Fatigue and malaise

Fatigue is a persistent sense of physical or mental tiredness, lack of energy or exhaustion that is out of proportion to recent activity and is not fully relieved by rest. Malaise is a vague feeling of being generally unwell, often the first sign of acute infection or systemic disease. Both are nonspecific, very common, and usually have more than one contributing cause.

Clinical relevance. Up to one in five adults in primary care report significant fatigue. A single organic cause is found in a minority. Most cases combine poor sleep, mood disorder, drug effects, deconditioning and life stress, with or without a mild medical contributor.

Separate it from related complaints. Ask what the patient means by tired. True weakness is reduced muscle force on testing. Excessive daytime sleepiness is a tendency to fall asleep. Breathlessness, chest discomfort or leg pain on exertion point to cardiorespiratory or vascular disease. Apathy and loss of interest point to depression or frontal lobe disease.

Classification by duration. Recent fatigue lasts under 1 month and is usually infective, postinfective, drug related or situational. Prolonged fatigue lasts 1 to 6 months. Chronic fatigue lasts over 6 months.

Classification by mechanism.

• Central fatigue: reduced drive and effort tolerance (depression, sleep disorders, neurological disease, cytokine mediated sickness behaviour).
• Peripheral fatigue: failure of muscle energy supply or contraction (anaemia, hypothyroidism, electrolyte disorders, metabolic and mitochondrial myopathy, deconditioning).
• Mixed or functional: the commonest form.

Mechanisms. Interleukin 1, interleukin 6 and tumour necrosis factor produce sickness behaviour in infection, inflammation and cancer. Reduced oxygen delivery, hormone deficiency, fragmented sleep and a disturbed stress response sustain fatigue in other disorders. Malaise reflects the same cytokine effect early in acute illness.

Chronic fatigue syndrome (myalgic encephalomyelitis). A clinical diagnosis made after other causes are excluded. It requires fatigue of 6 months or more with a substantial fall in activity, postexertional malaise (worsening 12 to 48 hours after modest effort), unrefreshing sleep, and either cognitive impairment or orthostatic intolerance. It often follows a viral illness, including infectious mononucleosis and COVID-19.

History.

• Onset (abrupt or gradual), duration, course, and what the patient means by tired. Worse in the morning suggests depression or inflammatory disease. Worse late in the day suggests anaemia, heart failure, myasthenia or hypothyroidism.
• Relation to exertion: tiredness after effort that recovers within hours is usual. Worsening 12 to 48 hours after modest effort suggests postexertional malaise.
• Function: work, driving, caring duties, time spent in bed. A validated fatigue scale gives a baseline for follow up.
• Sleep: duration, latency, awakenings, snoring, witnessed apnoeas, morning headache, restless legs, shift work, naps. Epworth Sleepiness Scale (a score over 10 is abnormal).
• Mood and cognition: low mood, loss of interest, anxiety, bereavement, burnout, trauma, domestic or workplace stress. Alcohol, cannabis, sedatives, stimulants and caffeine intake.
• Systemic: fever, night sweats, weight change, appetite, cough, dyspnoea, orthopnoea, chest pain, palpitations, bowel habit, rectal bleeding, melaena, heavy menstrual bleeding, dysphagia, polyuria, thirst, cold or heat intolerance, constipation, dry skin, hair loss, joint pain, rash, dry eyes, muscle pain, headache, lumps.
• Infection exposure: recent viral illness, mononucleosis, COVID-19, travel, mosquito or tick bites, unpasteurised milk, tuberculosis contact, HIV risk, injecting drug use, freshwater exposure.
• Drugs: beta blockers, clonidine, methyldopa, benzodiazepines, opioids, sedating antihistamines, antidepressants, antiepileptics, antipsychotics, statins, recent corticosteroid withdrawal, chemotherapy, interferon, efavirenz, zidovudine, isoniazid.
• Diet (vegetarian, vegan, restriction), pregnancy, postpartum period, menopause.

Examination.

• General appearance, nutrition, body mass index, temperature, pulse, blood pressure lying and standing, respiratory rate, oxygen saturation.
• Pallor, jaundice, cyanosis, clubbing, hyperpigmentation (adrenal insufficiency, haemochromatosis), dry or myxoedematous skin, stigmata of chronic liver disease, rash, mouth ulcers, glossitis, angular stomatitis, candidiasis.
• Lymph nodes, thyroid, breasts.
• Heart (murmur, signs of failure), chest, abdomen (organomegaly, mass), rectal examination and prostate when indicated.
• Joints, muscle bulk and power, proximal weakness, fatigability on repeated effort, reflexes (slow relaxation in hypothyroidism), fundi.
• Mental state with a depression screen (PHQ-9 score of 10 or more suggests moderate depression), an anxiety screen (GAD-7 score of 10 or more), and a cognitive screen in older adults.

Red flags.

• Unintentional weight loss (over 5% in 6 months), persistent fever, drenching night sweats.
• Lymphadenopathy, hepatosplenomegaly, bone pain, easy bruising or bleeding.
• Progressive dyspnoea, chest pain, syncope, orthopnoea.
• Rectal bleeding, melaena, change in bowel habit, dysphagia, jaundice.
• Postural hypotension with hyperpigmentation, vomiting or hyponatraemia (adrenal insufficiency).
• Thirst and polyuria with weight loss (diabetes), symptoms of hypercalcaemia.
• Focal neurological deficit, fatigable ptosis or bulbar weakness, new confusion.
• New onset over age 60, known malignancy, HIV risk, immunosuppression.
• Suicidal thoughts.

Psychological and behavioural. Depression, anxiety disorders, burnout, grief, trauma related disorders, somatic symptom disorder, substance and alcohol use disorder, eating disorder, bipolar depression, insufficient sleep.

Sleep disorders. Obstructive sleep apnoea, insomnia, restless legs syndrome, periodic limb movement disorder, narcolepsy, shift work and circadian disorders, nocturnal hypoxaemia in chronic lung disease.

Infective and postinfective.

• Postviral fatigue: Epstein-Barr virus, cytomegalovirus, influenza, COVID-19 (post COVID-19 condition).
• Chronic or smouldering: HIV, tuberculosis, hepatitis B and C, infective endocarditis, brucellosis, Q fever, chronic malaria, schistosomiasis, trypanosomiasis, toxoplasmosis, Lyme disease, hookworm and other helminths, occult abscess or osteomyelitis.

Haematological. Iron deficiency with or without anaemia, vitamin B12 and folate deficiency, anaemia of chronic disease, haemolytic anaemia, sickle cell disease, thalassaemia, haemochromatosis, leukaemia, lymphoma, myeloma, myelodysplasia.

Endocrine and metabolic. Hypothyroidism, hyperthyroidism, diabetes mellitus, adrenal insufficiency, Cushing syndrome, hypopituitarism, hypercalcaemia (primary hyperparathyroidism), hypocalcaemia, hyponatraemia, hypokalaemia, hypomagnesaemia, vitamin D deficiency, hypogonadism, menopause, chronic kidney disease and uraemia, chronic liver disease, recurrent hypoglycaemia.

Cardiorespiratory. Heart failure, coronary disease, arrhythmia, valve disease, cardiomyopathy, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, interstitial lung disease, chronic pulmonary embolism.

Gastrointestinal and nutritional. Coeliac disease, inflammatory bowel disease, malabsorption, gastric or colorectal cancer with occult bleeding, malnutrition, Helicobacter pylori gastritis.

Rheumatological and autoimmune. Systemic lupus erythematosus, rheumatoid arthritis, polymyalgia rheumatica, giant cell arteritis, Sjogren syndrome, systemic sclerosis, vasculitis, sarcoidosis, myositis, fibromyalgia.

Neurological. Multiple sclerosis, Parkinson disease, myasthenia gravis, poststroke fatigue, traumatic brain injury, early dementia, chronic fatigue syndrome.

Malignancy. Any cancer, particularly haematological, lung, gastric, colorectal, pancreatic and breast; paraneoplastic fatigue.

Drugs and toxins. Antihypertensives, sedatives, opioids, antihistamines, antidepressants, antiepileptics, statins, antiretrovirals, antituberculous drugs, chemotherapy, alcohol, cannabis, chronic carbon monoxide exposure, lead.

Physiological. Pregnancy, postpartum period, ageing, deconditioning, overtraining.

1. Fatigue under 4 weeks with a clear explanation (recent infection, bereavement, new drug) needs no tests. Review at 4 weeks.
2. Fatigue persisting beyond 4 weeks without a pointer: take a full sleep, mood, drug and alcohol history and screen with PHQ-9, GAD-7 and the Epworth score, then order a limited panel.
3. First line panel: full blood count with film, ferritin, C reactive protein or ESR, urea, creatinine and electrolytes, corrected calcium, liver function tests with albumin, random glucose or HbA1c, thyroid stimulating hormone, urinalysis, and coeliac serology (tissue transglutaminase IgA with total IgA). Add creatine kinase when muscle symptoms are present, vitamin B12 and folate when there is anaemia, macrocytosis, neuropathy or restricted diet, HIV test with consent, pregnancy test, and hepatitis B and C serology when there is risk.
4. Interpretation.

• Anaemia: haemoglobin under 130 g/L in men, under 120 g/L in non pregnant women, under 110 g/L in pregnancy.
• Iron deficiency: ferritin under 30 microgram/L; ferritin up to 100 microgram/L with transferrin saturation under 20% still indicates deficiency when inflammation, heart failure or kidney disease is present.
• Vitamin B12 under 148 pmol/L (200 ng/L) is low; 148 to 258 pmol/L is borderline and needs methylmalonic acid or homocysteine.
• HbA1c 48 mmol/mol (6.5%) or more, or fasting glucose 7.0 mmol/L or more, confirms diabetes.
• Corrected calcium over 2.60 mmol/L is hypercalcaemia.
• Thyroid stimulating hormone reference range is about 0.4 to 4.0 mU/L; a raised value needs free thyroxine. Mild subclinical elevation rarely explains fatigue.

1. Second line, directed by findings: 08:00 to 09:00 cortisol (under 100 nmol/L makes adrenal insufficiency likely; 100 to 500 nmol/L needs a short tetracosactide test, 250 micrograms intravenously or intramuscularly, with failure to reach a 30 minute cortisol of about 420 to 500 nmol/L being abnormal, assay dependent); antinuclear antibody, rheumatoid factor and anti cyclic citrullinated peptide; Epstein-Barr and cytomegalovirus serology; sleep study (home polygraphy or polysomnography) when the Epworth score is over 10 or apnoea is suspected; ECG, echocardiography and NT-proBNP (a value under 125 pg/mL makes chronic heart failure unlikely); spirometry; serum protein electrophoresis and free light chains; transferrin saturation (over 45% suggests haemochromatosis); malaria film, tuberculosis testing and blood cultures where the history points there; 25 hydroxyvitamin D when there is bone pain, malabsorption or limited sun exposure.
2. Iron deficiency anaemia in a man or a postmenopausal woman needs upper and lower gastrointestinal endoscopy. In any patient with a red flag, proceed to chest radiograph and CT of chest, abdomen and pelvis.
3. Chronic fatigue syndrome is diagnosed only after a minimum panel is normal and the clinical criteria are met for 6 months (3 months in children and adolescents).

Limits. Most prolonged fatigue panels are normal; a normal panel does not make the symptom unreal. Ferritin rises with inflammation and can hide iron deficiency. Repeated broad testing adds false positives. Reassessment at 4 to 6 weeks is more useful than repeating tests.

General measures for all patients. Acknowledge the symptom, explain that fatigue is real and usually improves, and agree a realistic plan. Review and where possible stop non essential sedating drugs. Fix sleep timing, limit alcohol and caffeine, and use a structured activity plan with gradual increases. Keep a symptom and activity diary. Avoid empirical vitamins, iron, corticosteroids or stimulants without a documented indication.

Cause directed treatment.

• Iron deficiency: ferrous sulphate 200 mg (65 mg elemental iron) orally once daily or on alternate days, between meals if tolerated, continued for 3 months after haemoglobin normalises. Haemoglobin should rise by about 10 g/L within 2 to 4 weeks; if not, check adherence, ongoing loss, malabsorption and inflammation. Intravenous iron (for example ferric carboxymaltose 1000 mg once, maximum 20 mg/kg, repeated after at least 7 days if the calculated deficit is larger) is used for intolerance, malabsorption, chronic kidney disease, heart failure or ongoing loss; check phosphate after dosing. Find and treat the source of loss.
• Vitamin B12 deficiency: hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks then 1 mg every 3 months for pernicious anaemia. With neurological involvement give 1 mg on alternate days until no further improvement then every 2 months. Folic acid 5 mg orally daily for 4 months for folate deficiency, started only after B12 deficiency is excluded or covered.
• Hypothyroidism: levothyroxine 1.6 micrograms/kg orally once daily on an empty stomach (start 25 micrograms daily in older adults or coronary disease, increasing by 25 micrograms every 4 to 6 weeks). Check thyroid stimulating hormone 6 to 8 weeks after each change. Separate from iron and calcium by 4 hours.
• Adrenal insufficiency: hydrocortisone 15 to 25 mg daily in two or three divided doses (for example 10 mg on waking, 5 mg at midday, 5 mg mid afternoon), with fludrocortisone 50 to 100 micrograms daily in primary disease. Sick day rules and an emergency card. Adrenal crisis: hydrocortisone 100 mg intravenously at once, then 200 mg over 24 hours by infusion (or 50 mg every 6 hours), with 0.9% sodium chloride 1 litre over the first hour.
• Vitamin D deficiency (25 hydroxyvitamin D under 25 nmol/L): colecalciferol 50,000 units orally once weekly for 6 to 8 weeks, then 800 to 2,000 units daily; check calcium in primary hyperparathyroidism.
• Depression: psychological therapy and an antidepressant such as sertraline 50 mg orally once daily (usual range 50 to 200 mg), review at 2 weeks and 4 to 6 weeks; monitor sodium in older adults.
• Obstructive sleep apnoea: continuous positive airway pressure, weight loss, avoidance of alcohol and sedatives at night.
• Heart failure, chronic kidney disease, diabetes and chronic infection: treat the underlying disease, and correct anaemia and electrolytes.
• Postviral fatigue: reassurance, pacing, gradual return to activity; most improve over weeks to months.
• Chronic fatigue syndrome: individualised activity management with pacing (activity increased only within symptom limits), sleep management, treatment of pain, orthostatic intolerance and mood, and cognitive behavioural therapy for coping. No drug has proven benefit for the core condition. Structured exercise programmes that force increases are not advised.

Monitoring. Review at 2 to 4 weeks after starting treatment, and at 4 to 6 weeks for unexplained fatigue. Repeat haemoglobin 2 to 4 weeks after starting iron, thyroid stimulating hormone at 6 to 8 weeks, and repeat the mood and fatigue scores.

Referral and escalation. Urgent investigation for any red flag. Endocrinology for adrenal, pituitary or complex thyroid disease. Haematology for unexplained cytopenia or abnormal film. Rheumatology for autoimmune disease. Sleep medicine, mental health services, or a specialist fatigue service for severe chronic fatigue (housebound or bedbound) or symptoms beyond 6 months with marked disability.

Admission. Adrenal crisis, severe anaemia (haemoglobin under 70 g/L or symptomatic), corrected calcium 3.0 mmol/L or more, severe hyponatraemia or hypokalaemia, suspected endocarditis, suicidal risk, new neurological deficit.

Safety netting. Return for fever, weight loss, bleeding, new breathlessness, chest pain, fainting, black stools, severe headache, or worsening mood.

Special groups. Pregnancy: tiredness is common, but check ferritin and haemoglobin and thyroid function; iron in the second trimester. Older adults: look for anaemia, hypothyroidism, depression, drug effects, heart failure, sleep apnoea and cancer; screen cognition. Children and adolescents: consider infectious mononucleosis, anaemia, coeliac disease, type 1 diabetes, depression and sleep deprivation. HIV and endemic regions: include tuberculosis, malaria, schistosomiasis and helminth anaemia.