Potential for a Beneficial Effect of Theophylline on Extended Acute Inflammation: Review

Inflammation is often prolonged after sepsis, trauma and other acute pro-inflammatory events, particularly above the age of 80 years. Exposure to inflammation of inappropriate amplitude or duration is associated with a higher risk of delirium, anorexia, lethargy, low mood, weakness and other markers of frailty, and with less favourable clinical outcomes. Theophylline has been shown in vitro and in vivo to have an anti-inflammatory effect, probably mediated through induction of histone deacetylase-dependent gene switching in immune competent cells. This is mainly characterized by a reduction in the production and release of TNFα, IL-1β and IL-6, a consequent fall in CRP and increase in IL-10, and a shift of immune cell phenotypes to the anti-inflammatory mode. This effect occurs at theophylline concentrations in the 5-10 mg/L range, which is below the broncho-dilator range (10-15 mg/L) and carries a relatively low risk of toxicity. We hypothesize that low-dose theophylline treatment given to elderly subjects with acute inflammation, for example due to pneumonia, septicaemia or trauma, will alter the balance of their inflammatory status from an inappropriately extended pro-inflammatory pattern toward a more normalized baseline pattern and thereby reduce the risk of adverse clinical outcomes.