**1. Introduction**

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex, serious, multi-system disorder, which is very disabling, with marked diminutions in function in quality of life. Its symptoms include severe fatigue, which is disabling and not improved by rest, and in particular, post-exertional malaise. Other symptoms include sleep disturbance, muscle pain, and cognitive dysfunction [1–4]. Symptoms, many of which are autonomic in nature, persist for at least six months. There is marked variation in the severity, symptoms, and clinical course of the disease. About three quarters of all patients are female. It occurs in all age groups, but most frequently arises in the 20 to 50 age group [5–7]. There may be around two million people with ME/CFS throughout Europe.

The European Network on ME/CFS (EUROMENE) was created to facilitate collaborative research, through working groups on epidemiology, biomarkers, and diagnostic criteria, clinical research, and socioeconomics, Europe-wide, to meet substantial gaps in scientific knowledge. Researchers from twenty-two countries now participate in the network. Working Group 3 (socioeconomics) focuses on the economic and social aspects of ME/CFS, with the objective of estimating the societal burden of ME/CFS.

UK experience suggests that the total cost of ME/CFS in Europe, including direct and indirect healthcare and other costs and productivity losses, may be in the region of €40 billion per annum [8], so even a 1% reduction achieved through programmes of prevention would be a substantial sum, though would need to be compared to the costs of such programmes. This report addresses the extent to which there may be scope for preventive programmes for ME/CFS, and what economic benefits may accrue therefrom.

#### **2. The Economic Case for Prevention**

There is evidence showing that many preventive programmes represent value for money [9] and that, therefore, there is a strong economic case for implementing them. Such programmes include, for example, targeted supervised tooth brushing and smoking cessation services [10]. Investments in prevention can produce value in terms of reduced healthcare spending, increased productivity, and improved quality of life, particularly when directed at chronic diseases that are major drivers of healthcare costs [11,12]. There are also benefits, in terms of both health and economic consequences of illness, from programmes that are effective, either in preventing illness or in treating it at an early stage, and there is empirical evidence to support this for certain conditions, such as colorectal cancer [13].

Thus, in many cases, there are numerous good reasons to invest in a well-defined package of preventive services that are recognised as effective in preventing disease and offer good economic value. The economic case can be demonstrated by cost-effectiveness or cost-utility analyses and/or the calculation of social return on investment (a quasi-costbenefit analysis), or, where applicable, by cost-minimisation for two or more equivalent services. A review of economic evaluations of public health (PH) interventions assessed by the National Institute for Health and Care Excellence (NICE) found that three-quarters of preventative interventions were cost-effective at a threshold of £20,000 per quality-adjusted life year (QALY) [9].

There is evidence indicating that health promotion and primary prevention programmes are cost-effective [14,15], especially when the role of the recipients is passive, as in immunisation programmes, or when the programme is designed to deliver a public good to a whole community, such as fluoridation [16]. In the context of heart disease, as one example, and based on 19 economic evaluations informed by 15 randomised controlled trials, exercise therapy is cost-effective in patients with coronary heart disease, chronic heart failure, intermittent claudication, or with a body mass index (BMI) ≥ 25 kg/m<sup>2</sup> [17]. Treatments for heart disease are less cost-effective, with the majority of interventions (pharmacological and non-pharmacological) for heart failure associated with incremental cost-effectiveness ratios exceeding USD30,000 per QALY gained [18]. Preventive care, particularly for chronic diseases, can help patients and reduce costs and impacts on economic

activity [19]. A study of the impact on healthcare utilisation and expenditure trends of a programme of prevention through behaviour modification found that a primary care model based on the doctor–patient relationship can have a positive impact in improving health, reducing the prevalence of chronic disease and disability, and reducing expenditure [20]. This is confirmed by a Report of the Surgeon General, which concluded that a water fluoridation programme, coupled with other dental initiatives, would improve dental health and cut costs [21]. Another review concluded that there was indeed potential for preventive services to delay or avoid distressing medical conditions that are expensive to treat [22]. Preventive care, particularly for chronic diseases, can help patients and reduce costs and impacts on economic activity [23].

#### **3. Impediments to Prevention**

A major challenge to successful implementation of programmes of prevention and demonstration of its economic value lies in the innate conservatism of people, and their unwillingness to change behaviour, as well as reticence when it comes to paying for such programmes [24], particularly as they require both a long-term view and intersectoral cooperation, and it can take many years for benefits of prevention to emerge [25]. For example, there is a significant gap in the availability of full economic evaluation studies focused on primary prevention of mental health problems among the elderly, and some patients do not appreciate the benefits of preventive programmes [14]. The evidence base regarding prevention programmes is very limited. In addition, the empirical evidence on individual prevention activities is rarely precise or definitive and there is a lack of high-quality studies. The economic benefits diffuse and appear abstract, and it is not always clear which individuals benefit [22]. In some cases, prevention (e.g., fitness, organic food, and clothing) can cause a prohibitive burden to individual and family budgets.

#### **4. The Content of Prevention**

Prevention may be primary, secondary, or tertiary. Primary prevention is designed to stop the onset of disease, often through behaviour modification, while secondary prevention consists of early detection when the disease is asymptomatic, in order to 'nip it in the bud'. Tertiary prevention is designed to mitigate the consequences of disease through disability limitation and rehabilitation. All three have the potential to reduce the costs of disease [11,24]. Prevention should address the causes of illness, be they social, economic, or environmental, including housing, education, and employment [25]. A focus on health behaviour and environmental and occupational risks is directed towards the main causes of preventable ill health, and important factors to consider in developing prevention programmes include lifestyle, social and community influences, living and working conditions, as well as socioeconomic, cultural, and environmental circumstances [26].

#### **5. Evaluation of Prevention**

Economic efficiency does not imply that cost should be minimised, or benefit maximised, but rather that cost be compared with benefit, and that net health benefits (the incremental cost divided by the opportunity cost threshold) be maximised [24]. The focus of investigation should be to determine whether the benefits accruing for the minority who benefit from a preventive intervention offset the costs (that is, the health benefits foregone) to the population as a whole.

The studies required to support evidence-based decisions on funding preventive programmes include effectiveness studies, simulation modelling, and economic evaluations [11]. In evaluating prevention programmes, aspects to consider include long-term impacts, non-health and non-monetary impacts, differential impacts across groups, and time preference [27]. Methodologically robust economic evaluations are needed to support decision-making in the allocation of healthcare resources, but especially in the context of prevention, where there are significant uncertainties in determining effectiveness, challenges in the measurement and valuation of outcomes, and often a lack of consideration of inter-sectoral costs, consequences, and equity implications [14,25].

There is a variety of possible approaches to evaluating the health and economic impacts of preventive programmes. Some are of more use to decision makers than others, particularly where they cover a long time-span [21]. Interventions for the prevention of chronic non-communicable diseases (NCDs) and certain types of injuries mainly address programmes designed to modify health-related behaviours and their interaction with environmental influences [28]. Research conducted in the UK since the 1970s stressed the relationship between socioeconomic position and health [26]. The World Health Organization (WHO) Commission on the Social Determinants of Health worked on the basis of a conceptual framework in which two main groups of determinants were identified, structural (e.g., socioeconomic and political contexts, social structures, and socioeconomic position) and intermediary factors (e.g., biological, behavioural, health system and psychosocial factors, living and working conditions) [29].

There is a need to elucidate the nature and extent of the evidence that demonstrates cost-effectiveness of disease and injury prevention programmes and clinical prevention services [11]. Estimating the cost-effectiveness of prevention, generally, is problematic, because such an evaluation may combine interventions of proven effectiveness with others— the effectiveness of which is less certain [23]. Recent reviews of economic evaluations of prevention programmes highlight the methodological limitations and challenges [9,25]. The choice of discount rate, as one example, to account for time preference, can impact significantly on the cost-effectiveness of prevention programmes, as even large future health benefits may result in low net present value.

In considering approaches to evaluation, it is necessary to consider the extent to which modelling methods could be used to project the clinical and spending impact of prevention programmes and whether wider impacts on employment should be taken into account. There is also a need to determine appropriate time horizons for evaluations, to consider how health benefits, including health-related quality of life, should be measured, and the extent to which it is possible to evaluate prevention programmes using traditional economic models [21,29].

Methods for quantifying the (social) return on investment of a proposed prevention programme are gaining popularity. These are consistent, in the UK, with the National Institute for Health and Care Excellence public health guidance, which comments on the appropriateness of cost-benefit analysis for public health programmes. Social return on investment analyses incorporate considerations of effectiveness and its time period, as well as of cost and perspective (i.e., which costs and benefits are included in the analysis) [30,31]. As public health has impacts extending beyond health alone, a broader perspective is often warranted. The pertinent question for prevention is whether it offers good value, in terms of return on investment, bearing in mind that addressing a single risk factor can impact on a broad range of conditions, and that the long-time horizon creates an opportunity for the compounding of health benefits [23].

Taking into account the above considerations, two main questions should be addressed: first, as to whether there is scope for preventive programmes for ME/CFS, and secondly, if so, whether there are health and economic benefits to be derived from the implementation of such programmes [32]. The answer to the first question depends on whether there are risk factors for ME/CFS which are capable of modification by means of such programmes, and this is considered next.

#### **6. Risk Factors for ME/CFS**

Although the exact pathogenesis of ME/CFS is still unknown, the most plausible hypothesis is that it is a complex multifactorial syndrome in which immunological and environmental factors play a crucial role [33,34].
