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Introduction

There is a great clinical and social need to search for treatments that can effectively ameliorate the consequences of systemic inflammation, particularly in elderly people in a pre-frail or overtly frail condition. This includes taking opportunities for drug “discovery” research on a range of established drugs in common use that, in addition to their main licensed effects, have been shown to modulate or down-regulate inflammatory biochemical networks. In this commentary the authors will summarize the extant evidence with particular reference to theophylline, then make a case for systematized research into similar properties for other drugs such as statins and 4-aminoquinolones.

Background

The innate immune system in older people often exhibits different characteristics when compared to younger adults. It has been shown that established biochemical markers of inflammation, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor (TNF) are frequently 2-4 -fold higher in the plasma of older subjects, and become increasingly so with advancing age, especially in people older than 80 years, when compared to the levels in adults aged 20-60 years [1-3]. In one particularly well conducted study of healthy people there was a mean baseline plasma TNF concentration of 0.6 pg/ml in adults below the age of 30 years compared to a mean of 1.5 pg/ml in those above the age of 70 years [4]. This is part of the phenomenon that has been described as “inflammaging”, a term that is gaining currency in the fields of geriatric medicine and the immunology of ageing [1]. In many individual patients this observation can be explained by clinically obvious co-morbid chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis (RA) [3]. Further, similar raised levels of biochemical indicators of inflammation are often found in elderly people with other disorders that re-set the innate immune network in a pro-inflammatory direction, examples being central obesity, atheromatous disease, and type 2 diabetes [5-7]. Chronically raised pro-inflammatory markers have been found in association with Alzheimer’s disease (AD), a sedentary lifestyle, chronic renal disease and osteoarthritis [5,8-10]. Intriguingly, some well elderly people have raised baseline chemical inflammatory markers that appear to have no apparent pathological cause, and age itself appears to be accompanied by an augmented baseline inflammatory state [11,12]. Healthy young adult volunteers were found to have mean blood C-reactive protein (CRP) levels of 0.9 mcg/ml compared to 3.0 mcg/ml in healthy people over the age of 65 [11]. IL-6 and IL-1 appear to be significantly correlated with age [13]. These observations have clinic-pathological relevance because persisting low-amplitude inflammation is associated with higher all-cause mortality, reduced skeletal muscle strength, impaired instrumental function affecting activities of daily living and lower self-reported wellbeing and health status [14,15]. The measured plasma levels of inflammatory markers, such as CRP, IL-1, IL-6 and TNF vary between studies, depending on methodology, but the respective adverse outcomes were generally associated with 1.5 to 3-fold elevation above those found in healthy age-matched controls. Another clinically important factor that has immediate relevance to the contention we are putting forward in this commentary is the persisting augmentation of the pro-inflammatory state that often fails to resolve, or resolves slowly and incompletely, after an acute inflammatory event. This is an important factor in the rate and completeness of observed returns to pre-event function and presents a ripe target for research into effective interventions [16-23].

It is probable that chronic disease progression in a range of pathological states is to some extent due to chronic inflammation and not just an indicator of it [19]. There is evidently a complex interactive relationship between cause and effect. As a case in point, the endothelial inflammation found in atheromatous vascular disease has been extensively studied and is often cited as typifying the interaction between inflammation, ageing changes and pathology [20]. In many elderly people, the inflammatory response to acute stimuli, such as infection or injury, resolves more slowly than it does in younger adults. The observed rises in TNF, IL-1 and IL-6 persist longer and the sequential rise in the anti-inflammatory cytokine interleukin-10 (IL-10) is delayed and of lower amplitude. This effect has been clearly demonstrated for pneumococcal and Gram-negative endotoxin antigens [21,22], with an approximately 2-fold increase in the time to return to baseline in elderly older subjects, despite similar pro-inflammatory peak levels. This indicates that regulatory anti-inflammatory function is impaired and can consequently cause a delay in re-setting the normative baseline surveillance state of the innate immune system. It can be argued that this is a likely candidate for the slower post-acute clinical recovery and chronic low-level inflammation often seen in old age [24].

Other mechanisms for chronic age-associated inflammation might contribute to “inflammaging”, such as a reduction in anti-oxidant capacity and thereby greater oxidative stress. The pro-inflammatory effect of oxidative stress appears to be by stimulation of toll-like receptors on various immune cells. However, the evidence for cytokines having a central role in age-associated inflammation is now well established.

Systemic inflammation is closely associated with key components of frailty, including sarcopenia and cachexia [24]. The molecular mechanisms are clearly complex. Components of the innate immune systems, notably chemokines, the catecholamine-cortisol axis, complement reactions, interferons, immune cells and other somatic cells communicate with and influence each other in a non-linear manner best visualized as a network. A full description is beyond the scope of this commentary, but the authors have published detailed background elsewhere [24]. Effective interventions are consequently more likely to be those that cause corrective changes to the innate immune network, often referred to as immune modulation, and thereby reduce the inflammatory burden that contributes to frailty.

Proposition

Theophylline, a methyl-xanthine drug, has a long history as a treatment for asthma and COPD. In patients with COPD it was noted that positive outcomes, such as improved walking performance, were reported in patients treated with theophylline even when little or no measurable change was demonstrated by spirometry, or arterial blood gas tensions. Importantly, the effect was also observed at plasma levels well below (<10 mg/L) those associated with significant toxic effects [25]. Pertinently, the anti-inflammatory properties of theophylline at these low concentrations were shown to act not only locally on airways inflammation but also systemically [26,27]. The full mechanism whereby the anti-inflammatory properties of theophylline modulates innate immune chemistry remains only partially understood, and probably varies over time, and between individuals, according to the pathophysiological context. Theophylline reduced post-acute TNF and IL-1, and increases IL-10, by around 25-50 per cent. Similarly, in vivo exposure to comparable concentrations of pentoxifylline, also a methyl-xanthine, caused a progressive reduction in the production of pro-inflammatory IL-1, IL-6, IL-8 and TNF of between 20 and 80 percent by harvested peripheral blood monocytes over 4 days [27]. This property appears to be mediated through an epigenetic mechanism that activates histone deacetylase-dependent gene switches toward a more anti-inflammatory phenotype [26-28]. Therefore, these effects appear to be due to theophylline-induced re-direction toward the anti-inflammatory state in macrophages and other immune cells which have been shown to have several dose-dependent gene switches that up- and down-regulate various cytokines. Subjects with COPD treated with the addition of theophylline to a standard regimen had lower baseline CRP levels and better functional scores compared with control subjects. These effects have been described as immune “modulation”. It appears that theophylline at typical therapeutic doses reduces inflammation without compromising the protective effect of an appropriate acute inflammatory response to infection. It has also been shown that a reduction in mortality occurs in patients with severe sepsis treated with theophylline in a critical care setting [29-41].

A call for research

We contend that a case can be made for further well conducted studies of the use of low-dose theophylline to modulate inflammation when it is inappropriately prolonged after stimuli such as sepsis, particularly in pre-frail or overtly frail older patients with clinical and laboratory features of extended inflammation. There might also be a role for the long-term use of theophylline to dampen chronic inflammation to reduce the progression from pre-frailty to established frailty. More specifically, the principal targets for further research should be placebo-controlled trials of low-concentration (5–10 mg/L) theophylline, given orally, as adjunctive treatment in elderly patients recovering from sepsis or trauma, and to establish whether chronic low-grade inflammation, as measured by peripheral blood biochemical markers such as TNF and IL-1 can be modified and functional outcomes improved. In any such studies defined outcomes would need to include mortality, mobility scores, functional scores, return to independent living, measurements of muscle strength, cognition, wellbeing scores, and duration of hospital treatment.

We have used theophylline as an exemplar in this commentary. However, similar clinically translatable property discovery research needs to be conducted on other drugs with immune modulating characteristics, including but not exclusively, statins, 4-aminoquinolones, salicylates, beta-adrenergic blockers, thalidomide, metformin and monoclonal antibodies.

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