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Michael R. Wasserman

, MD, Los Angeles Jewish Home

Last full review/revision Mar 2021| Content last modified Mar 2021
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Fatigue occurs most often as part of a symptom complex, but even when it is the sole or main presenting symptom, fatigue is one of the most common symptoms.

Fatigue is difficulty initiating and sustaining activity due to a lack of energy and accompanied by a desire to rest. Fatigue is normal after physical exertion, prolonged stress, and sleep deprivation.

Patients may refer to certain other symptoms as fatigue; differentiating between them and fatigue is usually, but not always, possible with detailed questioning.

  • Weakness, a symptom of nervous system or muscle disorders, is insufficient force of muscular contraction at maximum effort. Disorders such as myasthenia gravis and Eaton-Lambert syndrome can cause weakness that worsens with activity, simulating fatigue.

  • Dyspnea on exertion, an early symptom of cardiac and pulmonary disorders, can decrease exercise tolerance, simulating fatigue. Respiratory symptoms usually can be elicited upon careful questioning or develop subsequently.

  • Somnolence, a symptom of disorders causing sleep deprivation (eg, allergic rhinitis, esophageal reflux, painful musculoskeletal disorders, sleep apnea, severe chronic disorders), is an unusually strong desire to sleep. Yawning and lapsing into sleep during daytime hours are common. Patients can usually tell the difference between somnolence and fatigue. However, deprivation of deep nonrapid eye movement sleep can cause muscle aches and fatigue, and many patients with fatigue have disturbed sleep, so differentiating between fatigue and somnolence may be difficult.

Fatigue can be classified in various temporal categories, such as the following:

  • Recent fatigue: < 1 month duration

  • Prolonged fatigue: 1 to 6 months duration

  • Chronic fatigue: > 6 months duration

Chronic fatigue syndrome is one cause of chronic fatigue. There are now 2 other terms for chronic fatigue syndrome—myalgic encephalomyelitis and systemic exertion intolerance—although there is no clear delineation between these at this time. Patients with COVID-19 may have symptoms that last for weeks or even months, which is known as "long COVID" or "long-haul COVID" and resembles postviral fatigue (and can be called post-viral fatigue syndrome) and chronic fatigue syndrome.

Etiology of Fatigue

Most serious (and many minor) acute and chronic illnesses produce fatigue. However, many of these have other more prominent manifestations (eg, pain, cough, fever, jaundice) as the presenting complaint. This discussion focuses on disorders that can manifest primarily as fatigue.

The most common disorders manifesting predominantly as recent fatigue (lasting < 1 month) are

The most common causes manifesting predominantly as prolonged fatigue (lasting 1 to 6 months) are

The most common causes manifesting predominantly as chronic fatigue (lasting > 6 months) are

Several factors commonly cause or contribute to a chief complaint of fatigue, usually prolonged or chronic fatigue (see table Some Factors Commonly Contributing To Prolonged Or Chronic Fatigue).


Some Factors Commonly Contributing To Prolonged Or Chronic Fatigue



Chronic disorders


Antidepressants, antihistamines (1st generation), antihypertensives, cocaine cessation (usually recent fatigue), diuretics that cause hypokalemia, muscle relaxants, recreational drugs, sedatives

Endocrine disorders

Adrenal insufficiency*, diabetes, hyperthyroidism* (usually apathetic), hypothyroidism, pituitary insufficiency


Psychologic disorders

Disorders of unknown cause

Other causes

* Usually does not cause chronic fatigue.

Evaluation of Fatigue

Fatigue can be highly subjective. Patients vary in what they consider to be fatigue and how they describe it. There are also few ways to objectively confirm fatigue or tell how severe it is. History and physical examination focus on identifying subtle manifestations of underlying illness (particularly infections, endocrine and rheumatologic disorders, anemia, and depression) that can be used to guide testing.


History of present illness includes open-ended questions about what "fatigue" is, listening for descriptions that could suggest dyspnea on exertion, somnolence, or muscle weakness. The relationships between fatigue, activity, rest, and sleep should be elicited, as should the onset, time course and pattern, and factors that increase or decrease fatigue.

Review of systems should be thorough because potential causes of fatigue are so numerous and diverse. Among important nonspecific symptoms are fever, weight loss, and night sweats (possibly suggesting cancer, a rheumatologic disorder, or an infection). Menstrual history is obtained in women of child-bearing age. Unless a cause is evident, patients should be asked questions from screening questionnaires for psychologic disorders (eg, depression, anxiety, drug abuse, somatoform disorders, domestic violence).

Past medical history should address known disorders. Complete drug use history should include prescription, over-the-counter, and recreational drugs.

Social history should elicit descriptions of diet, drug abuse, and the effect of fatigue on quality of life, employment, and social and family relationships.

Physical examination

Vital signs are checked for fever, tachycardia, tachypnea, and hypotension. General examination should be particularly comprehensive, including general appearance and examination of the heart, lungs, abdomen, head and neck, breasts, rectum (including prostate exam and testing for occult blood), genitals, liver, spleen, lymph nodes, joints, and skin. Neurologic examination should include testing of, at a minimum, mental status, cranial nerves, mood, affect, strength, muscle bulk and tone, reflexes, and gait. Usually if fatigue is of recent onset, a more focused examination will reveal the cause. If fatigue is chronic, examination is unlikely to reveal a cause; however, thorough physical examination is an important way to build rapport with the patient and occasionally is diagnostically helpful.

Red flags

  • Chronic weight loss

  • Chronic fever or night sweats

  • Generalized lymphadenopathy

  • Muscle weakness or pain

  • Serious nonfatigue symptoms (eg, hemoptysis, hematemesis, severe dyspnea, ascites, confusion, suicidal ideation)

  • Involvement of > 1 organ system (eg, rash plus arthritis)

  • New or different headache or loss of vision, particularly with muscle pains, in an older adult

Interpretation of findings

In general, a cause is more likely to be found when fatigue is one of many symptoms than when fatigue is the sole symptom. Fatigue that worsens with activity and lessens with rest suggests a physical disorder. Fatigue that is present constantly and does not lessen with rest, particularly with occasional bursts of energy, may indicate a psychologic disorder.

In the absence of red flag findings, a thorough history, physical examination, and routine laboratory testing (plus tests directed at specific findings—see Interpretation of Selected Findings in Evaluating Fatigue) should suffice for an initial evaluation. If test results are negative, watchful waiting is usually appropriate; if fatigue worsens or other symptoms and signs develop, the patient is reevaluated.

Several causes can be considered for patients with prolonged or chronic fatigue and selected other common or specific clinical findings.


Interpretation of Selected Findings in Evaluating Fatigue


Possible Causes

Tests to Consider*

Anorexia, abdominal pain, weight loss, or steatorrhea

Undernutrition secondary to gastrointestinal tract disorder, cancer

Endoscopy, MRI of abdomen, MRCP

Anorexia, abdominal pain, weight loss, orthostatic hypotension, skin hyperpigmentation

Adrenal insufficiency

Blood electrolyte, cortisol, and ACTH levels; Sometimes synthetic ACTH 1-24 (Cortrosyn®) stimulation test

Fever, night sweats, or weight loss

Infection, rheumatologic disorder (including vasculitis)

CBC, ESR, blood or other cultures, rheumatoid factor and ANA

Dyspnea with cough or hemoptysis

HIV/AIDS (with Pneumocystis jirovecii pneumonia), fungal pneumonia, tuberculosis, COVID-19

Chest x-ray, chest CT or PET-CT, HIV test, sputum cytology and/or culture, pulmonary function tests, PPD, molecular test for SARS-CoV-2

Dyspnea, orthopnea, and/or edema

Chest x-ray, renal function tests, echocardiography (if orthopnea)

Dyspnea, Roth spots, Janeway lesions, new or changing heart murmurs, IV drug use

Multiple blood cultures, echocardiography

Decreased exercise tolerance with dyspnea on exertion, pallor



Generalized lymphadenopathy

HIV test, CBC, EBV serologic tests

Combined arthritis, rash, and/or other organ involvement

Rheumatologic disorder (including vasculitis)

CBC, ESR, rheumatoid factor, ANA

Jaundice, ascites, confusion

Liver tests, viral hepatitis serologies

Polydipsia, polyuria, increased appetite, weight gain or loss

Fasting plasma glucose level, HbA1C, glucose tolerance testing

Cold intolerance, weight gain, constipation, coarse skin

Hypothyroidism, pituitary insufficiency

Thyroid function tests

Weight loss or atrial fibrillation in older patient

Hyperthyroidism (apathetic)

Thyroid function tests

Fatigue worse with exposure to heat, past neurologic symptoms (eg, numbness, ataxia, weakness), particularly > 1 episode

Brain and/or spinal cord MRI with contrast

Headache, jaw claudication, temporal artery tenderness or thickening, and/or muscle pains in an older adult

ESR, brain MRI or CT, temporal artery biopsy

Anxiety, sadness, anorexia, unexplained sleep disturbance

Anxiety, depression, domestic violence, somatization disorder

Clinical evaluation

Recent sore throat, lymphadenopathy, splenomegaly

EBV serologic tests; CBC, ESR, TSH, chemistries (as for suspected chronic fatigue syndrome)

Lymphadenopathy, splenomegaly

EBV serologic tests, sometimes CMV antibody testing

Frequent or opportunistic infections, candidiasis, lymphadenopathy, splenomegaly

HIV testing

Chronic, widespread musculoskeletal extra-articular pain, trigger points, irritable bowel symptoms, migraines, anxiety

ESR or C-reactive protein, CK, TSH, hepatitis C serology

Weight loss, steatorrhea, inadequate oral intake

Plasma albumin, total lymphocyte and CD4 counts, serum transferrin, serum vitamin B12, serum iron, serum folate, fecal elastase measurement

Constipation, lethargy, bone pain (eg, at night)

Serum chemistries, including calcium

Postexertional malaise, unrefreshing sleep, difficulty with concentration or short-term memory, orthostatic intolerance, sore throat, myalgias, headaches

CBC, ESR, TSH, serum electrolytes, glucose, calcium, renal and liver tests

* Choice of specific tests is dictated by which causes are clinically suspected.

ACTH = adrenocorticotropic hormone; ANA = antinuclear antibodies; CBC = complete blood count; CK = creatine kinase; CMV = cytomegalovirus; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; MRCP = magnetic resonance cholangiopancreatography; PET = positron emission tomography; PPD = purified protein derivative; TSH = thyroid-stimulating hormone.


Testing is directed at causes suspected based on clinical findings. If no cause is evident or suspected based on clinical findings, laboratory testing is unlikely to reveal a cause. Still, many clinicians recommend testing with the following:

  • Complete blood count (CBC)

  • Ferritin

  • Erythrocyte sedimentation rate (ESR)

  • Thyroid-stimulating hormone (TSH)

  • Chemistries, including electrolytes, glucose, calcium, and renal and liver tests

Creatine kinase (CK) is recommended if muscle pain or weakness is present. HIV testing and purified protein derivative (PPD) placement are recommended if the patient has risk factors. Chest x-ray is recommended if cough or dyspnea is present. Other testing, such as for infections or immunologic deficiencies, is not recommended unless there are suggestive clinical findings.

  • Chronic fatigue that affects daily function, is not relieved by rest, and is not explained by clinical findings or abnormal findings on the laboratory tests mentioned above

  • For systemic exertion intolerance disease/chronic fatigue syndrome, postexertional malaise and unrefreshing sleep, as well as either cognitive impairment or orthostatic intolerance

  • For myalgic encephalomyelitis/chronic fatigue syndrome, the presence of ≥ 4 of the following: sore throat, unrefreshing sleep, difficulty with concentration or short-term memory, myalgias, multiple joint pains without joint swelling, new or different headaches, and tender cervical or axillary nodes

Treatment of Fatigue

Treatment to lessen fatigue is directed at the cause. Patients with myalgic encephalomyelitis/systemic exertion intolerance disease/chronic fatigue syndrome and idiopathic chronic fatigue are treated similarly. They should be told clearly that the etiology is presently unknown. Treatment is more often successful if the practitioner is patient and nonjudgmental and acknowledges the real effects of fatigue. Potential treatments include physical therapy (eg, graded exercise therapy) and psychologic support (eg, cognitive-behavioral therapy). Focusing on improving sleep and relieving pain may also help. Goals include returning to work and maintaining normal activity levels.

Geriatrics Essentials

Fatigue is more often the first symptom of a disorder in older patients. For example, the first symptom of pneumonia in an older woman may be fatigue rather than pulmonary symptoms. The first symptom of other disorders, such as giant cell arteritis, may also be fatigue in an older patient. Because serious illness may become apparent soon after sudden fatigue in older patients, the cause should be determined as quickly as possible. Fatigue is also somewhat more likely to be caused by giant cell arteritis or another serious physical disorder in older adults.

Key Points

  • Fatigue is a common symptom.

  • Fatigue caused primarily by a physical disorder increases with activity and lessens with rest.

  • Laboratory testing is low yield in the absence of suggestive clinical findings.

  • Successful treatment is more likely if the practitioner is patient and understanding.

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