Approach

The history is the most important part of the evaluation of fatigue, while the physical examination and laboratory studies provide supporting data.[93][94][95]

The evidence on the yield of clinical evaluation is poor, and the recommendations that follow are based on a few observational studies and experts' opinions.[93][94][95][96][97][98]

A 7-step approach to the diagnosis of fatigue

  1. Characterise the fatigue

  2. Assess presence of complaints suggesting organic illness associated with fatigue

  3. Evaluate medicines used and/or substances misused

  4. Perform psychiatric screening

  5. Ask questions on sleep quantity and/or quality

  6. Perform a physical examination

  7. Undertake investigations

History

Key components of a detailed history include:

  • Characteristics of the fatigue based on:

    • Duration (recent, prolonged, or chronic)

    • Sudden or progressive onset (e.g., chronic fatigue syndrome is usually sudden-onset, with normal levels of physical fitness, activity, and energy existing prior to onset)

    • Recovery period (e.g., the course of chronic fatigue syndrome is associated with intermittent periods of recovery lasting hours or days)

    • Impact of rest (physiological versus non-physiological fatigue)

    • Impact of physical activity or mental activity (e.g., chronic fatigue syndrome is typically exacerbated by relatively minor physical or mental activity)

    • Level of physical activity (sedentary lifestyle is a cause of fatigue, and patients may benefit from exercise therapy) and concomitant presence of weakness (e.g., reduced muscle power at rest may point to a neuromuscular disorder)

    • Seasonality and any current influenza outbreak (which occur most commonly in the winter).

  • Historical features and risk factors for specific diseases:

    • Age: people 60 years or older usually have an underlying cause for chronic fatigue, whereas in the 30 to 39 years age group the cause is more likely to be prolonged fatigue with no obvious causes[6][99]

    • Residence in, or travel to, areas where certain infections are endemic (e.g., tuberculosis) or where community transmission has been reported (e.g., COVID-19)

    • Exposure to infections via work with cows or ingestion of unpasteurised dairy products (brucellosis); or via ingestion of uncooked meat or contact with a kitten (toxoplasmosis)

    • History of immunosuppression or use of immunosuppressive drugs (cytomegalovirus infection)

    • Occupational, recreational, and residential exposure to tick-infested woods or fields near woods (Lyme disease)

    • History of intravenous drug use and unprotected sexual intercourse (HIV/hepatitis B or C virus infection)

    • Sleep deprivation and a sedentary lifestyle are important causes of fatigue but are often overlooked

    • Cardiovascular risk factors (acute coronary syndrome)

    • Steatorrhoea, weight loss (coeliac disease)

    • Sore throat (Epstein-Barr virus [EBV] infection)

    • Fever with cough, sore throat, runny nose (influenza infection, COVID-19)

    • Menometrorrhagia (anaemia)[100]

    • Polyuria, polydipsia (diabetes mellitus, hypopituitarism)

    • Dyspnoea (cardiac failure, chronic lung disease)

    • Visual field defect (multiple sclerosis)

    • Cold intolerance, overweight (hypothyroidism)

    • Heat intolerance, decreased weight despite increased appetite (hyperthyroidism)

    • Arthralgia or rash (autoimmune disease)

    • Weight loss, blood in stool (malignancy, anaemia)

    • Recent viral infection (post-viral illness)

    • Neurological symptoms such as paraesthesias, blurred vision, psychiatric changes, cognitive decline, tremor, ataxia (heavy metal toxicity)

    • History of stroke (cerebrovascular disease).

  • Evaluation of medicines, both prescribed and over-the-counter, should be undertaken and recreational drug use carefully explored. Drugs frequently associated with fatigue include:

    • Anti-arrhythmics

    • Antidepressants

    • Anti-emetics

    • Antiepileptics

    • Antihistamines

    • Antihypertensives

    • Corticosteroids

    • Diuretics

    • Neuroleptic agents.

    An occupational history should be taken if heavy metal toxicity is suspected. Risk factors for lead toxicity include battery production, glass artisans, use of very old household paints, or the use of Ayurvedic medicines. Risk factors for mercury toxicity include consumption of fish and amalgam dental fillings.[51] In one study, fatigue was one of the most common symptoms in patients with elevated levels of cobalt and chromium after metal-on-metal hip implant.[52]

  • Screening for psychiatric disorders (depression, anxiety disorders, somatisation disorders, and substance abuse):

    • Because one quarter to one third of patients presenting with fatigue in a primary care setting are depressed, early diagnosis of depression is important in clinical practice.[96][101]

    • The 2-question patient health questionnaire (PHQ-2) enquires about the frequency of depressed mood and anhedonia (if people are able to experience any joy or pleasure) over the past 2 weeks, scoring each question as 0 ('not at all') to 3 ('nearly every day').[102][ Depression (any) Screening by a Two Item PHQ-2 ][ Depression (major) Screening by a Two Item PHQ-2 ]

    • PHQ-9 is adapted from PRIME MD (The Primary Care Evaluation of Mental Disorders) as a brief screening instrument aiding in recognition of depression in the primary care setting. PRIME MD requires 8 minutes to complete, whereas the PHQ-9 takes less than 3 minutes.[103][104][105]

    • The CAGE Questionnaire is a simple screening tool to assess alcohol dependence: Have you ever felt the need to cut down on drinking? Have you ever felt annoyed by criticism of your drinking? Have you ever had guilty feelings about your drinking? Do you ever take a 'morning eye opener' (a drink first thing in the morning to steady your nerves or get rid of a hangover)?[106]

    • The Alcohol Use Disorders Identification Test (AUDIT) is a 10-item questionnaire and is especially helpful in identifying less severe drinking problems.[107][ Alcohol Consumption Screening AUDIT Questionnaire ]

  • Questions on sleep quantity and/or quality to investigate whether fatigue is due to or causing sleep disturbance:

    • A brief self-reported insomnia questionnaire has been evaluated: this short insomnia questionnaire (known as the Sleep Disturbance Questionnaire or SDQ) has a sensitivity of 95%, a specificity of 87%, and a positive likelihood ratio of 7 for screening insomnia. Sleep problems such as excessive sleepiness, sleep apnoea, and parasomnias are also investigated in this questionnaire.[108]

    • For the screening of obstructive sleep apnoea, the use of the Epworth Sleepiness Scale is advised.[109][110][ Epworth Sleepiness Scale (ESS) ]

Measurement of fatigue

Fatigue is very subjective and difficult to measure. Because there is no reference standard to evaluate fatigue, clinicians generally prefer to use a single question using a visual analogue scale that rates the patient’s fatigue on a 0-to-10 scale: '0' represents no fatigue and '10' the worst fatigue. More sophisticated instruments have been developed, especially for research purposes. A systematic review found that only 4 measures demonstrate the ability to detect change over time:[111]

  • Brief fatigue inventory (BFI)[112]

  • Fatigue severity scale (FSS)[113]

  • Fatigue symptom inventory (FSI)[114]

  • Multidimensional assessment of fatigue scale (MAF).[115]

Physical examination

Performing a physical examination is important not only to rule out specific causes of fatigue, such as cancer or hypothyroidism, but also to ensure that the patient feels his or her complaint is being taken seriously and viewed as a health problem worth investigating.[4][22][95]

After assessing the general appearance of the patient for possible signs of a psychiatric disorder (e.g., diminished level of alertness, psychomotor agitation or retardation, and poor grooming), evaluation for lymphadenopathy, a possible sign of chronic infection or malignancy, should be performed. The search for pallor, tachycardia, and a systolic ejection murmur should then be undertaken; presence of these signs suggests anaemia. Iron deficiency leads to impaired collagen synthesis, and therefore the choroids can be seen through a thin sclera; this results in a bluish tinge to the sclera.[116] One study noted that the presence of blue sclera had a positive predictive value of 87% for iron deficiency, and 70% for mucosal pallor.[116]

Eventually, more specific signs suggesting a particular disease should be sought. These are usually guided by history. A formal cardiopulmonary examination should focus on excluding congestive heart failure (CHF) and chronic lung disease, both important causes of fatigue. Finally, a preliminary neurological examination is warranted, including assessment of muscle bulk, tone, and strength; abnormalities would suggest an underlying neurological disorder accounting for the patient's fatigue.

Specific clinical signs of organic diseases associated with fatigue include the following:

  • Pallor, tachycardia, systolic ejection murmurs: anaemia

  • Blue sclera: iron deficiency

  • Jaundice, palmar erythema, Dupuytren's contracture: chronic liver disease

  • Goitre or thyroid nodule, dry skin, delayed deep tendon reflexes, peri-orbital puffiness, ophthalmological changes: hypothyroidism

  • Weight loss, hyper-reflexia, tachycardia, atrial fibrillation, fine tremor, goitre: hyperthyroidism

  • Hypotension, pigmentation in skin creases, scars, and buccal mucosa: Addison's disease

  • Increased central adiposity, dry skin, reduced muscle mass and strength, visual field defects, circulatory collapse (if acute presentation): hypopituitarism[117]

  • Lip pursing, prolonged expiration, wheezing, cyanosis: COPD

  • Pulmonary stasis, elevated jugular venous pressure, ankle oedema: heart failure

  • Lymphadenopathy and/or hepatosplenomegaly: malignancy, chronic liver disease, HIV infection, EBV, cytomegalovirus, brucellosis

  • Decreased breath sounds and presence of rales (secondary bacterial pneumonia): influenza infection, COVID-19

  • Pruritus, excoriations, xanthelasma: primary biliary cirrhosis

  • Red butterfly rash on the face, joint deformity: systemic lupus erythematosus (SLE)

  • Tender points evaluation: fibromyalgia[118]

  • Tremor, rigidity, bradykinesia: Parkinson's disease

  • Loss of sensation to light touch and vibration: diabetes mellitus

  • Babinski's reflex, ataxic nystagmus: multiple sclerosis

  • Erythema migrans, arthralgia: Lyme disease.[119]

Investigations

It should be acknowledged that in the absence of a positive history or physical examination, laboratory tests are rarely helpful.[95] Although minor laboratory abnormalities are common, they do not often contribute to the diagnostic process.[95] However, even though laboratory evaluations rarely play a crucial role, they should be used to exclude underlying organic illness.

Initial tests to order include FBC with differential, erythrocyte sedimentation rate (ESR) (in patients ≥65 years, ESR helps to screen for systemic disease and neoplasia), chemistry screen (urea, electrolytes, and creatinine) as well as LFTs, fasting blood glucose, and measurement of serum creatine kinase, calcium, phosphate, and thyroid-stimulating hormone (TSH) levels. Serum levels for heavy metals (e.g., lead, mercury, cobalt, chrome) should be ordered if heavy metal toxicity is suspected.

An ECG, cardiac enzymes, natriuretic peptide biomarkers, and CXR are indicated if an underlying cardiac or pulmonary disorder is suspected.[120] A nocturnal polysomnography or overnight pulse oximetry are helpful in characterising specific sleep disorders.

Further testing for specific underlying causes is highly variable and depends on the clinical evaluation. A ferritin level should be measured to screen for iron deficiency (particularly in menstruating females) and a urinalysis performed to detect the presence of protein, blood, and glucose.

The carbohydrate-deficient transferrin (CDT) test is a useful tool to identify possible chronic heavy alcohol consumption. It has a better performance than liver enzymes.[121] Urine and serum toxicology are indicated if a history of drug dependence is suspected. In patients with suspected cardiac failure, an elevated B-type natriuretic peptide (BNP) and echocardiogram abnormalities will support this diagnosis.

Addison's disease may be detected on serum cortisol level; however, if this is normal and the disease is clinically suspected, a short ACTH stimulation test should be performed.[122]

The endocrine assessment of a patient with suspected hypopituitarism usually involves measurement of basal anterior pituitary hormones and their respective target gland hormone levels (cortisol, TSH, free T4, free T3, FSH, LH, oestrogen, testosterone, prolactin, and GH). Serum electrolytes should be performed as part of the initial evaluation. Hyponatraemia is present in ACTH and TSH deficiencies.[123] Hypernatraemia suggests diabetes insipidus. A cosyntropin (synthetic ACTH) test may be required to assess the adrenal axis. Insulin tolerance test (ITT) may be required in some patients at risk of panhypopituitarism, to assess the ACTH-adrenal axis and GH secretory reserves comprehensively. Cosyntropin test is safer and more common than ITT. Patients with clinical symptoms or biochemical evidence for diabetes insipidus should have a urine specific gravity and osmolality, and consideration for possible water deprivation or desmopressin tests performed under expert guidance.

HIV testing and hepatitis serology should be considered based on a history of at-risk behaviour, or if lymphoma is suspected (e.g., constitutional or B symptoms present [fevers, night sweats, and/or weight loss]). The monospot test is suggested if EBV is suspected (e.g., history of fever, sore throat, rash, drowsiness, myalgia, loss of appetite), with EBV antibodies performed if there is a high clinical suspicion and the monospot test is negative. All patients residing in, or having recently travelled to, an endemic area should be tested for TB. Testing includes the tuberculin skin test, sputum microscopy and culture, and CXR. If COVID-19 is suspected, a real-time reverse transcription polymerase chain reaction test for SARS-CoV-2 RNA should be performed. Specific testing for Lyme disease involves immunological studies, such as the immunofluorescence assay (IFA) and ELISA studies. Western blot is used to confirm the diagnosis if the IFA or ELISA is positive or equivocal. Patients who are at risk for brucellosis (e.g., those with a history of animal contact or ingestion of unpasteurised dairy products) should have a blood and bone marrow culture. Toxoplasmosis and cytomegalovirus serology are indicated when such diagnoses are suspected (e.g., history of ingestion of uncooked meat and contact with a kitten [toxoplasmosis], or history of immunosuppression or use of immunosuppressive drugs [cytomegalovirus infection]).

Patients with GI symptoms suggestive of coeliac disease (e.g., diarrhoea, steatorrhoea, abdominal pain, weight loss) require anti-tissue transglutaminase and endomysial antibodies, and confirmation of the diagnosis by small intestine biopsy. Testing for the presence of anti-mitochondrial antibodies via immunofluorescence or ELISA may help to establish a diagnosis of primary biliary cirrhosis.

CT or MRI of the head is indicated for patients with neurological examination findings suggestive of stroke or multiple sclerosis. Radioiodine scan may be indicated for patients with suspected hyperthyroidism (e.g., decreased weight, emotional lability, oligomenorrhoea, heat intolerance, goitre).

ANAs, dsDNA, and Smith antigen testing may be indicated if signs and symptoms suggest SLE. When considering a diagnosis of vitamin D deficiency, a serum vitamin D 25-hydroxy level should be requested.

Investigations for possible underlying malignancy will depend on clinical evaluation, and may include chest imaging, imaging of abdomen and pelvis, specimens sent for cytology, or biopsy. Abnormalities on FBC or blood film may indicate the need for bone marrow aspiration to exclude haematological malignancies. Tumour markers, such as LDH, may be an important indicator of disease activity in lymphomas.

Coronavirus disease 2019 (COVID-19)

Cough, fever, and dyspnoea are the most common symptoms of COVID-19. The cough is usually dry. Other symptoms include fatigue, anorexia, myalgia, and sore throat. There may be a travel history to an affected area or close contact with a suspected or confirmed case in the 14 days prior to symptom onset. The median time from onset of symptoms to hospital admission is reported to be approximately 7 days.[124]

Physical examination may detect fever (with or without chills/rigors) and obvious cough and/or difficulty breathing. Auscultation of the chest may reveal inspiratory crackles, rales, and/or bronchial breathing in patients with pneumonia or respiratory distress. Patients with respiratory distress may have tachycardia, tachypnoea, or cyanosis accompanying hypoxia.

The most common laboratory abnormalities in patients hospitalised with pneumonia include leukopenia, lymphopenia, leukocytosis, elevated liver transaminases, elevated lactate dehydrogenase, and elevated C-reactive protein. Other abnormalities include neutrophilia, thrombocytopenia, decreased haemoglobin, decreased albumin, and renal impairment.[124][125][126][127][128]

Blood and sputum specimens should be collected for culture in all patients to rule out other causes of lower respiratory tract infection and sepsis, especially in patients with an atypical epidemiological history. Specimens should be collected prior to starting empirical antimicrobials if possible. Molecular testing is required to confirm the diagnosis. Diagnostic tests should be performed according to guidance issued by local health authorities and should adhere to appropriate biosafety practices.

A chest x-ray should be ordered in all patients with suspected pneumonia. Unilateral lung infiltrates are found in 25% of patients, and bilateral lung infiltrates are found in 75% of patients.[124][125][129] All imaging procedures should be performed according to local infection prevention and control procedures to prevent transmission.

This is a rapidly evolving area; see our Coronavirus disease 2019 (COVID-19) topic for current diagnostic advice.

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