Community-acquired pneumonia (CAP) is considered the leading cause of death from infectious disease in developed countries. Increased mortality is associated with systemic manifestations and complications of CAP, with sepsis being the most common and challenging. The incidence of sepsis increases with age, while age is also a predictor of outcome in patients with pneumonia
Sepsis is characterised by a state of systemic immune dysregulation and coagulopathy produced by invasive microorganisms and/or their microbial products, such as lipopolysaccharide (LPS). The initial cytokine storm and systemic inflammatory response syndrome (SIRS) is followed by a compensatory anti-inflammatory response which leads to a state of significant immuno-paralysis. This has been implicated in the progression of sepsis and subsequent development of acute lung injury (ALI), multi-organ dysfunction (MODS) and death
Neutrophils constitute our main immune defence against microbial infection by rapidly migrating to sites of infection and/or inflammation. In a process known as chemotaxis, neutrophils are able to sense and subsequently respond to shallow gradients of chemoattractants formed of chemotactic peptides, including cytokines, bacterial products and complement proteins
. Once at the site of infection, neutrophils act to eliminate any foreign material in an effort to prevent widespread tissue damage and ultimately resolve infection. During the progression of sepsis, a state of neutrophil ‘paralysis’ develops resulting in the impairment of neutrophil anti-microbial functions including: chemotaxis, production of reactive oxygen species (ROS), and formation of neutrophil extracellular traps (NETs)
. Unable to contain the infection, widespread dissemination of pathogenic material occurs throughout the host, augmenting inflammation and leading to the development of ALI and MODS
. Secondary to the development of ALI and MODS, this immune paralysis or chronic immunosuppression leads to an increased risk of secondary infections further exacerbating the increased risk of mortality.
Mechanisms underlying defective neutrophil function remain elusive although NET formation has been implicated in the immunosuppression and increased rates of sepsis seen in neonates
, while other studies suggest NETs may exaggerate endothelial damage
[8, 9]. The term NETs refers to the formation of extracellular fibres composed of de-condensed chromatin laden with anti-microbial proteins. Although phenotypically and functionally distinct from apoptosis, ‘NETosis’ does result in cell death; however, this allows neutrophils to exert their anti-microbial functions beyond their typical lifespan
To date, there are no studies that specifically look at NET formation in CAP-associated sepsis. There is, however, increasing evidence that statins are able to modulate neutrophil function in sepsis with a recent study demonstrating the ability of statins to reduce the neutrophil infiltrate following LPS challenge in bronchoalveolar lavage fluid taken from patients receiving simvastatin prior to challenge
. Furthermore, the reduction in neutrophil counts was not associated with a decrease in pro-inflammatory mediator expression, suggesting it reflects a reduced neutrophil response or increased neutrophil apoptosis
. Statins inhibit 3-hydroxy-3 methylglutaryl coenzyme A reductase, a rate-limiting enzyme in the biosynthesis of cholesterol, and have been shown to exert numerous effects in addition to their lipid-lowering properties including potentially anti-inflammatory and immunomodulatory effects
. Several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality; however, most of this evidence is limited to retrospective and prospective observational studies
[12, 13]. In vitro, statins have also been shown to boost NET formation in healthy individuals with the consequent elimination of bacteria - an effect which could therefore be an important determinant of outcome in patients with CAP-associated sepsis
Impaired neutrophil chemotaxis in the elderly
Neutrophils from healthy elderly donors demonstrate features of immune-paralysis that resemble those seen in patients with sepsis: healthy elderly patients (over 60 years) demonstrate defective directional migration (chemotaxis) and overall accuracy (chemotactic index) whilst maintaining their speed of migration (chemokinesis) when migrating towards IL8 and the bacterial protein f-Met-Leu-Phe (fMLP)
Statins and sepsis
The ASEPSIS trial, a phase II randomised controlled trial, demonstrated that acute administration of atorvastatin reduces the progression of sepsis to severe sepsis
. These changes were not associated with systemic levels of cytokines or chemokines in contrast to other reported studies suggesting the cellular effects of statins may be more important than modulation of systemic mediators.
Community-acquired pneumonia-associated sepsis and neutrophil extracellular traps
During the early stages of CAP-associated sepsis, NET production is suppressed with improvements occurring during resolution. In addition, NET release was significantly lower in CAP patients who meet the criteria for severe sepsis. Taken together these data suggest that neutrophil function is a feature of CAP-associated sepsis, especially in the elderly, and that statin therapy may have potential to restore the defects in these neutrophils both in vivo and in vitro.
In light of these data, we hypothesise that the increased incidence and poorer outcomes observed in the elderly population in relation to pneumonia and sepsis may be due to defective neutrophil function, and that restoration of these functions may therefore improve outcome, especially in the elderly. The SNOOPI trial therefore aims to determine whether oral treatment with simvastatin optimises neutrophil anti-microbial functions in elderly patients admitted into Queen Elizabeth Hospital Birmingham (QEHB) with septic pneumonia, improving patient outcomes in the elderly. Alterations in neutrophil function will be related to clinical outcome, disease-relevant severity scores and biomarkers present in blood and urine.