Identifying and diagnosing ME/CFS

National Guideline Centre (UK)

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Identifying and diagnosing ME/CFS

Myalgic encephalomyelitis (or encephalopathy) / chronic fatigue syndrome: diagnosis and management

Evidence review D

NICE Guideline, No. 206

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2021 Oct.

ISBN-13: 978-1-4731-4221-3

Identifying and diagnosing ME/CFS

Review questions

In people with suspected ME/CFS, what are the criteria used to establish a diagnosis?
What is the diagnostic accuracy of specific tests to identify ME/CFS in people with suspected ME/CFS?
What are the predictive accuracies of specific clinical symptoms and signs to identify people who will subsequently be given a clinical diagnosis of ME/CFS?

Review questions

Key areas to be covered in the scope included identification and assessment before diagnosis and diagnosis of ME/CFS. This evidence report covers both areas of the scope.

ME/CFS affects people of all ages, races and socioeconomic groups. Discussion with the committee identified that the focus for identifying people with suspected ME/CFS and then diagnosing ME/CFS is clinical assessment. ME/CFS has historically been named and described in various ways. Names that have been used include: myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), Post Viral Fatigue Syndrome (PVFS), Post Infection Fatigue Syndrome (PIFS), systemic exertion intolerance disease (SEID) and, combined names such as CFS/ME and ME/CFS. In the absence of a definitive test or biomarker, diagnosis has been mainly based on patterns of reported symptoms. Nevertheless, clinical descriptions of ME/CFS are variable, with each set of existing diagnostic criteria prioritising different symptoms as primary indicators, for example: factors such as fatigue, fatiguability, cognitive difficulties and the after-effects of exertion. The majority of diagnostic criteria to date have focussed on fatigue as the primary symptom, along with a combination of other symptoms. People with ME/CFS have queried this primary use of fatigue for diagnosis, and instead emphasise that the condition can include a breadth of symptoms affecting multiple systems and environmental intolerances which significantly reduce ability to function.

People with ME/CFS report delays in diagnosis, and research has highlighted that many healthcare professionals including GPs lack the confidence and knowledge to recognise, diagnose and manage ME/CFS. Delays in diagnosis can have an impact on the physical and emotional health of the person wating for a diagnosis. It is important to identify people with ME/CFS as early as possible to ensure they are given information to try to prevent worsening of symptoms and any further deterioration of health.

To inform the recommendations in the areas of identification and diagnosis of ME/CFS three review questions were conducted. The committee used these reviews to inform their recommendations in these areas.

1. Diagnostic criteria

1.1. Review question

In people with suspected ME/CFS, what are the criteria used to establish a diagnosis?

This review examines the criteria currently in use in clinical practice and research to assess which of those criteria are most appropriate for suspecting and then establishing an ME/CFS diagnosis for clinical practice.

1.1.1. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 1

PICO characteristics of review question.

1.1.2. Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in Appendix A, and the methods document describes the methods for the quality appraisal of the identified diagnostic criteria.

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

1.1.3. Effectiveness evidence

1.1.3.1. Included studies

Nine studies (10 publications) were included.¹⁵^–¹⁷^, ⁴²^, ⁵⁵^, ⁵⁹^, ⁶⁶^, ¹²⁴^, ¹⁴⁰^, ¹⁴⁷

1.1.3.2. Excluded studies

See the excluded studies list in Appendix H

1.1.4. Summary of studies included in the effectiveness evidence

Table 2 summarises the criteria developed for both children and adults and Table 3 summarises criteria specifically designed for children. These include a description of their methodology and a summary of the quality appraisal (see Appendix D for an explanation of the quality criteria and Appendix E for the full quality appraisal for each study).

Table 4 provides a more concise ‘side-by-side’ summary of the criteria. Four of the criteria were developed for use in a clinical context¹⁵^, ⁵⁹^, ¹²⁴^, ¹⁴⁰, three were developed for research purposes⁴²^, ⁵⁵^, ¹⁴⁷ and two were developed for use in both settings.¹⁷^, ⁶⁶

Table 2

Summary of evidence for criteria aimed at both adults and children.

Table 3

Summary of evidence specifically for children.

Table 4

Overview of included ME/CFS criteria as categorised by the authors.

1.1.5. Economic evidence

The committee agreed that health economic studies would not be relevant to this review question, and so were not sought.

1.1.6. Evidence summary

1.1.6.1. Diagnostic criteria for both adults and children

Four studies¹⁵^, ⁵⁹^, ¹²⁴^, ¹⁴⁰ (Carruthers¹⁵^, ⁵⁹^, ¹²⁴^, ¹⁴⁰) with serious limitations to very serious limitations reported criteria developed for clinical use. Criteria were broadly overlapping, with all including post-exertional malaise, severe and prolonged fatigue unexplained by activity, cognition difficulties and unrefreshing sleep, although there were differences in whether the symptoms/signs were compulsory for diagnosis. There were also differences in the inclusion of other symptoms/signs such as motor and sensory deficits, pain, immunological and other systemic symptoms, description of a sudden onset, being life-long and exclusion of differential diagnoses. Minimum symptom duration ranged from 4 months to 6 months for adults and 3 months to 6 months for children.
Three studies⁴²^, ⁵⁵^, ¹⁴⁷ (Fukuda⁴²^, ⁵⁵^, ¹⁴⁷) with very serious limitations reported criteria developed for research purposes. All criteria included prolonged fatigue unexplained by activity and myalgia/joint pain and exclusion of differential diagnoses. The only compulsory features were fatigue/fatigability and exclusion of differential diagnoses. Criteria differed on the inclusion of other symptoms/signs such as post-exertional malaise, motor and sensory deficits, other types of pain, neurocognitive deficits, mood, sleep problems, immunological and other systemic symptoms, being life long and specific physician-conducted tests or objective clinical examination to detect ME/CFS. All criteria specified a minimum symptom duration of 6 months.
Two studies¹⁷^, ⁶⁶ (Carruthers 2011(ICC)¹⁷^, ⁶⁶) with very serious limitations reported a set of criteria developed for use in both clinical and research settings. The criteria included post-exertional malaise as a compulsory feature, prolonged fatigue unexplained by activity, motor and sensory deficits, pain, neurocognitive deficits, sleep problems, immunological and other systemic symptoms and exclusion of differential diagnoses. There was no minimum symptom duration.

Diagnostic criteria for children

One study with very serious limitations reported a set of criteria developed for clinical use. The criteria included post-exertional malaise, prolonged fatigue unexplained by activity and impaired function as compulsory features, pain, neurocognitive deficits, sleep problems and immunological symptoms and exclusion of differential diagnoses. The minimum symptom duration was 6 months.
One study with very serious limitations reported a set of criteria developed for use in both clinical and research settings. The criteria included post-exertional malaise, prolonged fatigue unexplained by activity and sleep problems as compulsory features, motor and sensory deficits, pain, neurocognitive deficits, immunological and other systemic symptoms and exclusion of differential diagnoses. The minimum symptom duration was 3 months.

1.2. The committee’s discussion and interpretation of the evidence

1.2.1. The outcomes that matter most

This review identified and described the published sets of criteria that have been developed through consensus to establish a diagnosis of ME/CFS. The symptoms and signs within each of the criteria are described and the similarities and differences between the sets of criteria outlined.

The diagnostic criteria have not been evaluated in terms of their measurement validity and accuracy in diagnosing ME/CFS. Without a biomarker it is not possible to definitively know if a person has or does not have ME/CFS. Without such a reference standard (or ‘gold standard’) it is not possible to assess the measurement validity of the different criteria.

There are published studies that assess how a new set of diagnostic criteria can differentiate between cases and controls; however, because the status of cases and controls are based on another set of criteria, this method only measures agreement between the different sets of criteria, and not measurement validity. In the absence of a reference standard it cannot be assumed previous criteria are superior and it is not possible to assess if the level of agreement between new and previous criteria represents a positive or negative outcome.

Other methods assess the prevalence of ME/CFS measured by a set of criteria, but again these do not establish measurement validity they compare the prevalence of the conditions as described by the criteria. Again, because one set of criteria cannot claim to be more accurate in diagnosing ME/CFS than the others, disagreements in prevalence cannot be extrapolated to differences in measurement validity.

1.2.2. The quality of the evidence

There is no current gold standard for diagnosing ME/CFS so it is not possible to validate the criteria used in different definitions. A pragmatic approach that bypasses the difficulties concerning measurement validity is possible. If the criteria cannot, due to the lack of a reference standard, be shown to be ‘correct’ or ‘not correct’, then the second best option is to show that the criteria have been developed using optimal methods. This is because an unbiased, clearly reported, evidence-based and consensus-driven process utilising the expertise of patients, clinicians and researchers is most likely to lead to more clinically useful criteria. This is the basis of the quality criteria used in this review. Quality was measured using a set of quality criteria based on the AGREE II quality criteria, as described in Appendix D.

All of the evidence had serious or very serious limitations, largely a result of lack of methodological rigour, lack of stakeholder involvement and lack of consideration of applicability/implementation of the criteria.

1.2.3. Benefits and harms

This review described the seven diagnostic criteria for adults and two diagnostic criteria for children and young people that met the inclusion criteria set out in the protocol (see Appendix A).

The committee acknowledged there is an ongoing discussion in the ME/CFS community about which diagnostic criteria are best and which should be used in the identification and diagnosis of ME/CFS. The factors influencing these discussions are the broadness of the inclusion criteria, the definition of some of the symptoms, and the usability of the criteria as a clinical tool.

1.2.3.1. Suspecting ME/CFS and making a diagnosis of ME/CFS – description of recommended criteria and committee discussion

The signs and symptoms common to most of the criteria are listed below, the criteria that do not include that sign or symptom is in the brackets:

Post exertional malaise (not included in the Oxford Criteria) and other severe and prolonged fatigue unexplained by activity
Pain, specifically joint pain (not included in the IOM) and headache/eye pain (not included in the Oxford Criteria or IOM)
Cognitive impairment, for example memory problems (not included in the Oxford Criteria or IOM) and brain fog (not included in the Oxford Criteria)
Unrefreshing sleep (not included in the Oxford Criteria or the CDC 1998)
Tender lymph nodes (not included the Oxford Criteria or IOM)

This overview of the criteria fitted with the committee’s clinical and/or personal experience about the core features of ME/CFS and increased their confidence in making a recommendation about the signs and symptoms present when ME/CFS should be suspected and diagnosed.

The committee considered the balance between over-diagnosis and missing a diagnosis. Whilst the IOM, 2015 criteria are potentially more encompassing than the ICC, reducing the probability of missing a diagnosis, the IOM criteria are also potentially narrower than some of the other criteria such as the Fukuda, reducing the risk of over-diagnosis. In this way the IOM, 2015 criteria were judged by the committee as allowing a reasonable compromise between over and under inclusion of people within the diagnostic criteria. The committee acknowledged that this judgement was made in the absence of formal measures of accuracy.

The IOM 2015 criteria requires a person has each of the following symptoms for a diagnosis:

A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest, and
Post-exertional malaise, and
Unrefreshing sleep and
either cognitive impairment or orthostatic intolerance.

The committee made a consensus decision that the IOM 2015 criteria were a useful set of criteria, having advantages over other criteria in terms of usability (see discussion in the other factors the committee took into account) and an optimum balance of inclusion/exclusion criterion. The committee agreed to use the IOM, 2015 criteria as a basis for their recommendation of when to suspect someone may have ME/CFS. The criteria were modified slightly and this is described below. The committee considered the modifications and clarifications improved the usefulness and usability of the IOM 2015 criteria.

The committee recognised this adds another set of consensus criteria to the literature. The committee noted the evidence calling for clarity over diagnostic criteria and terms used to describe ME/CFS and the symptoms from the information, education and support for health and social care professionals (see Evidence review B:Information and Support for health and social care professionals) and agreed that it was important to have a set of criteria that is informative and enables health and social care professionals to recognise ME/CFS. The committee decided that it was important to make a research recommendation to validated this consensus criteria agreed by the committee and hoped this research would inform future guidance.

Symptoms such as fatigue and sleep problems are generic to many conditions and the committee considered it was important that there was definition and explanation alongside the recommendation about how these proposed symptoms present in people with ME/CFS and how this may differ from presentations in other conditions. For example, the committee noted that fatigue and sleep problems specific to ME/CFS in adolescents can be difficult to distinguish from fatigue attributed to ‘normal’ teenager behaviour.

Fatigue

The committee considered that ‘fatigue’ required precise definition because the same term can potentially be used across a spectrum from a benign physiological response after activity (in well populations) to a disabling mental and physical exhaustion that bears little relationship to the stimulus that precipitated it (in ME/CFS populations). The committee agreed that ‘fatigue’ as it is commonly used is not a true description of the symptoms in someone with ME/CFS.

The committee considered the wording of the first paragraph of the original IOM criteria, where the effects on function from fatigue are stressed, did not give enough emphasis to the fatigue as the cause of the reduction in function.

The committee discussed the different types of fatigue identified in the ME/CFS literature and their own experiences. There was agreement that there is a marked difference between ‘normal tiredness’ and the profound fatigue caused by ME/CFS and that the term fatigue does not reflect the actual symptoms that people with ME/CFS experience. Several alternative terms were suggested by the committee members to capture this including: fatiguability, debilitating fatigue, post-exertional exhaustion; post-exertional debility; post-exertional weakness. The committee decided upon ‘‘debilitating fatigue’ with a short explanation in the recommendation clarifying that is not the result of ongoing excessive physical, emotional or mental exertion, and is not substantially alleviated by rest. A further explanation of fatigue has been added to the terms used in the guideline to provide further support for clinicians.

Post-exertional Malaise

The committee considered the term post exertional malaise (PEM) to be outdated and agreed that the term ‘post exertional symptom exacerbation’ (PESE) reflects better the interaction with pre-existing symptoms. Some of the committee considered ‘malaise’ can have the impression of a vague discomfort by people who do not have an understanding of ME/CFS. However, the committee acknowledged that PESE was a term not often understood by people outside of the ME/CFS community and agreed to use the term post exertional malaise (PEM) to avoid confusion in interpreting the recommendations.

The key feature of PEM is that the malaise (extreme fatigue and flu-like symptoms) and other symptoms experienced are not in proportion to the activity that has been done. PEM is often delayed and may be experienced hours or days after the activity took place, the committee were aware of some literature that suggested this is most likely to occur 1-2 days after the exertion. This delay can lead clinicians and people to believe that symptom exacerbations are random and unrelated to a trigger as their worsened condition is not attributed to activity that may have happened days earlier. The effects of PEM can last for hours, days, weeks or even months. Longer periods of PEM are often referred to as ‘crashes’ or flare ups by people with ME/CFS and may precede a sustained relapse.

The committee thought it was important to provide clarity about what is meant by activity in this context. Activity refers to any effort that requires energy expenditure and includes cognitive, physical, emotional and social activity, it is not limited to physical activity. The committee noted that misunderstanding of ‘activity’ can lead to people with ME/CFS being expected to participate in activities that while are not seen as physically demanding by someone without ME/CFS can have a damaging impact on their energy levels. One example could be engagement in social activity or being in any over stimulating environment. A definition of activity was added to the terms used in the guideline.

Unrefreshing sleep

The committee agreed that sleep difficulties are one of the central features of ME/CFS. As with fatigue and PEM the committee considered that the type of sleep difficulties people with ME/CFS experience are poorly understood. In people with ME/CFS unrefreshing sleep manifests especially as exhaustion, flu-like feelings and stiff upon waking, and may be caused by broken or shallow sleep, or a reversed sleep-wake cycle. Other manifestations of sleep dysfunction in people with ME/CFS can include insomnia, hypersomnia, and vivid nightmares. People with ME/CFS can have a full night’s sleep but this will not alleviate their fatigue (and other ongoing symptoms) and is non restorative as would be expected in a healthy population.

Cognitive difficulties

The committee noted that cognitive difficulties, such as brain fog, are not a compulsory feature in the IOM, 2015 criteria but as an ‘either or’ criterion alongside orthostatic intolerance. Based on the evidence that cognitive difficulties are described in most of the reviewed criteria (7 of the 9) and their experience as this being one of the most commonly reported features of ME/CFS the committee considered cognitive difficulties an essential criterion for suspecting ME/CFS and diagnosis.

Criteria agreed by the committee

On this basis the committee agreed the criteria and recommended that ME/CFS should be suspected in people with these 4 key features:

Debilitating fatiguability that is not the result of ongoing excessive physical, emotional or mental exertion, and is not substantially alleviated by rest.
Post-exertional malaise, which is disproportionate to the amount of exertion (cognitive, physical, emotional and, social), and can be delayed.
Unrefreshing sleep.
Cognitive difficulties.

These four symptoms were agreed by the committee as the best basis for identifying people with ME/CFS and as essential to a diagnosis of ME/CFS. The committee added further detail into the recommendation clarifying how to recognise these symptoms in people suspected with ME/CFS.

In addition to the four symptoms the committee agreed that as in the IOM 2015 criteria there should be a substantial reduction or impairment in pre-illness levels of function…

Associated symptoms

In addition to the key features discussed above (debilitating fatiguability, post-exertional malaise, unrefreshing sleep and cognitive difficulties) the committee noted that many of the criteria also included symptoms that are commonly experienced by people with ME/CFS. They agreed that while these symptoms were not key to diagnosis they are key to understanding ME/CFS and supporting the management of symptoms. The committee highlighted the following associated symptoms as being particularly important:

Orthostatic intolerance and autonomic dysfunction, including dizziness; palpitations; fainting; nausea on standing or sitting upright from a reclining position.
Temperature hypersensitivity resulting in profuse sweating, chills, hot flushes, or feeling very cold.
Neuromuscular symptoms, including twitching and myoclonic jerks.
Flu-like symptoms, including sore throat, tender glands, nausea, chills or muscle aches.
Intolerance to certain foods, alcohol and chemicals.
Heightened sensory sensitivities, including to light, noise, touch and smell.
Pain, including on touch, myalgia, headaches, eye pain, abdominal pain or joint pain without acute redness, swelling or effusion.

As discussed above the IOM, 2015 criteria listed orthostatic intolerance alongside cognitive difficulties as an ‘either or’ symptom for diagnosis. The committee considered that orthostatic intolerance is an important symptom that is often present in people with ME/CFS and can be very debilitating. In the committee’s experience recognition of orthostatic intolerance and the appropriate treatment can improve people’s functioning (see Evidence review G: non pharmacological management).

Pain and decreased pain threshold, and flu like symptoms were identified in most of the criteria as symptoms for suspecting ME/CFS and diagnosis and the committee agreed they were important to be aware of. In particular, they noted people with ME/CFS often described having flu like symptoms in the initial stages of ME/CFS. The committee agreed that temperature hypersensitivity, neuromuscular symptoms, intolerances and sensory sensitivities were all mentioned to some extent in the criteria and were common symptoms they were aware of.

The committee noted the difficulty in identifying the cause of symptoms in children and young people and commented that symptoms such as abdominal pain or a sore throat are particularly relevant to consider in children and young people as they can localise symptoms to these areas.

1.2.3.2. When to diagnose ME/CFS

The committee agreed that the signs and symptoms for suspecting ME/CFS are the same as those for diagnosing ME/CFS. The confirmation of diagnosis comes with duration of the symptoms and the exclusion of other conditions. The committee emphasised the importance of considering alternative diagnoses, as well as co-existing conditions and comorbidities when assessing a person for ME/CFS (see evidence review G: non pharmacological management on assessments and plans).

Duration of symptoms – suspecting ME/CFS

The committee discussed in depth the complexities around defining a period of time, first of all when ME/CFS should be suspected, and then when it should be diagnosed.

Throughout the evidence reviews (Evidence review A:Information and support for people with ME/CFS, Evidence review B:Information and support for health and social care professionals and evidence review C: Access to care), reports on children and young people and people with severe ME/CFS (Appendix 1 and 2) and Dr Muirhead’s expert testimony is the finding that people with ME/CFS experience delays in diagnosis. Early diagnosis is seen as critical to better care and may also improve prognosis. Appropriate advice on activity and rest given in the early stages of ME/CFS is seen as the key to prevent deterioration (see Evidence review E: pre diagnosis strategies). However, what is not clear is at what point ME/CFS should be suspected and then later diagnosed. Based on their experience the committee decided that ME/CFS should be initially suspected in people who have the four key features (debilitating fatiguability post-exertional malaise, unrefreshing sleep and cognitive difficulties) for a minimum of 6 weeks in adults and 4 weeks in children and young people. The rationale behind this was that it would be unusual for an acute illness, including a viral illness to persist longer than this with all the symptoms. The committee emphasised it is the combination and interaction of the symptoms that is critical in distinguishing ME/CFS from other conditions and illness. At this point advice on managing symptoms should be given (see Evidence review E: pre diagnosis strategies), in addition to advice children and young people should be referred to a paediatrician for further assessment and investigation of other causes. The committee considered it was important that children and young people with these symptoms did not wait longer to see a paediatrician but they did not consider it necessary they should be referred to a specialist ME/CFS paediatric service until further assessments and investigations had been done.

Duration of symptoms - diagnosing ME/CFS

All the criteria except the ICC criteria included a minimum symptom duration period. All the criteria stated 6 months for an adult except the NICE CG53 criteria which stated 4 months. The minimum duration for children ranged from 3 to 6 months. The committee drew on their experience and the evidence reviews on access to care (report C) and agreed that ME/CFS should be diagnosed in people with the key features (debilitating fatiguability, post-exertional malaise, unrefreshing sleep and cognitive difficulties) for 3 months. The committee reflected that the evidence across the guideline (Evidence review A: Information and support for people with ME/CFS, Evidence review B: Information and support for health and social care professionals and evidence review C: Access to care), reports on children and young people and people with severe ME/CFS (Appendix 1 and 2) and Dr Muirhead’s expert testimony) highlighted the lack of knowledge and education that health and social care practitioners have about ME/CFS. This lack of knowledge is perceived to underpin a lack of confidence in recognising and diagnosing ME/CFS resulting in delays to diagnosis. The committee agreed that as primary healthcare professionals are the most likely professionals that people with suspected ME/CFS will initially meet it was important to make a recommendation that they should have training relevant to their role (for example, in identifying people with ME/CFS).

The committee agreed that although a 6-month delay to diagnosis is built into the IOM criteria, the criteria could be safely amended by the reduction of this delay period to 3 months. It was agreed that the function of a delay is partly to reduce the number of misdiagnoses through allowing short-lived fatigue to be excluded. In addition to not being disadvantageous, removal of the delay was seen as beneficial, as this might facilitate earlier management and potentially allow improvement in longer term outcomes.

There are concerns with both a false positive and false negative diagnosis of ME/CFS. Both scenarios may lead to improper interventions, withholding of treatment and a prognosis for a disease or condition they do not have. The committee emphasised the importance of identifying and excluding other conditions, and that these should be appropriately investigated in people with suspected ME/CFS.

The committee were aware of people who had been wrongly diagnosed with ME/CFS and as a result had not received appropriate treatment for other conditions. To mitigate the risk of missing an alternative diagnosis, it is important that clinicians consider differential diagnoses carefully, and continue to monitor people with suspected ME/CFS for the emergence of new symptoms which could indicate an alternative diagnosis, especially when symptoms may overlap or be confused with those with ME/CFS. It is also important to recognise that a positive or suspected ME/CFS diagnosis does not mean someone does not have or could not develop a co-existing condition or a co-morbidity. If a clinician has any concerns about interpreting signs and symptoms they should consider referral to the relevant specialist.

Co-existing conditions and differential diagnoses are discussed further in the ‘other factors the committee took into account’ section below.

1.2.3.3. Unpredictability and severity of symptoms

One of the complexities of identifying ME/CFS is the fluctuating and unpredictable nature of the symptoms. Symptoms follow a characteristic pattern of variability and can develop over time. The committee noted that most people with ME/CFS have a fluctuating course, where symptoms wax and wane over the course of the day or longer. Fluctuations can be affected by any activity, infections, vaccinations, stress, food intolerances, temperature extremes and any other environmental stimuli.

The committee also discussed that when a patient first presents to a clinician they are unlikely to be experiencing their symptoms at the worst level. Severe physical fatigue may mean that someone is unable to physically visit a clinic and cognitive difficulties may mean they are less able to explain their symptoms to a clinician. Also, it can be difficult to judge severity when clinicians do not usually see the result of overexertion, especially if they do not understand PEM. The committee emphasised it was important for clinicians to be aware that a patient in their surgery is likely to be better than they are at other times, and to bear this in mind when making judgements about severity. To help the clinicians to gain a more complete picture of the person’s condition they should ask information about their symptoms over a longer course of time.

A recommendation was included to raise awareness about the fluctuating nature of ME/CFS and how this can mean that people can present differently throughout their illness. The committee noted that the unpredictability of symptom severity prevents planning ahead and reliability, even in the immediate- and short-term (for example, over the next couple of hours), and this may impact on attendance at work, education or training, social events, or medical appointments. This important information should be acknowledged when considering the impact of the illness on a person’s life and any support they may require (for example, in applications and assessments for social care support, benefits, education and adjustments) (see evidence review C: Access to care).

1.2.3.4. Children and young people

The committee acknowledged that the majority of the evidence identified in this report was conducted in adult populations with the exception of the criteria developed by the International Association of Chronic Fatigue Syndrome Paediatric Case definition Working group⁶⁶ and International Writing Group for Paediatric ME/CFS¹⁴⁰. They observed that these two criteria identified the same key symptoms as those identified in the adult criteria. The committee agreed that on this basis and reflecting on their own knowledge and experience the majority of the recommendations on suspecting and diagnosing ME/CFS could be generalised to children and young people. The committee made additional recommendations for referral and diagnosis and communication of symptoms in children and young people.

Referral to a paediatrician

The committee discussed the importance of recognising and referring children and young people with suspected ME/CFS as early as possible to a paediatrician, and after further assessment and investigation to a paediatrician that has expertise in ME/CFS for confirmation of a diagnosis. The committee took into account their own experience and evidence from the report on children and young people.

The journey to diagnosis was identified as one of the key themes in the report findings. The participants describe their symptoms initially as resolvable short-term illness but it soon became apparent they were experiencing something that was unknown and different. The symptoms lasted longer, were more debilitating and felt like a more serious illness. The understanding of their experiences, the process and how to manage their illness was difficult initially for all the participants. This was compounded by a lack of knowledge the healthcare professionals they met had about ME/CFS. Some of the participants expressed anger at the lack of support and advice they received before a diagnosis relying on research they or family members had done. The participants identified the need for an earlier diagnosis to reduce the extreme experience of symptoms.

This resonated with the committee and they recognised the uncertainty and anxiety for the child, young person and their families that can result from a long wait for referral and delays to diagnosis. The committee estimated that currently time to referral and before a diagnosis is confirmed by a paediatrician can be up to 6 months and some young people in the report delays of up to 18 months. As stated above the delay is accompanied by a lack of support and advice. The committee commented on the devastating impact this can have on a child or young person’s education and training and they were aware that ME/CFS is one of the most common causes of long-term school absence.

In order to address this and reduce the time waiting for a referral and diagnosis the committee recommended that ME/CFS should be suspected in a child or young person who had symptoms for a minimum of 4 weeks. This is two weeks less than adults in the recognition that it is unusual for children to be acutely ill for this length of time. This approach avoids the delays in diagnosis and the committee have made recommendations about the management of symptoms in people suspected ME/CFS and recommendations supporting education and training in children and young people. The committee noted that in their experience this was beneficial and enabled children, young people and their families to access support in continuing their education before a diagnosis had been made.

The committee acknowledged there is a risk that someone might not have ME/CFS, but they agreed none of the recommendations on advice in the guideline before diagnosis are likely to cause harm. The recommendations are clear there should be review of symptoms and that when suspecting ME/CFS the possibility of another condition should not be excluded. This the committee agreed addressed and outweighed the impact of delayed and late diagnosis.

Description of symptoms by children

The committee discussed the difficulty that children and young people can have in describing their symptoms. They took into account their own experience and evidence from the children and young people report. The committee highlighted that children may experience difficulty articulating their symptoms either because they regard them as normal as a result of experiencing them for a long time or because they lack the vocabulary to describe them; and that clinicians should be aware of that they may find consultations difficult after being in isolation or after previous negative experiences of not being believed by clinicians, teachers and peers. One participant in the children and young people commissioned report commented that being in a medical appointment without their mother was scary.

While recognising that it is not unusual for children and young people to have difficulty in describing how they feel the committee considered it very important this was acknowledged here considering that it is the combination of symptoms, clinical examination and history-taking are vital to the diagnostic process.

The committee were aware that the Royal College of Paediatrics and Child Health have developed resources, with input from children and young people, to aid their communication with health professionals. The ‘Being Me’ resources help children and young people to share who they are, how they are feeling and what support they would like. The materials include: feelings poster, children’s health and wellbeing passport and top tips for doctors. These tools are especially effective for children and young people that do not feel comfortable to freely share their experiences, as described by this young person: “Emojis are an easy and fun way for us to tell doctors how we are feeling when we can’t fully explain or don’t want to. Children can point to an emoji or draw with their doctor.” RCPCH &Us Voice Bank, 2018.

1.2.4. Cost effectiveness and resource use

It was agreed by the committee should not be sought for this question.

The committee’s criteria for diagnosing ME/CFS are more restrictive than in the previous NICE guideline (CG53), since patients are required to have all the following: debilitating fatiguability, post-exertional malaise, unrefreshing sleep and cognitive difficulties. However, compared with CG53, the duration of symptoms required for diagnosis is shorter (3 months). This is to allow faster access to appropriate care for those that clearly meet the diagnostic criteria. In line with the committee’s experience, expert witness testimony and the views and experiences of people with ME/CFS emerging from qualitative reports, it is very common for people with ME/CFS to experience delays in diagnosis. This negatively impacts not only their physiological and psychological well-being, but is also likely to influence prognosis, as diagnostic delay leads to delayed management advice and often to deterioration of symptoms. An earlier diagnosis provides a window for early intervention that can be critical to better care which by preventing the deterioration of symptoms can reduce the long-term costs involved in the care of people who become severely affected and those who do not improve over time.

The committee have recommended that diagnosis is confirmed by a specialist team. This has been informed by the qualitative evidence included in other reviews for this guideline, that describe the barriers people have faced in reaching a diagnosis. In the case of children, referral should be sooner than 3 months to ensure that there is not significant damage to the child’s education and development.

The net resource impact of these could mean a shift of resources rather than an increase. The main outcome should be earlier access to appropriate care, which should improve efficiency by avoiding unnecessary and harmful treatment.

1.2.5. Other factors the committee took into account

Usability of the criteria

The committee acknowledged that many different case definitions exist with some being developed for use in clinical practice and others for research. In this review four of the criteria identified were developed for use in a clinical context¹⁵^, ⁵⁹^, ¹²⁴^, ¹⁴⁰, three were developed for research purposes⁴²^, ⁵⁵^, ¹⁴⁷ and two were developed for use in both settings.

The committee noted that some of the criteria are harder to use than others and ease of use is important to increase confidence in clinicians that are not familiar with ME/CFS. For clinical practice criteria that are simple and not time consuming are likely to be most helpful. The committee agreed that the IOM, 2015 criteria were clinical criteria developed to facilitate clinical diagnosis and are user-friendly to clinicians because of their relative brevity, simplicity and clarity of symptoms. The IOM, 2015 criteria were regarded as easier to use, needing less specialist knowledge and experience of treating people with ME/CFS, compared to more complex criteria such as the ICC and therefore particularly suitable for non-specialists. The quality assessment rated them as partially meeting the domain evaluating applicability, due to lack of consideration of potential resource implications not being reported, however it was noted that all other items within this domain, including consideration of barriers and facilitators to implementation, strategies to improve uptake and monitoring of the impact were met.

The committee discussed that in practice no one criteria is used clinically with a ‘mix and match’ approach being used alongside clinical experience. For this reason none of the criteria were seen by the committee as having the added advantage of usability when considering if any should be used over the others in clinical practice.

Symptom assessment questionnaires

The committee noted as well as the difficulties in defining a set of diagnostic criteria there is no standardised way of symptomology assessment. The committee discussed the use of symptom assessment questionnaires and in particular the DePaul Symptom Questionnaire (DSQ) developed to assess the symptomatology and case definition of people with ME/CFS. This tool was identified in the literature search for the diagnostic criteria but did not meet the inclusion criteria as it was not clear from the original publication of the criteria upon which it was based what methods were used to develop them, that is, whether or not they were developed though consensus/guidelines.

Differential and coexisting diagnosis

The committee discussed that the non-specific nature and common presentation of some of the symptoms (for example, cognitive difficulties such as brain fog) that are characteristic of ME/CFS make it difficult to diagnose and initially to distinguish from other conditions. Children and young people can have difficulty in describing their symptoms, children in particular may not be able to explain how they feel and will often describe musculoskeletal pain, migraine, abdominal pain and sore throats. This is compounded by HCPs lack of understanding about the symptoms and the relationship with other conditions (for example, fatigue and depression). This has led to misdiagnosis, missed diagnosis, delays in the diagnosis of ME/CFS and of other conditions. This was highlighted in the evidence review B: Information for health and social care professionals.

Differential diagnosis

As noted above the committee agreed it is important that clinicians when suspecting ME/CFS in a person also consider the possibility of an alternative explanatory diagnosis or a co-existing condition. The IOM 2015, states that, ‘the presence of other illnesses should not preclude patients from receiving a diagnosis of ME/CFS (SEID) except in the unlikely event that all symptoms can be accounted for by these other illnesses.” The committee were clear that when ME/CFS is suspected the possibility of another condition should not be excluded, investigations to exclude other diagnoses should continue to be carried out and where there is uncertainty about interpreting the person’s signs and symptoms advice from a relevant specialist should be sought.

The committee noted that the previous NICE guideline (CG53) provided a list of exclusionary tests (for example, tests for differential diagnoses such as multiple sclerosis) to carry out as part of the diagnostic process. The committee gave examples of tests that should be done to exclude other diagnoses. The committee noted that these are tests that are routine in practice and that clinical judgement should be used when deciding on additional investigations to exclude other diagnoses.

The committee decided it was important to raise awareness of the clinical conditions that may produce similar symptoms. The committee based their decision making on the conditions from the literature from the diagnostic criteria review.

Eight of the 9 criteria in the review identified exclusion of other conditions through a process of differential diagnosis. While it is possible for ME/CFS to occur concurrently with other disorders, it is important to be aware that many medical conditions are associated with fatigue and may share additional features with the criteria for ME/CFS.

The committee took the view that an exhaustive list of all possible conditions which might be considered was not possible, nor was it appropriate to provide advice on these conditions in this guideline, where there is relevant NICE guidance it is referenced in the recommendations.

Examples of differential diagnosis are as follows:

Auto-immune and inflammatory disorders: including primary Raynaud’s, systemic lupus erythematosus, Sjogren’s syndrome, vasculitis, inflammatory bowel disease, coeliac disease, primary biliary cirrhosis, sarcoidosis, kidney disease; endometriosis
Cardiorespiratory disorders: including cardiac failure, chronic obstructive pulmonary disease, respiratory failure, chronic endocarditis.
Endocrine, nutritional and metabolic disorders: including thyroid disorders, primary and secondary adrenocortical insufficiency, Haemochromatosis, chronic kidney disease.
Genitourinary system disorders: chronic bladder infection, chronic vulvar pain.
Haematological disorders: anaemias, lymphoma, chronic leukaemia, myeloma.
Infections and infection- related disorders: including HIV, chronic viral hepatitis, tuberculosis, Lyme disease and post-Lyme syndrome, other chronic infections including those rare in the UK. Also, recurrent infection associated with immune deficiency disorders.
Iatrogenic conditions: particularly side effects of medications used for chronic pain.
Malignant disease: particularly those cancers which are often not easy to detect and present with fatigue as a primary symptom, such as ovarian carcinoma.
Mental health conditions: anxiety, depression or mood disorders. Separation anxiety in children.
Neurological disorders: including multiple sclerosis, myasthenia gravis and migraine.
Other chronic pain and multisystem disorders: including fibromyalgia and hypermobility spectrum disorder.
Sleep-wake disorders: including obstructive sleep apnoea and narcolepsy.
Vitamin deficiencies: B12 deficiency and Vitamin Deficiency.

Co-existing conditions

As noted it is possible for ME/CFS to occur concurrently with other conditions and there are some conditions that occur commonly with people with ME/CFS. Examples of common co-existing conditions are as follows:

Autonomic dysfunction: orthostatic intolerance, including Postural tachycardia syndrome (PoTS).
Auto-immune and inflammatory disorders: including primary Raynaud’s, systemic lupus erythematosus, Sjogren’s syndrome, vasculitis, inflammatory bowel disease, coeliac disease, primary biliary cirrhosis, sarcoidosis, kidney disease; endometriosis.
Cardiorespiratory disorders: including cardiac failure, chronic obstructive pulmonary disease, respiratory failure, chronic endocarditis.
Endocrine, nutritional and metabolic disorders: including thyroid disorders, primary and secondary adrenocortical insufficiency, Haemochromatosis, chronic kidney disease, vitamin deficiencies.
Gastro intestinal conditions: Irritable bowel syndrome, gastroparesis.
Genitourinary system disorders: chronic bladder infection, chronic vulvar pain, chronic abacterial/sterile prostatitis, prostate pain syndrome.
Haematological disorders: anaemias, lymphoma, chronic leukaemia, myeloma
Infections and infection- related disorders: including HIV, chronic viral hepatitis, tuberculosis, Lyme disease and post-Lyme syndrome, other chronic infections including those rare in the UK. Also, recurrent infection associated with immune deficiency disorders.
Iatrogenic conditions: particularly side effects of medications used for chronic pain.
Malignant disease: particularly those cancers which are often not easy to detect and present with fatigue as a primary symptom, such as ovarian carcinoma.
Mental health conditions: anxiety, depression or mood disorders.
Neurological disorders: including multiple sclerosis and myasthenia gravis.
Other chronic pain and multisystem disorders: fibromyalgia and hypermobility spectrum disorder, including hypermobile Ehlers Danlos Syndrome.
Sleep-wake disorders: including obstructive sleep apnoea and narcolepsy.

1.2.5.1. Development of criteria for research or clinical use

Four of the criteria identified were developed for use in a clinical context, three were developed for research purposes and two were developed for use in both settings.

The criteria developed for research appear to be broader than the criteria developed for clinical use. For example, the Oxford Criteria have more inclusive criteria than the ICC and the IOM 2015 has the least inclusive criteria. The committee noted that this variance results in diagnostic unreliability, with the ICC criteria identifying a smaller subset of people with ME/CFS with more severe symptoms than the Fukuda criteria.

When broader criteria are applied more people are diagnosed with ME/CFS, reducing the chances of a missed diagnosis of ME/CFS but increasing the number of false diagnoses. In clinical practice this may appear a conservative strategy ensuring the number of people with a missed diagnosis is low. However, there is the possibility that there are a number of people with another illness that receive a false positive diagnosis. The clinical implications of this can be serious with people not receiving appropriate treatment for an undiagnosed condition or a treatment being implemented that are not targeted to any one condition.

Similarly using broad diagnostic criteria to recruit to a research study will have a larger data sample set. As a result, the population could be heterogeneous and may not only be comprised (in the case of this guideline) of a ME/CFS population. Here specificity, not sensitivity, of diagnostic criteria is more important in ensuring the validity of research studies with true cases recruited.

The committee discussed the distinction between research and clinical criteria and the implications of this for the diagnosis of ME/CFS and the impact on other areas of the guideline when interpreting the evidence. If interventions are based on evidence that include other populations (for example using the broader criteria) this could result in the implementation of interventions that are potentially ineffective for subsamples of patients.

The committee noted that the majority of the studies conducted in this area have recruited participants using criteria that do not include post exertional malaise as key inclusion criterion and include broader interpretations of fatigue alongside PEM. Arguably this has resulted in heterogeneous study populations with subsamples of people with different conditions. It is difficult to know the number of people that have PEM and are considered in the tighter criteria to have ME/CFS. The committee agreed this proposed some difficulties in interpreting evidence that did not include PEM as a key diagnostic criterion with the potential of an overestimation or underestimation of association or effect. As a result, the committee agreed to consider the evidence based on inclusion criteria that did not include PEM as a compulsory feature for diagnosis as ‘indirect’, on the basis that it was difficult to be sure if the population consisted only of people with ME/CFS. There is further discussion in the evidence reviews on management of ME/CFS (reports G and H) and how this impacts on the quality assessment and interpretation of the evidence.

2. Diagnostic tests

2.1. Review question

What is the diagnostic accuracy of specific tests to identify ME/CFS in people with suspected ME/CFS?

2.1.1. Introduction

This review aims to identify up to date evidence in relation to tests which may help to identify ME/CFS, and to assess which of these may be useful to incorporate into clinical practice.

2.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 5

PICO characteristics of review question.

2.1.3. Methods and process

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

2.1.4. Effectiveness evidence

2.1.4.1. Included studies

No relevant studies were identified.

See also the study selection flow chart in Appendix C and study evidence tables in Appendix E.

2.1.4.2. Excluded studies

See the excluded studies list in Appendix H.

2.1.5. Summary of studies included in the effectiveness evidence

No relevant studies were identified.

2.1.6. Summary of the effectiveness evidence

No evidence was identified.

2.1.7. Economic evidence

2.1.7.1. Included studies

No health economic studies were included.

2.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

2.1.7.3. Unit costs

Most test costs are not routinely recorded but here is some information that might help to indicate the approximate cost of the tests in the review protocol.

Blood tests

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are routine tests of inflammatory response. In the NICE Multiple Sclerosis guideline, a few trusts were surveyed, and the laboratory cost of a CRP varied from £3.03 to £9.68.

Cytokine profile, Immunosignaturing and mitochondrial function tests (ATP profile) are not used routinely and so are likely to be a bit more costly.

Other tests

The cost of a cardiopulmonary exercise testing (CPET) is submitted by NHS Trusts (by specialty) as part of the NHS reference costs. The average cost was £160 in 2017-18 (n=34,040). However, this did vary by specialty. For example, it was £104 for cardiology and £212 in respiratory medicine. For a 2-day CPET, required to confirm post-exertional malaise, one would expect the cost to be double that of a single CPET.

Postural hypotension can be confirmed by measuring a person’s blood pressure after they have been lying down, and again after standing. If this were to take 10 minutes of a practice nurse’s time then this would cost about £6 a test.

Grip strength can be measured with a hand dynamometer, which can be purchased at a cost of £149-£532, according to the NHS supply chain catalogue. This is for use multiple times and hence the cost per patient could be low if it was in routine use.

General considerations

Tests that are higher cost might still be cost effective or even cost saving overall, if they result in an improvement in management.

2.1.8. Evidence statements

2.1.8.1. Effectiveness

No relevant published evidence was identified.

2.1.8.2. Economic

No relevant economic evaluations were identified.

2.2. The committee’s discussion and interpretation of the evidence

2.2.1. The outcomes that matter most

Diagnostic RCT

Mortality, quality of life, general symptom scales, fatigue/fatigability, physical function, cognitive function, psychological status, pain, sleep quality, treatment-related adverse events, activity levels, return to school/work and exercise performance measures were considered by the committee to be critical outcomes for decision making.

Fatigue/fatigability, unrefreshing sleep and physical and cognitive dysfunction are recognised as key symptoms of ME/CFS. The worsening or improvement of these symptoms reflect the impact of an intervention or strategy. The committee agreed that pain though not key to the diagnosis of ME/CFS, is a common symptom in people with ME/CFS and should be considered by the committee in their decision making. The committee agreed that any decisions on interventions and strategies should be informed by treatment related adverse events as a possible indicator of harm.

Care needs, impact on families and carers and ability to resume occupation, school or study were considered important outcomes for decision making reflecting the effectiveness of an intervention.

The committee acknowledged the lack of existing objective outcome measures of effectiveness of interventions for ME/CFS and the limitations of subjective measures (see Professor Edwards expert testimony – Appendix 3: Expert testimonies). Only validated outcome measurement scales were included in the evidence review.

No RCT evidence was identified.

Diagnostic accuracy

The outcomes were sensitivity and specificity. The committee prioritised sensitivity over specificity on the basis that at this early point in the diagnostic process, it is of greater importance to avoid false negative results and excluding people from a diagnosis. The committee acknowledged that a false positive result could result in a delayed alternative diagnosis for some people.

No diagnostic accuracy evidence was identified.

2.2.2. The quality of the evidence

No evidence was identified in the review.

2.2.3. Benefits and harms

Tests

The committee acknowledged the lack of evidence for any tests to diagnose ME/CFS. Therefore, no recommendations were made for any specific tests.

The committee were aware of people being offered tests to diagnose ME/CFS and being encouraged to pay for tests that were not proven to be useful. The committee agreed it was important that people should be aware there are no diagnostic tests currently available and drafted a recommendation making this clear. The committee made a recommendation that people presenting with possible symptoms of ME/CFS should be told that there is no diagnostic test for ME/CFS and it is recognised on clinical grounds alone. In line with this a medical assessment should be done that includes relevant symptoms and history, comorbidities, overall physical and mental health.. The committee agreed that in this context, there are no tests to replace clinical judgement and that thorough clinical examination and history-taking are vital to the diagnostic process.

The committee identified 2-day cardiopulmonary exercise testing, grip strength, immuno-signature, cytokine profile, erythrocyte sedimentation rate, mitochondrial function tests, postural hypotension test and C-reactive protein as potential diagnostic tests. These tests were considered to be emerging areas of research that have been identified as potentially showing differences in people with diagnosed ME/CFS compared to people without ME/CFS. The committee noted that the review provided an indication of the absence of evidence rather than of evidence of absence. The committee decided to make a research recommendation to help identify effective diagnostic tests for ME/CFS that will facilitate early diagnosis and potentially lead to better outcomes for people with ME/CFS. They hoped this research would inform future guidance.

2.2.4. Cost effectiveness and resource use

There were no published economic evaluations of testing for ME/CFS.

Since there was not good quality evidence of clinical effectiveness of testing strategies or of diagnostic accuracy, the cost effectiveness of specific tests is uncertain.

Therefore, the committee did not recommend testing for ME/CFS. Patients will require a physical assessment and full history to assess whether they meet the diagnostic criteria.

2.2.5. Other factors the committee took into account

Testing for viruses

The committee discussed that viral infections are often described as a potential trigger of ME/CFS and could therefore constitute a useful pre-diagnosis indicator. The committee noted that in its initial stages, ME/CFS can often feel like having a virus one does not fully recover from. Experience from the committee suggested that this feeling can continue and flares of symptoms can feel like a resurgence of a virus. It was discussed that the illness may be caused by the physiological stress response elicited by infection and not by the virus. The committee were aware of a body of epidemiological literature examining the association between viral infection such as Epstein-Barr and glandular fever and the development of ME/CFS. It was noted that these studies would not meet the review protocol because they were based on a different population, that is, those with viral infection rather than those suspected of having ME/CFS. The committee noted that no single test can identify all viral infections and specific viruses have to be tested for in order to detect their presence, which would be likely to complicate the diagnostic process.

Additional investigations

The committee agreed the importance of performing relevant tests for differential diagnoses, both pre- and post-diagnosis of ME/CFS. The committee agreed that although they could not give a list of standard tests, it was important to carry out investigations to exclude other potential diagnoses. They reviewed the tests listed in CG53 and agreed that these were still appropriate and included them as some examples of tests that could be done to exclude reversible conditions with similar symptoms to ME/CFS and that are often missed.

It was considered that new symptoms can develop after a diagnosis and that these should still be fully investigated rather than immediately attributed to ME/CFS. During investigation of new symptoms, both differential and comorbid diagnoses should be considered where appropriate. A recommendation was made to remind clinicians that while waiting for diagnosis of ME/CFS to be confirmed they should continue with any tests needed to exclude other conditions and explain to people this does not affect their provisional diagnosis of ME/CFS.

3. Clinical signs and symptoms

3.1. Review question

What are the predictive accuracies of specific clinical symptoms/signs to identify people who will subsequently be given a clinical diagnosis of ME/CFS?

3.1.1. Introduction

This review aims to identify up to date evidence in relation to symptoms and signs which may help to identify ME/CFS early, and to assess which of these may assist in making a clinical diagnosis.

3.1.2. Summary of the protocol

For full details see the review protocol in Appendix A.

Table 6

PICO characteristics of review question.

3.1.3. Methods and process

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

3.1.4. Effectiveness evidence

3.1.4.1. Included studies

One study was included in the review;⁸² this is summarised in Table 7 below. Evidence from this study is summarised in the clinical evidence summary below (Table 8).

See also the study selection flow chart in Appendix C, study evidence tables in Appendix E, and forest plots in Appendix F.

3.1.4.2. Excluded studies

See the excluded studies list in Appendix H.

3.1.5. Summary of studies included in the effectiveness evidence

Table 7

Summary of studies included in the evidence review.

See Appendix E for full evidence tables.

3.1.6. Summary of the effectiveness evidence

Table 8

Clinical evidence summary: clinical signs/symptoms to predict later diagnosis of ME/CFS.

3.1.7. Economic evidence

3.1.7.1. Included studies

No health economic studies were included.

3.1.7.2. Excluded studies

No relevant health economic studies were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in Appendix G.

3.1.8. Evidence statements

3.1.8.1. Effectiveness

No relevant published evidence was identified.

3.1.8.2. Economic

No relevant economic evaluations were identified.

3.2. The committee’s discussion and interpretation of the evidence

3.2.1. The outcomes that matter most

One prospective cohort study was included.

3.2.2. The quality of the evidence

Evidence for the accuracy of muscle weakness, insomnia, hypersomnia, irritable bowel syndrome, unrefreshing sleep, impairment of memory/concentration and post-exertional malaise for predicting later diagnosis of ME/CFS was based on a single study and was of very low quality. This was due to risk of bias, imprecision and methodological limitations.

The signs and symptoms examined in this review are included in various existing criteria used to diagnose ME/CFS and informed the eventual diagnosis (reference standard), which meant that associations were potentially confounded. The period between measurement of the index tests (signs/symptoms) and the reference standard was of a long duration (10 years), during which some people moved out of one diagnostic category into another. There was a high rate of attrition and differences between diagnostic groups in the number of people followed up. These factors, combined with the uncertainty around the sensitivity and specificity estimates reduced the committee’s confidence in the evidence.

The committee acknowledged that the study was a natural history study which was not designed to test the diagnostic accuracy of tests/signs/symptoms. Therefore, whilst technically it met the inclusion criteria and the results were interesting, it did not provide sufficient evidence upon which to base any recommendations.

3.2.3. Benefits and harms

The sign/symptom with the highest sensitivity was unrefreshing sleep, followed by impairment of memory/concentration. However, these signs/symptoms also had the lowest specificity, indicating a high proportion of false positive results. The committee considered this as well as the very low quality of the evidence and decided that there was insufficient evidence to make a recommendation for prioritisation for early pre-diagnosis management based on any particular signs/symptoms alone. The committee highlighted that each sign/symptom in isolation is of low predictive value, but it is the combination of them that is of importance in a clinical setting.

Ideally evidence would have been identified that confirmed the inclusion of symptoms in the recommended diagnostic criteria. Despite this uncertainty about which of the signs and symptoms should be prioritised for diagnosis the committee agree that it is important to have a set of criteria that include the signs and symptoms commonly agreed to be features of ME/CFS (as outlined above in the discussion of the diagnostic criteria).

The committee noted the lack of good quality evidence on specific signs or symptoms to predict a later diagnosis of ME/CFS. The committee discussed the key symptoms which should prompt suspicion of ME/CFS (see diagnostic criteria section above) and agreed that it is a combination of these symptoms (as well as the overall clinical picture), rather than a specific sign or symptom that is important.

3.2.4. Cost effectiveness and resource use

There were no relevant published economic evaluations.

Appendices

Appendix A. Review protocols

A.1. Review protocol: diagnostic criteria (PDF, 324K)

A.2. Review protocol: diagnostic test accuracy (PDF, 306K)

A.3. Review protocol: predictive accuracy of clinical signs and symptoms (PDF, 276K)

A.4. Health economic review protocol (PDF, 197K)

Appendix B. Literature search strategies

This literature search strategy was used for the following review questions:

In people with suspected ME/CFS, what are the criteria used to establish a diagnosis?
What are the predictive accuracies of specific tests, or clinical symptoms/signs, to identify people who will subsequently be given a definitive diagnosis of ME/CFS?

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual.¹²⁵

For more information, please see the Methodology review published as part of the accompanying documents for this guideline.

B.1. Clinical search literature search strategy (PDF, 280K)

B.2. Health economics literature search strategy (PDF, 279K)

Appendix H. Excluded studies

H.1. Clinical studies

Download PDF (303K)

H.2. Health Economic studies

Published health economic studies that met the inclusion criteria (relevant population, comparators, economic study design, published 2004 or later and not from non-OECD country or USA) but that were excluded following appraisal of applicability and methodological quality are listed below. See the health economic protocol for more details.

None.

Appendix I. Research recommendations

I.1.1. Research recommendation

What diagnostic tests are clinically and cost effective in people with suspected ME/CFS?

I.1.2. Why this is important

Currently there is no diagnostic test or pattern of tests for ME/CFS and it is recognised on clinical grounds alone. People with ME/CFS report delays in diagnosis and it is important to identify people with ME/CFS as early as possible to ensure they are given information to try to prevent worsening of symptoms and any further deterioration of health. Research has highlighted that many healthcare professionals lack the confidence and knowledge to recognise and diagnose ME/CFS and can find it difficult to distinguish from other conditions. Accurate diagnostic tests that correctly identify ME/CFS will support healthcare professionals to identify people who have ME/CFS and rule out those who do not. Based on their clinical experience the committee identified the following tests as potentially promising in the diagnosis of ME/CFS:

2-day cardiopulmonary exercise testing
repeat grip strength
cytokine profile
ESR
mitochondrial function tests
postural hypotension test
CRP
Immunological profile

No studies were identified in the review on the diagnostic accuracy of any of those tests to inform recommendations in the area of identification and diagnosis of ME/CFS. There is therefore a need for high quality trials into the clinical and cost effectiveness of diagnostic tests for ME/CFS that will facilitate early diagnosis and potentially lead to better outcomes for people with ME/CFS.

I.1.3. Rationale for research recommendation / modified PICO

Download PDF (152K)

I.1.4. Research recommendation

In people with suspected ME/CFS, how effective is the NICE 2021 consensus diagnostic criteria in identifying people with ME/CFS?

I.1.5. Why this is important

There is an ongoing discussion in the ME/CFS community about which diagnostic criteria are best and which should be used in the identification and diagnosis of ME/CFS. The factors influencing these discussions are the broadness of the inclusion criteria, the definition of some of the symptoms, and the usability of the criteria as a clinical tool. There are concerns that many of the existing criteria do not accurately identify people with or without ME/CFS. This review described the seven diagnostic criteria for adults and two diagnostic criteria for children and young people that met the inclusion criteria set out in the protocol. Currently there is no validated diagnostic criteria for ME/CFS and this leads to confusion about which criteria to use.

People with ME/CFS report delays in diagnosis and it is important to identify people with ME/CFS as early as possible to ensure they are given information to try to prevent worsening of symptoms and any further deterioration of health. Research has highlighted that many healthcare professionals lack the confidence and knowledge to recognise and diagnose ME/CFS and can find it difficult to distinguish from other conditions. Validated diagnostic criteria that accurately identify ME/CFS will support healthcare professionals to identify people who have ME/CFS and rule out those who do not.

I.1.6. Rationale for research recommendation / modified PICO

Download PDF (139K)

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Final

Evidence reviews underpinning recommendations and research recommendations in the NICE guideline

These evidence reviews were developed by National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK579530PMID: 35438857

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National Guideline Centre (UK). Identifying and diagnosing ME/CFS: Myalgic encephalomyelitis (or encephalopathy) / chronic fatigue syndrome: diagnosis and management: Evidence review D. London: National Institute for Health and Care Excellence (NICE); 2021 Oct. (NICE Guideline, No. 206.)
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