulatory effects of statins in community-acquired pneumonia.

Methods

We performed a systematic review of available literature on experimental and clinical studies. We used a PubMed/MEDLINE and EMBASE search to identify potential articles.

Results

We identified 34 original studies, 17 experimental and 17 clinical studies, published up to March 2013.

Conclusions

Statins attenuated pulmonary inflammation by modulating neutrophil function, by reducing cytokine expression and release, and by protecting against disruption of pulmonary integrity. However, additional experimental studies are needed to fully elucidate the exact mechanisms. Several clinical studies suggested a decreased risk of CAP or a reduction in mortality due to CAP for current statin users, but the mostly observational design of these studies hampers the interpretation of their results. Therefore, appropriately designed studies, such as randomised controlled trials, are required to demonstrate the usefulness of statins in the prevention and treatment of CAP.

Introduction

Community-acquired pneumonia (CAP) is a leading cause of hospitalisation and mortality in the world.1, 2 The mortality in Europe can vary from <1 to 48% depending on several factors e.g. age, gender, or comorbidities representing heterogeneity of disease severity.³ Since the introduction of antimicrobial therapy in the 1950s, the mortality rate associated with CAP has remained rather stable.⁴ Although an effective inflammatory response is necessary to clear pathogens, it has been proposed that excessive inflammation is an important cause of early treatment failure and mortality in CAP by causing pulmonary and systemic damage.⁵ Therefore, effective tempering of this inflammation surplus could potentially lead to reduced organ injury, better treatment response, and improved patient survival. Attempts to modulate inflammation have been made with drugs such as macrolides or corticosteroids, but the lack of uniform beneficial results impede widespread implementation of these drugs as anti-inflammatory treatment in CAP, to date.⁶

Immunomodulatory therapy in patients with CAP might be possible with hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, otherwise known as statins. These drugs are used as lipid-lowering agents in the prevention and treatment of cardiovascular disease,⁷ and their anti-inflammatory, immunomodulatory, and trombogenetic effects i.e. pleiotropic effects, also seem to play a major role herein.⁸ Statins competitively inhibit the enzyme HMG-CoA reductase, the enzyme controlling the rate-limiting step of cholesterol biosynthesis - the conversion of 3-hydroxy-3-metyl-glutaryl-CoA to mevalonic acid. Their pleiotropic effects are probably the result of inhibition of the mevalonate pathway, which leads to a reduction in isoprenoid molecules. As a result, prenylation of important intracellular signalling molecules like Rho, Ras, and Rac cannot take place, making it impossible for these signalling molecules to act as intracellular messengers. This consequently leads to inhibition of their respective pathways and to different tempering effects on the inflammatory cell response.5, 9 In spite of the available evidence from experimental research, little is known about the direct effects of statin treatment on CAP. Furthermore, uncertainty still exists regarding the impact of statin use on the risk of developing CAP and CAP outcome in terms of treatment failure, complications and mortality. In this review, we aim to discuss the evidence from both experimental and clinical studies on the potential immunomodulatory benefits of statins in CAP.