A Critical Examination of the Potential Benefits of Theophylline on Extended Acute Inflammation in Old Age

This chapter presents a critical review of the potential benefits of theophylline as a means to reduce the burden of post-acute inflammation in older age groups. A pro-inflammatory state often persists, or is extended, after sepsis, trauma and other acute illnesses in old age, particularly above the age of 80 years. The presence of inflammation at above-baseline amplitudes or excessive duration is associated with a higher likelihood of delirium, anorexia, unplanned weight loss, lethargy, depression, weakness and other markers of frailty. There is also an association with less favourable clinical outcomes and a higher risk of losing personal independence. Theophylline has been shown to have an anti-inflammatory effect, probably mediated through the induction of histone deacetylase-dependent gene switching in immune competent cells, that has been observed at cellular and whole organism levels. The main effects are a reduction in the production and release of TNF, IL-1 and IL-6, with a sequential fall in CRP and increase in IL-10, and a change of immune cells to their anti-inflammatory phenotypes. This happens when theophylline levels are between 5 and 10 mg/L, which is lower than the range for bronchodilators (10 to 15 mg/L) and presents a relatively low risk of toxicity. We hypothesize that low-dose theophylline treatment given to elderly subjects with acute inflammation, for example due to respiratory infection, septicaemia or trauma, will change the setting of their biochemical status from an inappropriately extended pro-inflammatory pattern toward a more normalized baseline pattern and consequently reduce the risk of adverse clinical outcomes.