ME/CFS: The current state of knowledge

Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a chronic illness that severely limits the quality of life of many people affected. Symptoms include fatigue (i.e. severe exhaustion), pain, and difficulties sleeping and concentrating. Symptoms can worsen for days or weeks after even mild physical or mental activities. This exertion intolerance, or post-exertional malaise (PEM), is considered the core symptom of the illness.

In spring 2021, the German Federal Ministry of Health (BMG) commissioned the Institute for Quality and Efficiency in Health Care (IQWiG) to review the current scientific state of knowledge on ME/CFS in both a scientific and easily understandable way and to publish the results. The final German-language report and an English extract are now available, following a preliminary report in autumn 2022 and a commenting procedure in which scientific societies and researchers, as well as patients and other people affected and their organizations, actively participated.

The information in the comments submitted, as well as an update of the literature search, led to changes in two parts of the report in particular: Firstly, the estimate of the number of patients affected in Germany is now higher than in the preliminary report. Secondly, in the overall weighing of benefits and harms for activation therapy, IQWiG no longer concludes that there is a hint of a benefit, because serious treatment-related side effects cannot be ruled out on the basis of the study data.

Four-part report

The report, which the Institute has now published on its website, consists of four parts.

• The first part includes a systematic presentation of the current state of knowledge about ME/CFS: symptoms, putative causes, epidemiological and health care aspects, as well as current diagnostic criteria are presented.
• The second part includes evidence mapping, i.e. an overview of the evidence on health care-relevant treatment options for selected treatment goals.
• The third part includes benefit assessments of the two treatment interventions identified in the evidence mapping, i.e., where possible, the benefits and harms for patients with ME/CFS were determined and weighed against each other.
• The fourth part includes several health information texts that communicate the relevant knowledge in an easily understandable way. These texts were evaluated in user tests and are now published on IQWiG’s health information website (gesundheitsinformation.de / informedhealth.org).

Causes unclear, diagnosis difficult, prevalence changing

Although ME/CFS was classified as a neurological illness by the WHO in 1969, the causes are still unclear. The first symptoms of ME/CFS often occur after an infection or trauma (e.g. to the cervical spine). In the absence of clear biomarkers for ME/CFS, such as lab test or imaging results, the diagnosis is based on symptoms, which, however, can vary widely.

In addition, the diagnostic criteria have changed over the past few decades: In many older publications, PEM was not considered a core symptom that must be present to diagnose ME/CFS. Such uncertainties influence estimates of the number of people affected (prevalence). In contrast to the preliminary report, the prevalence in children and adolescents was considered in the final report. Overall, IQWiG estimates that before the COVID pandemic, about 140,000 to 310,000 people in Germany were affected by ME/CFS.

Since some patients with long COVID meet the diagnostic criteria for ME/CFS, the number has probably increased since then. However, a reliable estimate is not yet possible due to a lack of data.

Only few conclusions possible on the benefits and harms of treatments

With regard to the overview of treatment options (evidence mapping), the hearing on the preliminary report and the update of the literature search provided no new information. As before, only cognitive behavioural therapy (CBT) and activation therapy or graded exercise therapy (GET) showed statistically significant positive effects compared to standard medical care (in 2 studies each).

In the benefit assessment of these two interventions, particular attention was paid to evidence of risk of harm based on information received during the commenting procedure. For CBT, IQWiG continues to see a hint of a benefit in the short and medium term, for example in the outcomes of fatigue, return to school/work or feeling ill after exertion. No longer-term data are available. There are no appropriately designed studies to assess the benefits or harms of CBT in patients with more severe ME/CFS.

Daniel Fleer, Division Head in IQWiG's Department of Non-Drug Interventions states: "Our results make it clear that CBT cannot cure the illness. But it is an option, especially for patients with milder illness, to help them cope a little better with their situation."

For GET – i.e. a gradual increase in physical activity starting from an individual baseline – 2 studies in people with mild to moderate ME/CFS show statistically significant, but on average only small advantages over standard treatment for several patient-relevant outcomes. The clinical relevance of most of the activation effects remains questionable. For example, after GET many patients were able to walk a few metres further within a six-minute period, but still markedly less than healthy people.

During the hearing on the preliminary report, several participants pointed out that patients with ME/CFS reported a deterioration of their condition after treatments involving an increase in physical activity. It is unclear to what extent this occurred after appropriate use of GET as described in the study manuals or after other treatments increasing physical activity. In any case, the data from the studies are too inconclusive to rule out harm from GET due to serious side effects. Therefore, it is currently not possible to reliably weigh benefits and harms of GET for people with mild to moderate illness. There is also a lack of suitable study data for patients with more severe ME/CFS.

Health information needs

IQWiG identified key information needs from the experiences of people with ME/CFS reported in the literature. Based on this information and the results of the other parts of the IQWiG report, a four-part health information text was produced providing an overview of the illness, as well as in-depth information on the diagnosis, treatment and everyday support for patients and their relatives.

Eleven patients with varying disease severity and 4 relatives tested the draft texts for comprehensibility, acceptance and fulfilment of information needs. Most respondents found the texts clear and understandable. From their point of view, the content was largely complete. The subheadings, formulated as questions, were also well received. For most sections there were only a few suggestions for changes and additions, which were examined by IQWiG and in part implemented. For example, the final versions now emphasize more clearly that PEM is the core symptom of ME/CFS. The information published on gesundheitsinformation.de / informedhealthonline.org will be updated regularly.

Recommendations for action for health policy, the medical profession and research

In its report for the Federal Ministry of Health, IQWiG identified gaps in knowledge and deficits in health care that should be addressed through a combination of different measures. Klaus Koch, Head of IQWIG’s Health Information Department notes: "These include easily accessible, objective and understandable information about ME/CFS. This is especially needed by people newly diagnosed with ME/CFS, but also by the general public." Appropriate educational content should also be integrated into the education and training of health care professionals.

Daniel Fleer adds: "There is also an urgent need for an international consensus on diagnostic criteria, with diagnostic parameters that are as clear as possible. On this basis, research efforts to clarify the aetiology of ME/CFS, as well as to determine the type of treatment and care required, should be intensified. There is insufficient interdisciplinary research in all these areas.”

The potential benefits and harms of activation therapies such as GET should be further investigated in appropriately designed studies. It should also be clarified whether the risk of harm is primarily associated with an inappropriate application of such therapies or also occurs with correct application.

Daniel Fleer also notes: “There is a striking lack of robust studies on the benefits and harms of a form of personal activity management known as pacing. Yet pacing seems to play an important role in the daily care of many people with ME/CFS. This evidence gap should be filled quickly. In our opinion, such studies are relatively easy to conduct.“