• Take a full history. In particular:
• Ask the person to say what they mean by tiredness or fatigue (or a synonym).
• Sleepiness may indicate sleep apnoea or another sleep disorder — see the CKS topics on Sleep apnoea and Insomnia.
• Weakness suggests a neuromuscular cause.
• Ask about: onset, duration, severity, and precipitating factors; the effect of sleep, rest, and exercise; and the impact on activities.
• Onset is typically sudden with infection, myocardial ischaemia, toxins or drugs, and post-traumatic stress.
• Onset is usually gradual in uraemia, heart failure, liver failure, diabetes, hypercalcaemia, hypothyroidism, electrolyte abnormalities, anaemia, and depression.
• Fatigue that is worst in the morning and which never goes away suggests depression.
• Fatigue that occurs only after exercise (and not at rest) suggests a neuromuscular cause.
• Elicit the person's concerns so that reassurance and explanation can be given, if possible and appropriate.
• Elicit the person's perceptions of the cause of their tiredness, which may be important for successful management.
• Take a sleep history: ask about sleep quality, quantity, patterns, and hygiene, snoring, witnessed sleep apnoea, nocturia, and restless legs (for further information, see the CKS topics on Insomnia, Restless legs syndrome, and Sleep apnoea).
• Take a lifestyle and psychosocial history: ask about stress and stressful life events, work, rest, recreation, exercise, quality of personal relationships, illicit drug use, diet, and alcohol consumption, and whether the person is a carer for others (such as children, or elderly or disabled relatives).
• Ask about and screen for the presence of a depressive illness or an anxiety disorder. Screen for depression using the following two questions (an answer of 'yes' to either question should trigger a more detailed assessment — see the CKS topic on Depression):
• 'During the last month have you often been bothered by feeling down, depressed, or hopeless?'
• 'During the last month have you often been bothered by having little interest or pleasure in doing things?'
• Review medication, including over-the-counter drugs.
• Tiredness may be caused by many drugs, including sedative-hypnotics, antidepressants, muscle relaxants, opioids, antihypertensives, and antihistamines.
• Ask about:
• Weight loss or gain (for malignancy, Addison's disease, diabetes mellitus, and thyroid dysfunction).
• Fever or night sweats (for malignancy, and infections such as hepatitis and tuberculosis).
• Muscle or joint pain, headache, sore throat, difficulty with memory or thinking, and chronic pain (symptoms of chronic fatigue syndrome and other conditions).
• Travel, insect or tick bites, and skin rash (for tropical infections and Lyme disease).
• Allergies, such as perennial rhino-sinusitis.
• Determine if the person may be at risk of HIV, hepatitis, or tuberculosis.
• Do a complete physical examination, unless the cause is evident from the history, when a focused examination is appropriate.
• If necessary, delay this until a second, longer consultation.
• Consider whether investigations are needed.

These recommendations are based on evidence from observational studies on the causes of tiredness, evidence on perceptions of the causes of tiredness, and on expert opinion from narrative reviews.

Nature of fatigue

• The recommendation to ask the person to say what they mean by tiredness or fatigue, and its justification, are derived from expert opinion in narrative reviews [Morrison and Keating, 2001; Rosenthal et al, 2008].
• Other recommendations on establishing the nature of tiredness are based on a National Institute for Health and Clinical Excellence guideline on the diagnosis and management of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis or encephalopathy (ME) [National Collaborating Centre for Primary Care, 2007] and expert opinion from narrative reviews [Ruffin and Cohen, 1994; Rodriguez, 2000; Morrison and Keating, 2001; Simon, 2008].

Eliciting concerns and perceptions

• The recommendation to elicit the person's concerns and perceptions of the cause of their tiredness is based on expert opinion [Ridsdale, 1989; Godwin et al, 1999; Rodriguez, 2000; Moncrieff and Fletcher, 2007], as well as the following:
• There is evidence from a UK study (n = 151) that at least half of people with chronic tiredness attribute their symptoms to a physical cause [Darbishire et al, 2003].
• There is evidence from a study of 220 people presenting to one of four general practices in the UK that GPs tend to perceive the cause of tiredness as psychological, whereas people with tiredness are more likely to perceive the cause as physical [Ridsdale et al, 1993; Ridsdale et al, 1994].
• One of the management strategies proposed in the literature is for the primary healthcare professional to try to broaden the person's perception of fatigue, so that psychosocial causes and solutions are validated and considered along with biomedical causes [Ruffin and Cohen, 1994].

Sleep history

• This recommendation is based on expert opinion from narrative reviews [Rodriguez, 2000; Morrison and Keating, 2001; Rosenthal et al, 2008].

Lifestyle and psychosocial history; screening for depression and anxiety

• These recommendations are based on expert opinion from narrative reviews [Godwin et al, 1999; Rodriguez, 2000; Ebell and Belden, 2001; Morrison and Keating, 2001; Rosenthal et al, 2008; Simon, 2008] and on limited evidence from mainly observational studies that, in people presenting to primary care with a complaint of tiredness or fatigue, the underlying cause is commonly psychological or psychosocial (in 18–62% of people), or there is an associated psychological disorder or psychosocial problem.
• The screening questions are derived from the National Institute for Health and Clinical Excellence guideline, Depression (amended): management of depression in primary and secondary care [NICE, 2007a].

Medication

• This recommendation is based on expert opinion from narrative reviews [Godwin et al, 1999; Rodriguez, 2000; Morrison and Keating, 2001; Rosenthal et al, 2008; Simon, 2008].

Other symptoms/history

• This recommended list is derived from narrative reviews [Rodriguez, 2000; Morrison and Keating, 2001] and from a North of England guideline on the medical assessment of people with suspected CFS/ME, which states that perennial rhino-sinusitis commonly causes fatigue [Spickett, 2009].

At risk of HIV, hepatitis, or tuberculosis

• This recommendation is based on expert opinion from a narrative review and a New Zealand guideline [Ruffin and Cohen, 1994; BPAC NZ, 2006].

Examination

• CKS found no evidence on the diagnostic yield of a physical examination (or its constituents) for people with tiredness presenting to primary care. However, a physical examination is good medical practice and generally regarded (in narrative reviews) as appropriate [Ruffin and Cohen, 1994; Epstein, 1995; Ebell and Belden, 2001; Morrison and Keating, 2001; Sharpe and Wilks, 2002; Cornuz et al, 2006; Rosenthal et al, 2008].
• Several authors suggest that a physical examination reassures the person (in particular, that their problem is being taken seriously) and cements the therapeutic relationship [Ruffin and Cohen, 1994; Cornuz et al, 2006; Moncrieff and Fletcher, 2007].
• In a specialist US chronic fatigue clinic, physical examinations were judged to have provided diagnostic information in only 2% of people [Lane et al, 1990]. However, a specialist clinic would exclude people for whom a diagnosis had already been made in primary care, and CKS expert reviewers report higher yields in secondary care.
• Some authors recommend a complete examination, particularly if the history does not suggest a cause [Ruffin and Cohen, 1994; Epstein, 1995; Rodriguez, 2000; Murtagh, 2003; Simon, 2008], while others recommend a more focused examination, guided by the history [Godwin et al, 1999; Moncrieff and Fletcher, 2007].
• The recommendation to delay a complete physical examination until a second, longer consultation, if necessary, is derived from narrative reviews [Ruffin and Cohen, 1994; Rodriguez, 2000].

• Identify and appropriately manage the following red flags or alarm features:
• Significant weight loss.
• Lymphadenopathy with signs of malignancy (for instance, a lymph node that is non-tender, firm, hard, larger than 2 cm across, progressively enlarging, supraclavicular, or axillary).
• Any other symptoms and signs of malignancy. For example:
• Haemoptysis — see the CKS topic on Lung cancer - suspected.
• Dysphagia — see the CKS topics on Head/neck cancer - suspected and GI (upper) cancer - suspected.
• Rectal bleeding — see the CKS topic on GI (lower) cancer - suspected.
• Breast lump — see the CKS topic on Breast cancer - suspected.
• Postmenopausal bleeding — see the CKS topic on Gynaecological cancer - suspected.
• Localizing/focal neurological signs.
• Symptoms and signs of inflammatory arthritis, vasculitis (such as giant cell arteritis and polymyalgia rheumatica), or connective tissue disease — see the CKS topics on Giant cell arteritis, Polymyalgia rheumatica, and Rheumatoid arthritis.
• Symptoms and signs of cardiorespiratory disease — see the CKS topics on Angina, Asthma, Chronic obstructive pulmonary disease, and Heart failure - chronic.
• Sleep apnoea — see the CKS topic on Sleep apnoea.

These recommendations are based on National Institute for Health and Clinical Excellence guidelines on referral for suspected cancer, and on the diagnosis and management of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis or encephalopathy (ME) [NICE, 2005; NICE, 2007b], on New Zealand guidelines on laboratory investigations of tiredness [BPAC NZ, 2006], and on a North of England guideline on the medical assessment of people with suspected CFS/ME [Spickett, 2009].

• In adults, suspect chronic fatigue syndrome (CFS)/myalgic encephalomyelitis or encephalopathy (ME) if both of the following criteria are met:
• The person has fatigue that has all of the following features:
• Persistent (for 4 months or longer) or recurrent.
• New or had a specific onset (that is, it is not lifelong).
• Unexplained by other conditions (including body mass index greater than 40 kg/m²).
• Has resulted in a substantial reduction in activity level.
• Characterized by post-exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days).
• The person has one or more of the following symptoms:
• Difficulty with sleeping (such as insomnia, hypersomnia, unrefreshing sleep, or a disturbed sleep-wake cycle).
• Muscle or joint pain that is multi-site and without evidence of inflammation.
• Headaches.
• Painful lymph nodes without pathological enlargement.
• Sore throat.
• Cognitive dysfunction (such as difficulty thinking, inability to concentrate, impairment of short-term memory, and difficulties with word-finding, planning/organizing thoughts, and information processing).
• Physical or mental exertion makes symptoms worse.
• General malaise or flu-like symptoms.
• Dizziness or nausea.
• Palpitations in the absence of identified cardiac pathology.
• The diagnosis of CFS/ME should be reconsidered if none of the following features are present:
• Post-exertional fatigue or malaise.
• Cognitive difficulties.
• Sleep disturbance.
• Chronic pain.

These recommendations are based on a National Institute for Health and Clinical Excellence guideline on the diagnosis and management of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis or encephalopathy (ME) [National Collaborating Centre for Primary Care, 2007], and in relation to body mass index greater than 40 kg/m², a North of England guideline on the medical assessment of people with suspected CFS/ME [Spickett, 2009].

• Offer investigations as indicated by the history and physical examination — see Assessment and Red flags.
• If a physical cause is not evident clinically:
• Consider delaying routine investigations until tiredness has lasted for 1 month.
• Offer the following routine first-line investigations:
• Full blood count.
• Erythrocyte sedimentation rate or C-reactive protein.
• Thyroid stimulating hormone.
• Random blood glucose.
• IgA tissue transglutaminase for coeliac disease (provided the person consumes gluten-containing foods).
• Also consider offering the following additional investigations:
• Liver function tests — particularly if the person is obese, or is 60 years of age or older.
• Creatinine and electrolytes — particularly if the person is 60 years of age or older.
• Bone biochemistry — particularly if the person is 60 years of age or older.
• Serum ferritin — in women of child-bearing age, as there is limited evidence that iron supplementation is effective even in the absence of anaemia.
• Testing for vitamin D deficiency, by bone biochemistry and serum 25–hydroxycholecalciferol concentration — if the person is at risk because of failure to spend time outdoors or regular use of sunscreens, inadequate diet, or reduced gut absorption.
• Testing for glandular fever (infectious mononucleosis), such as by the monospot test — if the person is younger than 40 years of age.
• HIV test — if the person is at risk.
• Hepatitis serology — if the person is at risk.
• Testing for tuberculosis (chest radiography and sputum samples) pending referral — if the person is at risk (see the CKS topic on Tuberculosis).
• If tiredness/fatigue lasts for 3 months or longer, offer second-line investigations.

These recommendations are based on evidence on the most common causes of tiredness in primary care, on evidence on investigations for tiredness, and on expert opinion.

Offer investigations as indicated by history and physical examination

• This is a pragmatic recommendation, also based on expert opinion from international guidelines [Godwin et al, 1999; BPAC NZ, 2006] and narrative reviews [Ridsdale, 1989; Rodriguez, 2000].

Delaying investigations until tiredness has lasted for 1 month

• This recommendation is based on limited evidence from a randomized trial that postponing blood tests does not appear to miss serious diagnoses (provided there are no red flags or other symptoms and signs indicating the need for immediate investigation), with few people returning for postponed investigations [Koch et al, 2009]. It is also supported by a New Zealand guideline [Godwin et al, 1999].

Choice of investigations for unexplained tiredness

• In the absence of large, prospective, randomized trials using reference standards for diagnoses and which are based in primary care, there is insufficient evidence to recommend withholding any investigations when the cause of tiredness is not identified clinically.
• There is limited evidence, from one randomized trial [Koch et al, 2009] and three observational studies [Sugarman and Berg, 1984; Ridsdale et al, 1993; Gialamas et al, 2003], that blood tests have low diagnostic yield in people presenting to primary care with tiredness or fatigue, detecting a physical cause in just 8–11% of people.
• Harms have not been fully evaluated. Possible harms of under-investigation and false-negatives include missing serious or treatable causes, and damage to the therapeutic relationship. Possible harms of over-investigation and false-positives include unnecessary anxiety and cost [Koch et al, 2009], and damage to subsequent efforts to address psychological or psychosocial causes of tiredness.
• Recommendations on the choice of initial, routine investigations are based on:
• Evidence from a randomized trial that a limited set of blood tests (including haemoglobin, erythrocyte sedimentation rate [ESR], glucose, and thyroid stimulating hormone) is almost as useful diagnostically as a more extensive set of tests [Koch et al, 2009].
• National Institute for Health and Clinical Excellence guidelines, which recommend tests for anaemia, thyroid function, and coeliac disease in people with persistent fatigue, even when there are no other indications [National Collaborating Centre for Primary Care, 2007; NICE, 2009].
• Evidence that, although physical causes are less frequently identified compared with psychosocial causes, anaemia and diabetes mellitus are the more common physical causes of tiredness in people presenting to primary care with tiredness as a complaint. However, these illnesses individually account for only 0.6–6% of the total number of people presenting with tiredness.
• Studies have identified malignancy in less than 1% of all people presenting to primary care with tiredness or fatigue [Valdini, 1985], but the rate may be higher in older people, who are poorly represented in aetiological studies.
• Consensus of expert opinion in the published literature that a full blood count is an appropriate first-line investigation [Rodriguez, 2000; Ebell and Belden, 2001; Sharpe and Wilks, 2002; Murtagh, 2003; BPAC NZ, 2006; Moncrieff and Fletcher, 2007; Rosenthal et al, 2008; Simon, 2008], with most also recommending ESR. C-reactive protein is recommended as an alternative to ESR on the basis of feedback from CKS expert reviewers. There was no consensus with regard to other investigations.
• Recommendations on the choice of additional investigations to consider
• Creatinine and electrolytes, liver function tests, bone biochemistry
• These investigations are recommended for older people on the basis of New Zealand and Canadian guidelines on the investigation of people with fatigue [Godwin et al, 1999; BPAC NZ, 2006]. The New Zealand guideline recommends additional investigations in people older than 50 years of age, whereas the threshold in the Canadian guideline is 65 years of age; 60 years of age is a compromise between these two opinions.
• Creatinine and electrolytes, and liver function tests were recommended by several CKS external reviewers for all people with tiredness/fatigue.
• There is evidence from one cohort study that fatigue is associated with non-alcoholic fatty liver disease (NAFLD) [Newton et al, 2008]. Fatigue in people with NAFLD was unrelated to severity of liver disease or to insulin resistance. People who were cases and controls were matched for body mass index, to prevent obesity confounding the relationship.
• Ferritin in women of child-bearing age
• This recommendation is based on evidence from one randomized, placebo-controlled trial that 4 weeks of iron supplementation reduced fatigue in women 18–55 years of age without anaemia who presented to primary care with fatigue [Verdon et al, 2003]. Only women with ferritin concentrations of 50 micrograms/L or less improved with treatment.
• Testing for vitamin D deficiency
• Although CKS found no published evidence on testing for vitamin D deficiency in people presenting with tiredness, this was recommended by several CKS expert reviewers. Risk factors for vitamin D deficiency are derived from an evidence-based narrative review [DTB, 2006].
• Testing for glandular fever in people younger than 40 years of age
• This recommendation is based on evidence that glandular fever is a relatively common cause of tiredness, and is detected even in people in whom it is not suspected [Morrison, 1980; Koch et al, 2009]. However, it is the cause of tiredness in only 0.6–6% of people (of all ages) presenting to primary care with tiredness.
• Glandular fever is rare in people 40 years of age or older [Petersen et al, 2006], and one prospective study which detected glandular fever in 1.4% of people used 40 years of age as a cut-off [Ridsdale et al, 1993].
• HIV test, hepatitis serology, and tuberculosis testing
• This recommendation is based on expert opinion from a New Zealand guideline [BPAC NZ, 2006] and on the CKS topic on Tuberculosis.

• If tiredness has persisted for 3 months or longer:
• Ensure that all of the following investigations have been done to rule out other diseases and conditions besides chronic fatigue syndrome (CFS)/myalgic encephalitis or encephalopathy (ME):
• Urinalysis for protein, blood, and glucose.
• Full blood count.
• Urea and electrolytes.
• Liver function tests.
• Thyroid stimulating hormone.
• Erythrocyte sedimentation rate or plasma viscosity.
• C-reactive protein.
• Random blood glucose.
• Serum creatinine.
• Serum calcium.
• Creatine kinase.
• IgA tissue transglutaminase for coeliac disease (provided the person consumes gluten-containing foods).
• Offer tests for the following infections only if the history is indicative:
• Chronic bacterial infections, such as borreliosis (Lyme disease).
• Chronic viral infections, such as HIV or hepatitis B or C.
• Latent infections, such as toxoplasmosis, Epstein–Barr virus, or cytomegalovirus.

• These recommendations are based on a National Institute for Health and Clinical Excellence (NICE) guideline on the diagnosis and management of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis or encephalopathy (ME) [National Collaborating Centre for Primary Care, 2007].
• The duration of tiredness for which second-line investigations are recommended (3 months) is pragmatic, based on the NICE recommendation that a diagnosis of CFS/ME should be made in adults when symptoms have persisted for 4 months [National Collaborating Centre for Primary Care, 2007].
• The choice of screening test for coeliac disease is based on the NICE guideline on the recognition and assessment of coeliac disease [NICE, 2009].