**1. Introduction**

*1.1. Standardization of Clinical Procedures and Services for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe: The Origins*

Initially designed by a group of ME/CFS researchers and health professionals, the European Network on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (EUROMENE) has received funding from the European Cooperation in Science and Technology (COST)— COST action 15111 [1] —from 2016 to 2020. The main goal of the Cost Action was to assess the existing knowledge and experience on health care delivery for people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in European countries and to enhance coordinated research and health care provision in this field.

One of the aims of the network was to *define a standardised clinical diagnosis for ME/CFS for clinical and research use.* With the paucity and lack of integration of clinical guidelines in European countries [1], a high need has been identified for addressing the uncertainties around diagnosis and treatment, and to support the development of health services and standard clinical practices for people with ME/CFS across the continent. We report here on the recommendations for clinical diagnosis and managemen<sup>t</sup> of ME/CFS in Europe, as prepared by the group of clinicians and researchers from 22 countries participating in the network activities (including on Near Neighbour Country–Belarus), and 55 European researchers and health professionals, who have been informed by people with ME/CFS. The participating countries are Austria, Belarus, Belgium, Bulgaria, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Latvia, Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovenia, Spain, Sweden, United Kingdom. The researchers' names and affiliations are listed in the COST Action website [1].

#### *1.2. The Population Burden of the Disease and the Need for Better Recognition*

ME/CF is characterised by intolerance to efforts expressed by profound or pathological fatigue, malaise, and other symptoms aggravated by physical or cognitive efforts at intensities previously well tolerated by the individual. Intolerance to efforts may be experienced immediately or typically be delayed for hours or a day or more after exertion and is

associated with slow recovery. This marked and prolonged exacerbation of symptoms of ME/CFS, which follows physical activity and, in some cases, cognitive activity, is termed post-exertional malaise (PEM) and may last several days.

Other key symptoms include unrefreshing sleep, cognitive impairment, orthostatic intolerance, and pain, including muscle and joint pain and headaches. The symptoms are persistent or recurrent over long periods of time and lead to a significant reduction in previous levels of functioning. Diagnosis is clinical, owing to the absence of biomarkers, and based on detailed clinical history and physical examination by a competent clinician [2–5]. There is no causal treatment for the disease. With symptom-oriented support, there can be improvement with time, or patients may learn to manage their illness. There is little evidence on long term prognosis. However, full recovery is not the norm, particularly in adults [2–7], and in addition, there has been a small number of studies reviewing mortality among people with ME/CFS. These are consistent in demonstrating increases in mortality from suicide, in the UK [8] and in the US [9,10]. One American study demonstrated increased cardiovascular and cancer mortality [11], but this has not been confirmed by other studies.

Prevalence rates have been estimated as between 0.1 and 0.7%, and the incidence rate as 0.015 new cases/1000-year [12]. This could represent between 1 million and over 5 million people, probably around 3 million, in the European continent living with ME/CFS. However, there are no European-wide estimates of disease burden [13]. A much larger number of people will have chronic fatigue for other reasons, and many of them will also be significantly incapacitated. At least 2/3 of the cases are in women [12,13], with young people in their most productive phases of life being preferentially affected. However, ME/CFS has been reported in all age groups [14,15]. Quality of life of those with ME/CFS is on average lower than with other chronic or disabling diseases, such as multiple sclerosis [16], cancer, rheumatoid arthritis, depression [17], diabetes, epilepsy, or cystic fibrosis [18]. Economic costs are considerable [19–23] with repercussions for the individuals affected, their families and society, as well as to educational and occupational services.

Many will be unable to work or do so only on a part-time basis; with some in the milder spectrum of the disease able to work full time, however, often at the cost of enduring significant symptoms and sacrificing their social life and other interests due to the need to rest when not working [24,25]. In the absence of economic analysis on the costs of the disease in Europe, we estimate, based on data from the UK, ME/CFS may cost some 40 billion Euros per year to health services and society [22]. There is, however, a large degree of imprecision in these estimates, due to variation in coverage and costs of health services provision and living costs across the Continent, as well as in many cases failure to recognize or diagnose the disease, which not only contributes to this imprecision but also may result in patients being treated inappropriately through their being misdiagnosed as having a psychiatric illness.

Despite the substantial disease burden, the health needs of people with ME/CFS remain largely unmet in Europe, as in many other parts of the world. Clinical services for people with the disease are in small numbers and sparse. A large proportion of the population with the disease has very limited access to health services, including in the public, mixed, and private sectors, because of either geographical inaccessibility, disability, or unsympathetic responses from healthcare professionals. The still limited knowledge of health professionals about the disease, including those in primary care, who are often the first port of call for those with ME/CFS, means diagnosis is often missed or delayed, and not infrequently patients remain undiagnosed and do not receive appropriate care for long periods of time. While waiting for diagnosis, patients often encounter difficulties in getting help from the health and other services, and their suffering and needs are not fully recognised, not only by health professionals but also by employers and educators. On the other hand, on some occasions, patients are over-investigated, with inherent risks and unnecessary costs to individuals and society. People with ME/CFS may easily ge<sup>t</sup> trapped into a situation where, while unable to carry on or start meaningful work- or school-related

activities, they receive very little guidance from the health sector or support from social services—where they feel disbelieved and neglected and are often failed by the welfare system [24]. Their disability contributes to social isolation, which adds to their burden, and limits their chances of recovery or re-integration in society, by restricting access to healthcare and social support.
