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.
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 can be classified in temporal categories:
Recent fatigue: < 1 month duration
Prolonged fatigue: 1 to 6 months duration
Chronic fatigue: > 6 months duration
Myalgic encephalitis/chronic fatigue syndrome is one manifestation of chronic fatigue. Systemic exertion intolerance disease is another term used to describe this condition (1). Patients with COVID-19 may also have symptoms, including fatigue, that last for weeks or even months (known as post-COVID-19 syndrome, long COVID, or long-haul COVID) and has significant overlap with postviral fatigue (also called postviral fatigue syndrome) and chronic fatigue syndrome (2).
Patients may refer to certain other symptoms as fatigue; a careful history can help differentiate fatigue from other symptoms, including:
Weakness, a symptom of nervous system or muscle disorders, is the insufficient force of muscular contraction at maximum effort. Disorders such as myasthenia gravis and Eaton-Lambert syndrome can cause weakness simulating fatigue.
Dyspnea on exertion, an early symptom of cardiac and pulmonary disorders, can decrease exercise tolerance, simulating fatigue. Respiratory symptoms can usually be elicited by taking a careful history.
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.
References
1. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); February 10, 2015.
2. Unger ER, Lin JS, Wisk LE, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome After SARS-CoV-2 Infection. JAMA Netw Open. 2024;7(7):e2423555. Published 2024 Jul 1. doi:10.1001/jamanetworkopen.2024.23555
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 (1).
The most common disorders manifesting predominantly as recent fatigue (lasting < 1 month) are
Stress and/or depression
The most common causes manifesting predominantly as prolonged fatigue (lasting 1 to 6 months) are
Sleep disturbances (eg, sleep apnea)
The most common causes manifesting predominantly as chronic fatigue (lasting > 6 months) are
Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease
Postviral fatigue syndrome
Mental health conditions (eg, depression) (2)
Medications
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
Category | Examples |
|---|---|
Chronic disorders | Chronic kidney disease, systemic rheumatic diseases (eg, giant cell arteritis, rheumatoid arthritis, systemic lupus erythematosus) |
Medications or drugs | 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 in older adults), hypothyroidism, pituitary insufficiency |
Infections | Cytomegalovirus infection, endocarditis, fungal pneumonias, hepatitis, HIV/late-stage HIV, mononucleosis, parasitic infections*, tuberculosis, SARS, COVID-19 |
Mental health conditions | Anxiety, depression, drug dependence, panic disorder, somatization disorder |
Disorders of unknown cause | Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease, fibromyalgia, idiopathic fatigue |
Other causes | Anemias, cancers, deconditioning, pregnancy*, undernutrition, hypercalcemia*, multiple sclerosis, trauma including domestic violence |
* Usually does not cause chronic fatigue. | |
Etiology references
1. Raizen DM, Mullington J, Anaclet C, et al. Beyond the symptom: the biology of fatigue. Sleep. 2023;46(9):zsad069. doi:10.1093/sleep/zsad069
2. Hanson MR. The viral origin of myalgic encephalomyelitis/chronic fatigue syndrome. PLoS Pathog. 2023;19(8):e1011523. Published 2023 Aug 17. doi:10.1371/journal.ppat.1011523
Evaluation of Fatigue
Fatigue can be highly subjective. Patients vary in what they consider to be fatigue and how they describe it, and there are 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
History of present illness includes open-ended questions about what "fatigue" is and 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. If a cause is not evident, patients should complete screening questionnaires for mental health conditions (eg, depression, anxiety, substance use disorder, somatoform disorders) as well as for domestic violence.
Past medical history should address known disorders. Complete medication history should include prescription, over-the-counter, and recreational drugs.
Social history should elicit descriptions of diet, drug and alcohol use, 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 (especially orthostatic).
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.
If fatigue is of recent onset, a focused examination will usually reveal the cause. If fatigue is chronic, examination is less likely to reveal a cause; however, a thorough physical examination may be diagnostically helpful, and is an important way to build rapport with the patient.
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 suggestive of polymyalgia rheumatica and/or giant cell arteritis.
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 general medical condition. Fatigue that is present constantly and does not lessen with rest, particularly with occasional bursts of energy, may indicate a mental health condition.
In the absence of red flag findings, a thorough history, physical examination, and routine laboratory testing (plus tests directed at specific findings—see table 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
Symptoms | 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) | Chest radiograph, CBC, ESR, blood or other cultures, rheumatoid factor and ANA |
Dyspnea with cough or hemoptysis | HIV/late-stage HIV (with Pneumocystis jirovecii pneumonia), fungal pneumonia, tuberculosis, COVID-19 | Chest radiograph, chest CT or PET-CT, HIV test, sputum cytology and/or culture, pulmonary function tests, PPD, molecular or antigen test for SARS-CoV-2 |
Dyspnea, orthopnea, and/or edema | Chest radiograph, 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 | Anemia | CBC |
Generalized lymphadenopathy | HIV test, CBC, EBV serologic tests | |
Combined arthritis, rash, and/or other organ involvement | Systemic rheumatic disease (including vasculitis) | CBC, ESR, rheumatoid factor, anti-CCP, ANCA, 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 adult | Hyperthyroidism (including 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 | Mononucleosis, myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease | EBV serologic tests; CBC, ESR, TSH, chemistries (as for suspected chronic fatigue syndrome) |
Lymphadenopathy, splenomegaly | CMV infection, lymphoma | EBV serologic tests, sometimes CMV antibody testing; flow cytometry, excisional biopsy of a lymph node |
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 | Myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease | 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; ANCA = antineutrophil cytoplasmic antibodies; anti-CCP = anticyclic citrullinated peptide; 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
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 testing for tuberculosis with purified protein derivative (PPD) placement or interferon-gamma release assays are recommended if the patient has risk factors. Chest radiograph 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.
Diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease requires specific diagnostic criteria.
Treatment of Fatigue
Treatment to lessen fatigue is directed at the cause.
Patients with myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease 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 health care professional is patient and nonjudgmental and acknowledges the real effects of fatigue.
There are no approved pharmacologic treatments for myalgic encephalomyelitis/chronic fatigue syndrome/systemic exertion intolerance disease; however, this should not diminish the future potential of treatments (1). Nonpharmacologic treatments include physical therapy (eg, graded exercise therapy) and psychological 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.
Treatment reference
1. Seton KA, Espejo-Oltra JA, Giménez-Orenga K, et al. Advancing Research and Treatment: An Overview of Clinical Trials in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Future Perspectives. J Clin Med. 2024;13(2):325. Published 2024 Jan 6. doi:10.3390/jcm13020325
Geriatrics Essentials: Fatigue
Fatigue is often the first symptom of a disorder in older adults, and should not be disregarded as part of normal aging. For example, the first symptom of pneumonia in an older adult 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 adult. Because serious illness may become apparent soon after sudden fatigue in older adults, the cause should be determined as quickly as possible.
Key Points
Fatigue is a common symptom.
Fatigue caused primarily by a general medical condition usually increases with activity and lessens with rest.
Laboratory testing is low yield in the absence of suggestive clinical findings.
Successful treatment of chronic fatigue is more likely if the health care professional is patient and understanding.
