**Diagnostic categories**


#### **Examples of stratification categories:**


\* CCC 2003 [2], IOM 2015 [6], and Rowe et al., 2017 [4], criteria require 6 months of symptoms; experienced clinicians should be able to diagnose adults with 3 months of symptoms. For children, CCC criteria requires 3 months [2], and Rowe et al., 2017 [4], require 3 months in post-infectious cases. \*\* The 2 additional symptoms criterium is not required when the fatigue symptoms can be clearly linked to the triggering infection and are not explained by other pathologies.

#### *3.7. Recommendations for Health Care provision*

Primary care professionals have an important role in the initial diagnosis, including consideration of alternative conditions leading to similar symptoms. It is important to note that many symptoms commonly reported in ME/CFS have a low disease-specificity and may occur in a number of diseases. Acute infectious onset and PEM should always prompt to consider ME/CFS. Although diagnostic confirmation may require a 3- to 6-month period, it is important to contemplate the diagnosis at earlier stages, so that disease managemen<sup>t</sup> may start, and diagnosis and treatment of alternative diseases are not delayed (See Box 7).

Careful medical history, including social and occupational history and circumstances associated with the start of symptoms and subsequent progress will give significant clues on diagnosis. Information should be obtained on current and previous treatments, including prescribed and over the counter medicines and supplements as well as self-management strategies and alternative therapies. It is important to check for medications potentially leading to fatigue as well as autonomic-related and other symptoms. Physical examination and routine bloods tests are required to increase diagnostic accuracy and detect alternative conditions explaining the symptoms [51].

Patients with ME/CFS tend to be multi-symptomatic and often have long clinical histories, which may include various failed attempts to obtain a diagnosis and treatment. Multiple previous investigations are not uncommon; however, often, symptoms presented are discarded by clinicians as "exaggerated" or "imagined", related to excessive work or studies or as mood-related. Such a scenario is to be avoided through early recognition and diagnosis, which are reliant on better knowledge of the disease and education of doctors and other health professionals.

When a diagnosis is suspected in primary care, regular reviews are warranted, when the possibility of alternative diagnoses is explored at the same time as initial management, strategies are put in place. In such cases, it may be helpful to ask the patient to record their symptoms and other health parameters using standard instruments in advance of follow-up consultations (see Core Assessments, Box 8).

Education of patients in advance of, during, and following consultation may be useful, and reliable educational materials should be recommended, e.g., booklets, videos, or other online information materials. These should cover concepts and practical recommendations for "pacing" (pacing is a self-management tool to implement a strategy designed to help people live within their energy envelope, minimise PEM, and improve quality of life [52]) with adequate rest periods or breaks in activity, sleep hygiene, and pain managemen<sup>t</sup> strategies. Both mental and physical activities should be taken in such a way to avoid over-exertion, which may trigger post-exertional aggravation of symptoms or "crashes", and as a key strategy to optimise chances of recovery. A main goal of educational activities is to empower the patient for self-management and to be in control of their disease and healing process.

#### *3.8. Criteria for Referral for Specialist Services*

Although with good education of primary care physicians, diagnosis and monitoring of people with ME/CFS in primary care are possible and desirable, and referral for specialist services may be indicated in some circumstances (Box 10), viz. for confirmation of diagnosis, when there is doubt; for cases who may benefit from a multi-disciplinary team with specific expertise, including drug treatments or care of those with severe or complicated disease; and for a range of service offerings, such as occupational therapy, supportive counselling, education on self-management and energy/activity managemen<sup>t</sup> with "pacing", social services, and advice on access to community support, e.g., for educational, occupational, and social matters, such as benefits (see below on secondary services). Patients with more recent disease onset, such as those with less than 1–2 years of symptoms and the young (children, adolescents, and young adults) may also benefit from referral for initiation of multicomponent therapy, as early referral at this age might especially affect long-term prognosis. The more severely affected, including those who are house- or bedbound and severely disabled, should also be priority for referral, especially where appropriate homevisits or telemedicine are available, and, when necessary, for occupational, educational, and disability support. Note that some cases may be best served by referral to alternative

services, especially where ME/CFS or Complex Chronic Diseases (CCD) Services are not well developed, such as to pain management, rehabilitation, neurology, psychiatry, and rheumatology services.

**Box 10.** Examples of criteria for referral to secondary services caring from people with ME/CFS.


#### *3.9. The Continuing Role of Primary Care and the General Practitioner*

In general, irrespective of referral to secondary care, whenever possible, the primary care team should continue to take responsibility for the long-term care and monitoring of patients with ME/CFS and their treatment, whenever possible in partnership with the specialist team. This includes facilitating the provision of emotional, social care, and occupational health support, and medical advice to teachers, employers, and caregivers, in response to the specific needs of patients. This could involve access to resources in the community, such as to physiotherapy, occupational therapy, dietician, or home visits by the primary care team (especially for the more severely affected), e.g., by district nurses. Support for self-management, education, and work activities may require further contacts with the patients and their carers/families, as well as with educators and employers. Here, online educational materials may be of value, as well as group educational activities for patients. Organization of care for people with ME/CFS and in particular the severely affected may be complex and requires communication by primary care professionals with others from various disciplines.

The primary care provider will still have major responsibilities for searching for alternative diagnoses where relevant and dictated by clinical judgement, for dealing with co-morbidities, the onset of new co-morbidities, and other diseases that may be not directly related to the diagnosis of ME/CFS, and for referring to different specialists as appropriate. Pharmacological and non-pharmacological approaches to treatment and clinical progress should be reviewed. It is important to consider that patients with ME/CFS may be more sensitive to a range of medications; this also needs to be considered when treating other conditions, having in mind also the possibility of drug interactions.

Needless to say, the strength of primary and secondary care services in particular settings will be relevant to determine roles at each care level and the best ways of cooperation between services at different levels. We appreciate limitations of access and service provision in primary care in many places, and local solutions will need to be found in line with local needs and resources. Virtual healthcare or virtual support from the specialist to the primary care team may have an important role.

#### **4. The ME/CFS Specialist Consultation**

#### *4.1. Preparing for the Consultation and the Waiting Room*

Before specialist consultation, it may be helpful to obtain relevant information, using standardised questionnaires or data/information otherwise obtained that may help with diagnostic confirmation, characterization of symptoms and their severity, and life impact. Forms may also be used as baseline clinical information for monitoring disease progress and response to managemen<sup>t</sup> or treatment. These can be completed before consultation.

Standard questionnaires include the UKMEB Symptoms Assessment Questionnaire (SAQ) [53], to aid diagnosis and the Participant Phenotyping Questionnaire (PPQ), for severity profiling [54] or the DePaul Symptom Questionnaire, allowing diagnosis and symptom severity profiling [6]. The Impact on function and quality of life may be measured by standard instruments, such as Rand-36 [55,56], some of which have been validated in many languages. The Epworth Sleepiness Scale [57] can be used to assess excess daytime sleepiness and as a screening for obstructive sleep apnoea. Other instruments may be used to screen for mood disorders, e.g., neuroQOL [58] or HADS [59] for depression and anxiety or GAD-7 [60] for anxiety. Fatigue severity may be measured by instruments validated for ME/CFS, e.g., the fatigue severity scale [61]; visual scales such as pain and fatigue analogue scales are simple to use [62,63]. The same applies to sleep disorders (e.g., the Pittsburgh Sleep Quality Index [64]), and autonomic symptoms (e.g., Compass 31 [65]. A diagnosis of fibromyalgia may be established with a good degree of confidence by the annotation of pain symptomatology in pictorial representation of the human body [66]. The same is true for the evaluation of hypermobility syndromes, using the Beighton criteria [35].

#### *4.2. Diagnosis Confirmation and Continued Search for Alternative Diagnoses and Co-Morbidities*

The list of differential diagnoses of fatigue is exhaustive. Examples are listed in Box 7. Some conditions are often present concomitantly to ME/CFS (co-morbidities). Other conditions may potentially exclude a diagnosis if they may fully or mainly explain the symptoms. However, such conditions may also be co-morbid when their presence does not explain most of the symptoms and signs observed.

For diagnosis confirmation, we recommend the use of the CCC in both adults and children [2]. Additional tools for adults include The IOM criteria [6] and for children the paediatric "Diagnostic Work Sheet" [4] and/or the DSQ-PED [5]. Full consideration needs to be given to differential diagnosis and co-morbidities, and the need for detailed history, physical examination, and complementary tests, as appropriate, cannot be overestimated. Further tests may be recommended in secondary care settings, according to the need for supporting ME/CFS diagnosis and/or severity, and for differential diagnosis. Box 8 lists some assessments that may be considered. Those marked are suggested to be run routinely at the first assessment, and the others should be evaluated on a case-by-case basis, based on the clinical presentation. RAST tests for specific allergies, echocardiography, and serology for specific infectious diseases, as guided by clinical and epidemiological information, are other modalities that may be considered as appropriate.

Treatment for children and young people should usually be started by a paediatrician or a ME/CFS secondary care specialist centre that includes a paediatrician.

Further referral may be required when alternative diagnoses are suspected. This may include referral to a neurology or multiple sclerosis (MS) clinic and/or to specialists in ophthalmology, ENT, immunology (autoimmunity, immune dysfunction), allergology, orthopaedics, physical therapy, infectious diseases (travel-related disease), psychiatry, or gastroenterology.

#### *4.3. Management and Treatment*

In the absence of disease-specific treatment, key roles of the health professional include confirming the diagnosis, explaining to the patient the importance of avoiding overexertion and mental stress, "pacing", and symptomatic medication as needed and appropriate for the patient. Regular monitoring is important, when progress should be assessed, and the possible development of new diagnoses and co-morbidities considered, as the managemen<sup>t</sup> plan is reviewed. "Pacing" refers to breaking up physical or mental activities with periods of rest, before a significant level of tiredness or exacerbation of symptoms is achieved or is expected following exertion, e.g., PEM, which may manifest many hours after the effort. A general rule of thumb is the recommendation to keep the activity at 2/3 of the duration and of the intensity that is expected (based on previous experience) to cause post-exertional symptoms, though flexibility should be exercised in order to reflect the particular needs and circumstances of individual patients.

The goal of the management/treatment programme is to treat the most distressing symptoms (sleep disturbance, pain, orthostatic intolerance, or others) and empower the patients to be in control of symptoms and the disease by encouraging them to trust their own experiences and enhance their awareness of the activities and environments in which they can cope without exacerbating symptoms, and "pace" themselves accordingly. The program should aim at optimizing the patient's ability to maintain function in everyday activities, being as active as possible within their boundaries and then gently extending those boundaries [2]. This may be challenging, especially in the more severely affected who may be able to tolerate only very low levels of activity; those with less severe forms of disease are likely to "overdo" and may have frequent exacerbations of symptoms ("crashes") as a consequence.

Recent studies sugges<sup>t</sup> that there may be a role for cognitive behaviour therapy (CBT) in the managemen<sup>t</sup> of ME/CFS. It may have long-term benefits in chronic fatigue [67], but there is little evidence of this, and it needs to be used with considerable care to avoid distress [68]. It should be appreciated that it is a supportive therapy and not curative [69].

Wearables can assist objective measurement of activity and sleep patterns, and in some cases heart rate variability [70]. They may be combined with a symptom diary, which will help the interpretation of symptoms and management.

#### *4.4. Professional-Patient Partnership, Self-Management, and Support*

It is important to establish a supportive and collaborative relationship with the patient suffering from ME/CFS and, as appropriate, with their caregivers. Engagement with the family may be essential, especially for children and young people, and for people with severe ME/CFS. A named healthcare specialist should be involved for coordinating care for the person with ME/CFS. Information to people at all disease stages should be according to the person's circumstances, including clinical, personal, and social factors. Information should be available in a variety of formats as appropriate (printed materials, electronic videos, and audios).

The doctor-patient partnership, informed choices and risk minimisation are essential components of care. Partnership between patient and health care providers should be based on trust, and consideration of their interactions as encounters between two experts with different, but complementary backgrounds (the patient and the healthcare provider), who recognise that knowledge about the disease and its managemen<sup>t</sup> is incomplete. Basic managemen<sup>t</sup> principles should apply, but often different treatments may be attempted (preferably one at a time, on a trial-and-error basis) and reassessed according to response or potential adverse effects. This is when the strength of the partnership becomes even more important, as partners engage in a journey where uncertainty is gradually replaced by increasing understanding of the disease/health process, as treatment and managemen<sup>t</sup> strategies are regularly reviewed and adapted to suit patient characteristics and preferences. Over-investigation and over-treatment are discouraged, but a very passive approach to illness may also be counterproductive, and such discouragement should not result in patients being denied treatment or testing needed to monitor changes in their condition.

#### *4.5. Managing Patients' Expectations*

It is essential that the professional is upfront in explaining the current limits of treatment and understanding of potential pathophysiology and the approach to symptom management. This will greatly address discrepancies between patients' and doctors' expectations and set up the conditions for an open and positive patient-doctor relationship where patients are empowered to make informed choices.

There is no known pharmacological treatment or cure for ME/CFS. However, symptoms should be managed as in usual clinical practice. Physicians may consider starting symptomatic treatment at a lower than usual dose, due to frequent medication sensitivities in this population. The dose may be carefully increased. Treatment and repeat prescription may be continued in primary care, depending on the patient's preference and local circumstances.

#### *4.6. Non-Pharmacological Treatment for Symptoms Relief and Available Support Therapies*

Recommendations considered appropriate are shown in Box 11. It is important that these are provided by practitioners with experience in ME/CFS.

**Box 11.** Recommendations for a non-pharmacological approach to the relief of ME/CFS symptoms.
