Changes

March to May 2025 — new topic. A literature search was conducted in March 2025 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

Goals

To support primary healthcare professionals to:

• Be aware of when to suspect a diagnosis of ME/CFS.
• Arrange referral to an ME/CFS specialist team if a working diagnosis of ME/CFS is suspected.
• Advise about sources of information and support.
• Advise about strategies for symptom management if ME/CFS is suspected or confirmed, including for flare-ups or relapse.
• Arrange primary care review at least annually.
• Arrange referral to other healthcare professionals such as a specialist physiotherapist, occupational therapist, or practitioner in cognitive behavioural therapy (CBT) for support if appropriate.

Outcome measures

No outcome measures were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

QIPP — Options for local implementation

No QIPP indicators were found during the review of this topic.

What is it?

• Myalgic encephalomyelitis or encephalopathy (ME) or chronic fatigue syndrome (CFS) is a complex chronic medical condition defined by a specific pattern of different symptoms that impact a person's quality of life [NICE, 2021] [BACME, 2022a].
  • There is typically 'a clear relationship between normal everyday activity levels causing a disproportionate escalation in fatigue which does not improve with rest and is slow to recover over several days' [BACME, 2022a].
  • It is a fluctuating multisystem condition, in which symptoms can change unpredictably in nature and severity over a day, week, or longer [NICE, 2021].
• The terms 'ME' or 'CFS' may be used interchangeably in the literature [BACME, 2022a]. For the purposes of this CKS guideline, the term 'ME/CFS' will be used throughout.
  • The National Institute for Health and Care Excellence (NICE) guideline notes that 'many people with ME/CFS consider the name chronic fatigue syndrome too broad, simplistic and judgemental' and it uses the abbreviation 'ME/CFS' for consistency [NICE, 2021].
  • The British Association of Clinicians in ME/CFS (BACME) publication also uses the term 'ME/CFS' [BACME, 2022a].
  • The European Network on ME/CFS (EUROMENE) expert consensus document uses the term 'ME/CFS' on pragmatic grounds. It states the term 'ME' is unsatisfactory as it suggests that the pathological process underlying the disease is an inflammatory process affecting the brain, but there is a lack of convincing evidence for this. The term 'CFS' is also unsatisfactory as it implies that fatigue is the main symptom of the illness, when a range of other clinical features are needed for diagnosis  [Nacul, 2021].
• The NICE guideline defines severity according to the level of impact of symptoms on daily functioning. It states that 'definitions of severity are not clear cut because individual symptoms vary widely in severity and people may have some symptoms more severely than others' [NICE, 2021]:
  • Mild — a person can care for themselves and do some light domestic tasks (sometimes needing support) but may have difficulties with mobility. Most people are still working or in education, but to do this the person has probably stopped all leisure and social activities. They often have reduced hours, take days off, and use the weekend to cope with the rest of the week.
  • Moderate — a person has reduced mobility and is restricted in all activities of daily living, although they may have peaks and troughs in their level of symptoms and ability to do activities. They have usually stopped work or education, and need rest periods, often resting in the afternoon for 1–2 hours. Their sleep at night is generally poor quality and disturbed.
  • Severe — a person is unable to do any activity for themselves or can carry out minimal daily tasks only (such as face washing or cleaning teeth). The person has severe cognitive difficulties and may depend on a wheelchair for mobility. They are often unable to leave the house or experience a severe and prolonged impact if they do. They may also spend most of their time in bed and are often extremely sensitive to light and sound.
  • Very severe — a person is in bed all day and dependent on care. They need help with personal hygiene and eating, and are very sensitive to sensory stimuli. Some people may not be able to swallow and may need tube feeding.
• A flare-up is defined as a worsening of symptoms, more than would be accounted for by normal day-to-day variation, that affects the person's ability to perform their usual activities. Flare-ups may occur spontaneously or be triggered by another illness, overexertion, or other triggers. Flare-ups usually occur as part of post-exertional malaise. The worsening of symptoms is transient and flare-ups typically resolve after a few days, either spontaneously, or in response to temporary changes in energy management or a change in treatment [NICE, 2021].
• A relapse is defined as a sustained and marked exacerbation of symptoms lasting longer than a flare-up and needing a substantial and sustained adjustment to the person's energy management. It may not be clear in the early stages of a symptom exacerbation whether it is a flare-up or a relapse. Relapses can lead to a long-term reduction in the person's energy limits [NICE, 2021].

What causes it?

• ME/CFS is a complex, multisystem, chronic medical condition. The exact pathophysiology is not fully understood and is likely to be multifactorial [NICE, 2021] [Arron, 2024].
  • Symptoms may be triggered or worsened by acute infection or illness, overexertion, injury or trauma, other medical conditions, sleep disturbance, or stress. These may be known or new triggers, or in some cases, there is no clear trigger [NICE, 2021; BACME, 2022b; Arron, 2024].
  • There may be an overlap of causal mechanisms identified in long COVID in a subset of people [Steiner, 2023]. See the CKS topic on Long-term effects of coronavirus (long COVID) for more information. Other possible post-infectious causes include infectious mononucleosis and Lyme disease [Nacul, 2021]. See the CKS topics on Glandular fever (infectious mononucleosis) and Lyme disease for more information.
  • It has been proposed that ME/CFS may have a genetic predisposition in some people, but there is currently a lack of consensus in the literature [Arron, 2024].
• The British Association of Clinicians in ME/CFS (BACME) publication states that ME/CFS is a condition defined by symptoms which are caused by 'dysregulation in multiple dynamic systems in the body including the immune system, the autonomic nervous system, the endocrine system and the metabolic systems' [BACME, 2022a].

How common is it?

Attempts to estimate the prevalence and burden of ME/CFS are limited in the literature by selection bias, a lack of diagnostic biomarkers, and use of different case definitions in epidemiological studies [Nacul, 2021].

• The National Institute for Health and Care Excellence (NICE) guideline cites UK Biobank data suggesting there are over 250,000 people in England and Wales with ME/CFS, with about 2.4 times as many women affected as men [NICE, 2021].
• A more recent study of hospital episode statistics (HES) data collected during hospital admission and outpatient appointments of patients in England registered with a GP found [Samms, 2025]:
  • Overall, 100,055 people were diagnosed with ME/CFS between 1989 and 2023, representing a national prevalence of 0.16%, with a female-to-male ratio of 3.88:1.
  • The point prevalence in women peaked at around 50 years of age, and in men at about 60 years of age.
  • People of Caucasian ethnicity were fivefold more likely to be diagnosed with ME/CFS than people of other ethnicities.
  • The lifetime prevalence of ME/CFS for women and men was estimated at 0.92% and 0.25%, respectively, with an estimated 404,000 people in the UK overall affected by ME/CFS.
  • A GP practice in England with at least 2500 registered patients would be expected to have four or more patients with ME/CFS.
  • Primary care diagnoses of ME/CFS not included in HES data will result in an underestimation of ME/CFS prevalence.
• Expert opinion in a review article notes that ME/CFS can affect people in all age-groups and socio-economic groups [Arron, 2024]. Expert opinion in another review article states that disease onset has two peaks of onset between the ages of 10–19 years and 30–39 years. The average age at onset is 33 years [Bateman, 2021].
• The prevalence of CFS in community-based studies is low. A meta-analysis of 14 community- and primary care-based studies found the pooled prevalence for self-reported CFS was 3.28%, and the overall pooled prevalence following clinical assessment was 0.76%. High variability was observed among self-reported estimates [Johnston, 2013].
• A large primary care cross-sectional study in three regions of England (n = 143,000 adults aged 18–64 years) found [Nacul, 2011]:
  • The estimated prevalence rate was 0.2%, and the overall estimated annual incidence was 0.015%.
  • At least two-thirds of cases affect women.
• A UK primary care electronic database cohort study using data from 660 general practices assessed the incidence of ME/CFS and fibromyalgia and found [Collin, 2017]:  
  • The overall annual incidence of recorded cases of ME/CFS was 14.8 per 100,000 people.
  • The annual incidence rates for ME/CFS diagnoses decreased from 17.5–12.6 between 2001 and 2013.
  • The overall annual incidence of recorded fatigue symptoms was 2246 per 100,000 people.

What is the prognosis?

Prognostic studies of ME/CFS are limited by small sample sizes, high dropout rates, short follow-up times, inclusion of participants with other conditions, and inappropriate definitions of recovery [Bateman, 2021].

• ME/CFS is a fluctuating and unpredictable condition which affects each person differently, in which symptoms and their severity can change over a day, week, or longer. The long-term prognosis of ME/CFS varies between people, and although a proportion of people recover or have a long period of remission, many will need to adapt to living with the condition long-term [NICE, 2021; BACME, 2022a].
• The British Association of Clinicians in ME/CFS (BACME) publication cites limited evidence in the literature that [BACME, 2022a]:
  • Some studies suggest that about 5–20% of people with ME/CFS may eventually make a full recovery, but this may take years.
  • About 60% of people with ME/CFS may see improvement in symptoms and/or level of function over time.
  • Approximately 20% of people with ME/CFS continue to experience long-term debilitating symptoms.
• In a systematic review of 14 studies of people meeting diagnostic criteria for ME/CFS who did not receive 'systematic intervention' [Cairns and Hotopf, 2005]:
  • The median full recovery rate was 5%.
  • The median proportion of people who improved during follow-up periods ranging from 8 months to 5 years was 39.5%.
• A cohort study of adults with ME/CFS in specialist clinics in the UK and the Netherlands (n = 918 and 1392 respectively) concluded that [Collin, 2018]:
  • UK participants with multiple symptoms or pain-predominant symptom phenotypes were 57% and 67% less likely to report favourable treatment outcomes compared with people without these symptom phenotypes, when followed up for one year.
  • A similar outcome was observed in the Dutch patient cohort.

What are the complications?

ME/CFS can cause severe long-term disability, which may be worsened if healthcare workers, relatives, carers, and educational providers/workplaces do not properly recognize the condition and its impact [NICE, 2021]. The personal, social, and economic consequences and complications of ME/CFS may include:

• Social stigma — social stigma and a lack of belief may be experienced from friends, relatives, health and social care professionals, teachers, and work colleagues, for example, who do not understand or support the person's condition and related problems. This may cause a loss of trust in health and social care services, dissatisfaction with care, and the person may be hesitant to seek help or engage with services. In addition, symptoms and associated disability may lead to social isolation, which further restricts access to health and social care support, with reduced chances of recovery and social integration [Nacul, 2021; NICE, 2021].
• Reduced quality of life — ME/CFS symptoms and related conditions may impact daily activities, including work or education; family, relationships and sex life; and social life and leisure activities [NICE, 2021]. A study of adults with self-identified ME/CFS from four population samples found that about 25% of the participants had severe disease and self-reported being housebound or bedbound [Pendergrast, 2016].
• Mental health impact — there is an increased risk of comorbid anxiety and depression, for example [NICE, 2021; BACME, 2022a]. See the CKS topics on Generalized anxiety disorder, Depression, and Post-traumatic stress disorder for more information.
• Loss of employment — many people with ME/CFS are unable to work or may only be able to work part-time [Nacul, 2021]. Fewer than one-fifth of people with ME/CFS work full-time [NICE, 2021]. One UK study of patient-level data (n = 2170; 76.9% women) from the UK ME/CFS National Outcomes Database found that 50.1% of people had to stop working due to persistent fatigue and other fatigue-related symptoms. Total productivity costs were an estimated £49.2 million in the sample population, extrapolated to represent a £102.2 million cost to the UK economy [Collin, 2011].
• Excess mortality risk — a UK prospective population-based cohort study (n = 18,101) found that after adjusting for confounders, the hazard ratio for all-cause mortality was 1.4 for people who reported highest compared with lowest fatigue levels, during a mean follow-up period of 16.6 years. The association was particularly strong for deaths related to cardiovascular disease [Basu, 2016]. A retrospective cohort study using data from a register of secondary and tertiary care patients in England and Wales (n = 2147) found an increased risk of death from completed suicide compared with data from age- and sex-matched controls [Roberts, 2016].

When should I suspect a diagnosis of ME/CFS?

Be aware that there is no diagnostic test for ME/CFS, and it is diagnosed on clinical grounds alone, where symptoms may fluctuate in severity and change over time. Suspect a diagnosis of ME/CFS in adults if:

• The person has had all of the following symptoms for a minimum of 6 weeks:
  • Debilitating fatigue that is worsened by activity, is not caused by excessive cognitive, physical, emotional, or social exertion, and is not significantly relieved by rest.
  • Post-exertional malaise after activity, in which the worsening of symptoms:
    • Is often delayed in onset by hours or days, and symptoms typically worsen 12–48 hours after activity.
    • Is disproportionate to the activity, and can follow minimal activity or activity that could previously be tolerated.
    • Has a prolonged recovery time that may last hours, days, weeks or longer.
  • Unrefreshing sleep or sleep disturbance (or both), which may include:
    • Feeling exhausted, feeling flu-like and stiff on waking.
    • Disturbed or shallow sleep, altered sleep pattern, or hypersomnia.
  • Cognitive difficulties (sometimes described as 'brain fog'), which may include problems finding words or numbers, difficulty in speaking, slowed responsiveness, written or verbal communication difficulties, short-term memory problems, and difficulty concentrating or multitasking.
  • The person's ability to engage in occupational, educational, social, or personal activities is significantly reduced from pre-illness levels.
  • The person's symptoms are not explained by another condition. See the CKS topic on Tiredness/fatigue in adults for more information.
• In addition, the person has the following symptoms which may also be associated with, but are not exclusive to, ME/CFS:
  • Orthostatic intolerance and autonomic dysfunction, including postural orthostatic tachycardia syndrome (PoTS), postural hypotension, dizziness, palpitations, fainting, nausea on standing or sitting upright from a reclining position; may be unable to sit for any length of time. See the CKS topic on Blackouts and syncope for more information.
  • Temperature hypersensitivity resulting in profuse sweating, chills, hot flushes, or feeling very cold.
  • Neuromuscular symptoms, including weakness, twitching, and myoclonic jerks or neurological symptoms such as double vision.
  • Flu-like symptoms, including recurrent sore throat, tender lymph nodes, nausea, chills, or muscle aches. See the CKS topic on Influenza - seasonal for more information.
  • New intolerance or sensitivities to alcohol, foods, medications, and/or chemicals. See the CKS topic on Food allergy for more information.
  • Sensory hypersensitivities, including to light, sound, touch, taste, and smell.
  • Pain, including pain on touch, headaches, eye pain, abdominal pain, muscle or joint pains (without acute redness, swelling, or effusion). Pain may be at multiple sites and migratory, or severe or constant in severe or very severe ME/CFS. See the CKS topics on Chronic pain, Headache - assessment, Irritable bowel syndrome, and Neuropathic pain - drug treatment for more information.
  • Reduced ability or inability to speak or swallow in severe or very severe ME/CFS.
  • Gastrointestinal symptoms such as nausea, incontinence, constipation, and bloating. See the CKS topics on Constipation and Irritable bowel syndrome for more information.

How should I assess a person with suspected ME/CFS?

If an adult presents with suspected ME/CFS:

• Ask about:
  • The person's symptoms, including fatigue and post-exertional malaise, sleep difficulties or disturbance, and cognitive difficulties. Assess symptom onset, severity, frequency, duration, fluctuations, and any precipitating or relieving factors, including the effect of rest, sleep, and activity on symptoms.
    
    • Fatigue may be described by the person as a 'lack of energy or stamina', 'severe tiredness', or 'general weakness'. In contrast to physiological tiredness, fatigue is not improved with rest, sleep, or reduced physical or cognitive demands. See the CKS topic on Tiredness/fatigue in adults for more information.
    • The nature and severity of post-exertional malaise symptoms, the degree of reduction in function, and their time course can vary from episode to episode and with the type of activity.
    • A person may report fluctuating better and worse days, where they push themselves to do more on a better day and then experience escalating symptoms the following few days, and are forced to reduce their activity levels. Advise that the use of a self-completed activity/fatigue diary can help the person identify if a post-exertional malaise pattern is present.
  • Any additional symptoms, including timing of onset in relation to fatigue and post-exertional malaise (additional symptoms typically start after the onset of fatigue and are not due to pre-existing conditions).
  • Any clinical features suggesting an alternative diagnosis or coexisting condition(s), including other physical or mental health conditions, which may explain symptoms. See the CKS topic on Tiredness/fatigue in adults for more information.
    
    • If symptoms are progressive or rapidly changing, suspect an underlying condition and investigate and manage appropriately.
  • The impact of symptoms on the person and relatives/carers, including physical activity and mobility, dexterity, balance, and risk of falls; activities of daily living and independence; cognitive function; family life, impact on dependents, carer stress; sex and relationships; work, shifts, training, and/or education; psychological, emotional, and social wellbeing including leisure activities, hobbies, and social interaction.
  • Sources of social support including informal carer support.
  • Any additional symptoms of stress or stressful life events, or coexisting depression or anxiety. See the CKS topics on Depression, Generalized anxiety disorder, and Post-traumatic stress disorder for more information.
  • The person's diet including access to shopping and cooking facilities; weight history and use of any restrictive or alternative diets; alcohol consumption and any recreational drug use.
  • Any current or previous treatments or medications, including over-the-counter preparations and vitamin and mineral supplements; herbal remedies; and any drug intolerances or sensitivities.
• Examine the person, depending on the presenting clinical features.
  • Perform a general examination, including for signs of frailty, self-neglect, and lack of self-care.
  • Assess nutritional status including body mass index (BMI) and weight history.
  • Perform a physical examination including heart rate, blood pressure and assessment for postural hypotension; abdominal, musculoskeletal, and neurological examination; and mental state examination to assess mood and cognitive functioning.
    • Pale skin and cold peripheries may be present, which may be worsened by upright posture associated with autonomic nervous system dysfunction. See the CKS topic on Blackouts and syncope for more information, including detail on how to assess for postural hypotension.
    • Note that there may be signs of increasing physical difficulties, visible fatigue, and cognitive slowing during long consultations due to increasing fatigue, so multiple shorter consultations may be needed to assess a person fully.
  • Assess for any signs which may suggest an alternative diagnosis or coexisting condition(s).
• Explain that there is currently no diagnostic test for ME/CFS. Arrange investigations to exclude alternative diagnoses or coexisting conditions in which fatigue can be a primary feature, such as:
  • Full blood count and serum ferritin — to assess for anaemia, polycythaemia, and haematological malignancy. See the CKS topics on  Anaemia - B12 and folate deficiency, Anaemia - iron deficiency, and Haematological cancers - recognition and referral for more information.
  • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) — may be raised in infection, inflammation, autoimmunity, and rarely solid organ neoplasms and lymphoproliferation. See the CKS topic on Multiple myeloma for more information.
  • Liver function tests — to assess for underlying liver disease. See the CKS topic on Jaundice in adults for more information.
  • Renal function tests — to assess for acute kidney injury or chronic kidney disease and/or electrolyte imbalance. See the CKS topic on Acute kidney injury and Chronic kidney disease for more information.
  • Thyroid function tests — to assess for possible hypo- or hyperthyroidism. See the CKS topics on Hypothyroidism and Hyperthyroidism for more information.
  • HbA1c — to assess for possible type 1 or type 2 diabetes mellitus. See the CKS topics on Diabetes - type 1 and Diabetes - type 2 for more information.
  • IgA tissue transglutaminase — to assess for coeliac disease. See the CKS topic on Coeliac disease for more information.
  • Creatine kinase (CK) — to assess for a neuromuscular cause if there is muscle tenderness or weakness. A low CK level may suggest severe disease or very low physical activity levels.
  • Bone chemistry calcium and phosphate — to assess for metabolic bone disease. See the CKS topic on Hypercalcaemia for more information.
  • Urinalysis for protein and blood — to assess for renal tract infection, inflammation, or malignancy.
• Consider arranging additional investigations to exclude other diagnoses, depending on clinical judgement:
  
  • Vitamin D level — if the person is at risk of deficiency. See the CKS topic on Vitamin D deficiency in adults - treatment and prevention for more information.
  • Vitamin B12 and folate levels. See the CKS topic on Anaemia - B12 and folate deficiency for more information.
  • Viral serology — if there is a history of infection, the person is at risk, and/or there is a possibility of other latent infection, such as toxoplasmosis, Epstein-Barr virus, or cytomegalovirus. See the CKS topics on Hepatitis B, Hepatitis C, HIV infection and AIDS, Infectious mononucleosis (glandular fever),  Lyme disease, and Tuberculosis for more information.
  • 9am cortisol level — to exclude adrenal insufficiency. See the CKS topic on Addison's disease for more information.

What else might it be?

• Common alternative or contributing conditions to ME/CFS include:
  • Obstructive sleep apnoea. See the CKS topic on Obstructive sleep apnoea syndrome for more information.
  • Sleep disorders such as hypersomnia or narcolepsy. See the CKS topic on Insomnia for more information.
  • Rheumatological disease such as rheumatoid arthritis, psoriatic arthropathy, or systemic lupus erythematosus. See the CKS topics on Rheumatoid arthritis and Spondyloarthritis and psoriatic arthropathy for more information.
  • Cardiac disease, such as arrhythmias, cardiomyopathy, heart failure, and valvular heart disease. See the CKS topics on Heart failure - chronic and Palpitations for more information.
  • Respiratory disease, such as severe chronic obstructive pulmonary disease. See the CKS topic on Chronic obstructive pulmonary disease for more information.
  • Renal disease, such as end-stage kidney disease. See the CKS topic on Chronic kidney disease for more information.
  • Haematological disease such as anaemia, vitamin B12 deficiency, and haemachromatosis. See the CKS topics on Anaemia - iron deficiency, Anaemia - B12 and folate deficiency, and Jaundice in adults for more information.
  • Hypermobility spectrum disorder. See the CKS topic on Chronic pain for more information.
  • Mental health conditions such as anxiety, depression, obsessive-compulsive disorder, post-traumatic stress disorder, eating disorder, and dysthymia. See the CKS topics on Depression, Eating disorders, Generalized anxiety disorder, and Post-traumatic stress disorder for more information.
  • Neurodiversity, such as attention deficit hyperactivity disorder (ADHD) and autism. See the CKS topics on Attention deficit hyperactivity disorder and Autism in adults for more information.
  • Primary endocrine disorders such as Addison's disease, diabetes mellitus, thyroid disease, or other pituitary disorders. See the CKS topics on Addison's disease, Diabetes - type 1, Diabetes - type 2, Hyperthyroidism, and Hypothyroidism for more information.
  • Drug adverse effects or substance misuse, such as opiate use. See the CKS topic on Opioid dependence for more information.
• Specific clinical features or red flags that may indicate a potentially serious or life-threatening underlying condition include:
  • Significant unintentional weight loss (5% of body weight over 6–12 months) may suggest malignancy, Addison's disease, diabetes mellitus, or hyperthyroidism. See the CKS topics on Addison's disease, Diabetes - type 1, and Hyperthyroidism for more information.
  • Fever, night sweats, lymphadenopathy, and/or persistently elevated inflammatory markers may suggest a haematological malignancy or an infection, such as acute hepatitis, HIV, syphilis, or active tuberculosis. See the CKS topics on HIV infection and AIDS, Hepatitis B, Hepatitis C, Syphilis, and Tuberculosis for more information.
  • Muscle or joint pain may suggest inflammatory joint disease or connective tissue disease. See the CKS topics on Giant cell arteritis, Polymyalgia rheumatica, and Rheumatoid arthritis for more information.
  • Localizing or focal neurological signs may suggest a neurological condition, such as brain tumour, stroke, Parkinson's disease, or multiple sclerosis. See the CKS topics on Brain and central nervous system cancers - recognition and referral, Multiple sclerosis, Parkinson's disease, and Stroke and TIA for more information.
  • History of travel, insect or tick bites, and skin rash may suggest tropical infection or Lyme disease. See the CKS topic on Lyme disease for more information.

Scenario: Management of ME/CFS

From age 18 years onwards.

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of

May 2025 - unrestricted

The terms listed below are the core search terms that were used for EBSCOhost MEDLINE (searched 7th October 2019, update searches completed 28th January 2020). These were combined with filters to identify guidelines, systematic reviews and primary care relevant literature in EBSCOhost MEDLINE. The strategy was adapted for The Cochrane Library databases. 

• S5    S1 OR S2 OR S3 OR S4 
• S4    AB ( fatigue* or tired* or letharg* or TATT or CFS or myalgic encephalomyelitis or myalgic encephalopathy ) OR TI ( fatigue* or tired* or letharg* or TATT or CFS or myalgic encephalomyelitis or myalgic encephalopathy ) 
• S3    (MH "Lethargy") 
• S2    (MH "Fatigue Syndrome, Chronic") 
• S1    (MH "Fatigue+") 

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• Health Protection Agency
• World Health Organization
• National Guidelines Clearinghouse
• Guidelines International Network
• TRIP database
• GAIN
• NHS Scotland National Patient Pathways
• New Zealand Guidelines Group
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• University of Michigan Medical School
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• Patient UK Guideline links
• UK Ambulance Service Clinical Practice Guidelines
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work(occupational health practice)

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

• Bandolier
• Drug & amp; Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

• Department of Health
• Health Management Information Consortium(HMIC)

• Healthtalkonline
• BMJ - Patient Journeys
• Patient.co.uk - Patient Support Groups

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary(BNF)
• electronic Medicines Compendium(eMC)
• European Medicines Agency(EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency(MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

• Animal studies
• Original research is not written in English

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

None.