Malaise and fatigue - Knowledge @ AMBOSS

Summary

Malaise and fatigue can occur in almost any medical condition. The definitions of malaise, fatigue, asthenia, and weakness are imprecise and therefore these terms are sometimes used interchangeably in medical and lay contexts. Patients with malaise or fatigue require a detailed clinical evaluation, including a medical history, social and occupational history, mental health evaluation, and complete physical examination. It is important to distinguish fatigue caused by systemic metabolic abnormalities (e.g., disorders of circulation, oxygen delivery, or nutrition) from neuromuscular disorders, as they should be approached differently. Various diagnostic studies may be indicated to investigate malaise and fatigue. Routine studies (e.g., CBC, BMP) can help screen for common metabolic causes in most patients. Selective testing (e.g., sepsis workup, rheumatologic or oncological workup) is preferred and should be performed based on clinical findings and individual risk factors to prevent false-positive results and misdiagnoses. Critical causes include severe anemia, sepsis, and hypoglycemia. Management depends on the underlying cause and symptom severity.

See “Weakness and paralysis” for a detailed approach to neuromuscular weakness.

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Definitions

The following terms have imprecise definitions and their usage can vary and overlap in both medical and lay contexts. ^[1]^[2]

Malaise: a general feeling of unease, discomfort, or reduced well-being due to an underlying condition
Fatigue: the subjective feeling of tiredness, exhaustion, or lack of energy ^[1]
- Physiological fatigue may be normal and self-limited.
- Secondary fatigue may be due to a chronic or underlying condition.
- Can also refer to progressive loss of muscle strength, e.g., respiratory muscle fatigue
Weakness: a lack of strength in the body or a body part
- In medical contexts, “weakness” is best reserved for describing neuromuscular weakness (see “Weakness and paralysis”).
- Usage varies in the literature and in lay contexts; the term “generalized weakness” may also signify: ^[1]^[2]^[3]
  - Malaise, fatigue, lethargy, or asthenia
  - Disability, exercise intolerance, or functional decline
  - Related symptoms, e.g., muscle pain, incoordination, altered mental status, presyncope
Asthenia: a clinical syndrome manifesting as fatigue, malaise, muscle weakness, and loss or lack of strength and energy ^[4]

Clarify the meaning of potentially imprecise reported symptoms (e.g., generalized weakness) to avoid misdiagnosis, miscommunication, and unnecessary investigations.

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Etiology

Infectious

Acute: See “Infectious causes of acute malaise and fatigue” for details.
- Viral
- Bacterial
  - Sepsis
  - Bacteremia
- Vector-borne
  - Malaria
  - Dengue fever
  - Early Lyme disease
  - Other tick-borne diseases
Chronic: See “Infectious causes of chronic malaise and fatigue” for details.
- Chronic hepatitis
- HIV
- Lyme disease
- Tuberculosis (TB)
- Subacute endocarditis
- Osteomyelitis
- Postviral syndrome

Cardiovascular

Acute
- Acute myocardial infarction
- Acute heart failure (AHF)
Chronic

Respiratory

Gastrointestinal

Acute
Chronic
- Chronic liver disease, e.g., cirrhosis
- Inflammatory bowel disease
- Irritable bowel syndrome
- Gastroesophageal reflux disease
- Gallbladder disease
- Gastroparesis
- Colitis
- Celiac disease

Endocrine and metabolic

Acute
- Dehydration
- Electrolyte disorders
- Hypoglycemia
- Hyperglycemic crises, e.g., diabetic ketoacidosis (DKA)
- Thyroid storm
- Myxedema coma
- Adrenal crisis
Chronic
- Diabetes mellitus
- Hypothyroidism
- Adrenal insufficiency
- Hashimoto thyroiditis, subacute thyroiditis
- Cushing syndrome
- Hyperparathyroidism
- Hypoparathyroidism
- Pheochromocytoma
- Vitamin D deficiency
- Nutritional, e.g., B₁₂ deficiency

Inflammatory or autoimmune

Neoplastic

Malaise and/or fatigue caused by these conditions can be acute or chronic.

Genitourinary

Acute
Chronic

Hematologic

Acute
- Acute anemia
- Hemorrhage
- Acute leukemia
Chronic
- Anemia, e.g., iron-deficiency anemia (IDA)
- Pancytopenia
- Hematologic malignancies
- Hemochromatosis
- Sickle cell disease
- Thalassemia
- Aplastic anemia
- Polycythemia vera

Toxicological and substance-related

Acute: See “Substance-related causes of acute malaise and fatigue” for details.
Chronic: See “Substance-related causes of chronic malaise and fatigue” for details.

Polypharmacy can cause acute or chronic malaise and/or fatigue, especially in older adults.

Psychiatric and behavioral

Acute
- Acute stress reaction
- Panic attack
Chronic
- Major depressive disorder
- Anxiety disorders
- Sleep disorders
- Burnout syndrome
- Substance misuse
- Posttraumatic stress disorder
- Bipolar disorder
- Eating disorders
- Somatic symptom disorder
- Schizophrenia

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Initial management

Approach ^[1]

Assess for red flags in malaise and fatigue.
Rule out life-threatening conditions; see “Critical causes of acute malaise and fatigue.”
Consider adjacent and/or associated features, e.g., vertigo, presyncope.
Assess for fatigue that exceeds the amount or intensity of physical activity.
Narrow the diagnosis based on clinical evaluation and onset.
- See “Causes of acute malaise and fatigue.”
- See “Causes of chronic malaise and fatigue.”
Obtain focused diagnostic studies.
Provide supportive care as needed.
Treat the underlying cause if identified.

Maintain a high index of suspicion for serious causes in women and older adults presenting to the ED with nonspecific fatigue or malaise. ^[5]^[6]^[7]

Red flags in malaise and fatigue

Red flag features that indicate a serious underlying cause requiring urgent investigation include:

Acute supportive care

Consider the following as needed:

Oxygen therapy
Fluid resuscitation
Electrolyte repletion
Pain management
Antiemetics
Antipyretics
Glycemic control
Withdrawal management, e.g., nicotine replacement therapy, calming medications
See “Long-term supportive care for malaise and fatigue” for chronic management.

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Clinical evaluation

Focused history ^[1]

A comprehensive medical history is often required for diagnosis and should include the following:

Symptom onset, duration, pattern, and course
Associated symptoms, aggravating or alleviating factors
Degree of functional disability
Cognitive symptoms, e.g., memory loss, difficulty concentrating
Past medical and surgical history
Recent medications, treatments, and hospitalizations
Diet, hydration, physical activity
Psychosocial stressors and supports
Habits, environmental exposures, occupational history, and travel history
If applicable, menstrual history and/or sexual history

Assess cardiovascular risk in patients who may experience anginal equivalents in the form of malaise or fatigue, e.g., older adults and women.

Inquire about postexertional malaise in patients with suspected ME/CFS. ^[1]

Focused examination ^[1]

A complete physical examination is often required, but a focused examination may be indicated if a specific cause or system involvement is suspected. Key findings include:

Fever, hypothermia, tachycardia, hypotension, altered mental status
Skin rashes, signs of poor peripheral perfusion, pallor, cyanosis
Signs of heart failure, signs of respiratory distress
Abdominal distention and/or tenderness, clinical features of GI bleeding
Focal neurological deficits, nonfocal neurological deficits
Muscle atrophy, joint abnormalities, e.g., tenderness, swelling, reduced ROM
Lymphadenopathy, organomegaly

Consider obtaining orthostatic vital signs in patients with positional or exertional symptoms. ^[1]

Specific assessments and screening

Consider the following as appropriate:

Focused toxicological history and physical examination
Functional status assessment and frailty assessment
Screening for geriatric syndromes and falls risk assessment
Mental health screening, e.g., anxiety, psychosis, depression screening
Screening for sleep disorders
Screening for intimate partner violence

Remember to screen for depression in patients presenting to primary care clinics with fatigue. ^[8]

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Diagnosis

The workup for malaise and fatigue is often broad. Obtain studies based on careful clinical evaluation. See “Diagnostics for neuromuscular weakness” for an approach to patients with weakness and paralysis.

Routine studies ^[1]^[2]^[9]

Consider screening for common systemic conditions, e.g., anemia, electrolyte disturbances, metabolic and hormonal disorders, and pregnancy.

Laboratory studies
- CBC
- BMP
- Renal function tests
- LFTs
- TFTs
Bedside studies

Specific studies ^[1]^[2]^[9]

Studies are guided by clinical suspicion; advanced (e.g., sleep studies) and invasive studies (e.g., colonoscopy) are typically obtained by specialists. ^[9]

Acute infectious workup: e.g., sepsis workup, respiratory viral panel, monospot test, Lyme serology, malaria parasite testing, HIV testing, viral hepatitis panel
Metabolic workup: e.g., diabetes screening, serum ketones, ammonia, CPK, serum cortisol, ACTH, lead levels
Cardiorespiratory workup: e.g., CXR, cardiac enzymes, BNP, echocardiogram, Holter monitor, PFTs
Hematologic studies: e.g., coagulation panel, iron studies, hemolysis workup, vitamin B₁₂, folate
Oncological workup: e.g., tumor markers, imaging (CT, PET scan, bone scan)
Rheumatologic workup: e.g., rheumatoid factor, ANAs, ESR, CRP

Selective testing is suitable for most patients, as causes are rarely critical. Consider more liberal testing in patients in whom fatigue is associated with poor outcomes (e.g., women, older adults). ^[8]^[10]^[11]^[12]

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Acute-onset or rapidly progressive causes

Acute critical causes

Critical causes of acute malaise and fatigue ^[1]
	Distinguishing clinical features	Diagnostics	Management
Sepsis and septic shock	Hypotension Tachycardia Fever Altered mental status	Blood cultures Lactate See “Sepsis workup” for details.	Empiric antibiotics for sepsis Vasopressors for septic shock See “Acute management checklist for sepsis.”
Severe anemia	Pallor Shortness of breath Signs of bleeding	CBC: Hb ≤ 7 g/dL Iron studies, hemolysis workup Digital rectal examination See “Anemia workup” for details.	Blood transfusion Hemostatic measures if necessary Treat underlying causes of anemia, e.g., treatment of GI bleeding, treatment of IDA.
Acute coronary syndrome	Chest pain Diaphoresis Dyspnea	ECG Cardiac enzymes, e.g., troponin See “Diagnosis of ACS” for details.	Reperfusion therapy Antiplatelet agents See “STEMI management.” See “NSTEMI management.”
AHF	Shortness of breath Orthopnea Rales Peripheral edema	ECG BNP, NT-proBNP CXR Echocardiogram	Respiratory support for AHF Diuretics for AHF Vasodilators for AHF See “Acute management checklist for AHF.”
AECOPD	Increased shortness of breath Increased sputum production Wheezing	Blood gas analysis: CO₂ retention CXR	Corticosteroids Bronchodilators See “Acute management checklist for AECOPD.”
AKI	Reduced urine output Fluid imbalance: hypovolemia or fluid overload Symptoms of uremia, e.g., confusion	Creatinine, BUN CMP Urinalysis and urine electrolytes	IV fluid therapy Treatment of complications, e.g., hyperkalemia Renal replacement therapy if necessary See “Management of AKI” for details.
ALF	Jaundice Abdominal pain Signs of hepatic encephalopathy	LFTs Coagulation studies Ammonia Liver imaging, CT head	Treatment of the underlying cause, e.g., acetaminophen overdose Liver transplant See “Treatment of ALF” for details.
DKA	Polydipsia, polyuria Abdominal pain Altered mental status	Hyperglycemia Serum or urine ketones BMP: high anion gap Blood gas analysis: metabolic acidosis	Insulin therapy Fluid and electrolyte repletion See “Acute management checklist for DKA.”
Myxedema coma	Hypothermia Bradycardia Altered mental status	TFTs	Thyroid hormone replacement See “Acute management checklist for myxedema coma.”
Adrenal crisis	Hypotension and/or shock Severe abdominal pain Recent corticosteroid withdrawal	Clinical diagnosis BMP: hyponatremia, hyperkalemia, hypoglycemia Cortisol	Glucocorticoid replacement See “Acute management checklist for adrenal crisis.”
Acute leukemia	Fever Signs of anemia Signs of thrombocytopenia Clinical features of infection	Peripheral blood smear Bone marrow aspiration and biopsy	Chemotherapy Multidisciplinary cancer care See “Management of acute leukemia” for details.
Acute bacterial meningitis	Fever Meningismus Altered mental state	CSF analysis Blood cultures CT head or MRI brain	Empiric antibiotics for bacterial meningitis See “Acute management checklist for meningitis.”
Acute poisoning or withdrawal	See “Substance-related causes of acute malaise and fatigue.”

Acute infectious causes

The following conditions typically manifest acutely with fever and significant malaise and/or fatigue.

Infectious causes of acute malaise and fatigue ^[1]
	Distinguishing clinical features	Diagnostics	Management
COVID-19	Dry cough Anosmia Shortness of breath	COVID-19 testing	Isolation precautions Supportive care Antiviral therapy if indicated See “Management of COVID-19” for details.
Influenza	Sudden-onset fever, headache, myalgia	Clinical diagnosis during seasonal epidemics Diagnostics for influenza, e.g., PCR	Supportive care Antiviral therapy if indicated See “Treatment of influenza” for details.
Viral URTI	Nasal congestion, rhinorrhea Sore throat, cough Myalgia	Clinical diagnosis Respiratory viral panel Disease-specific studies, e.g., COVID-19 testing	Supportive care See “Treatment of URTI” for details.
Pneumonia	Productive cough Dyspnea Fever	CXR findings in pneumonia Microbiological studies, e.g., blood and sputum culture	Empiric antibiotics for community-acquired pneumonia Empiric antibiotics for hospital-acquired pneumonia See “Acute management checklist for pneumonia.”
Infectious mononucleosis	Prominent fatigue Severe sore throat Lymphadenopathy Splenomegaly	Clinical diagnosis EBV serology CBC: atypical lymphocytes	Supportive care Corticosteroids for severe symptoms See “Treatment of infectious mononucleosis” for details.
CMV mononucleosis	Fever Headache Myalgia	CBC: > 10% atypical lymphocytes CMV-specific antibodies PCR	Antiviral therapy for immunosuppressed patients and severe cases Supportive care for immunocompetent patients See “Treatment of CMV” for details.
Early localized Lyme disease	Headache Erythema migrans Myalgia, arthralgia	Lyme serology	Antibiotics See “Treatment of Lyme disease” for details.
Malaria	Intermittent fever with chills Headache	Thick and thin blood smear Rapid diagnostic tests for malaria-specific antigens	Antimalarial medication See “Acute management checklist for malaria.”
Dengue fever	Sudden-onset high fever, severe myalgia, arthralgia, and headache Persistent vomiting Petechiae, epistaxis	CBC: leukopenia, thrombocytopenia Serology NS1 antigen test	Supportive treatment: IV fluids, acetaminophen Blood transfusions for bleeding
Typhoid fever	Headache Relative bradycardia Persistent fever Rose-colored spots	Blood cultures Stool cultures	Antibiotics Supportive care See “Treatment of typhoid and paratyphoid fever” for details.
Acute hepatitis infection	Jaundice Nausea, vomiting RUQ pain	Acute viral hepatitis panel	See “Treatment of hepatitis A.” See “Treatment of hepatitis B.” See “Treatment of hepatitis C.”
Acute HIV infection	Acute retroviral syndrome, e.g., fever, generalized rash Myalgia, arthralgia	HIV testing, e.g., RNA PCR	Antiretroviral therapy See “HIV treatment” for details.

Acute substance-related causes

Substance-related causes of acute malaise and fatigue
	Distinguishing clinical features	Diagnostics	Management
Alcohol withdrawal	Agitation Tremors Seizures	Clinical diagnosis CIWA-Ar score Blood alcohol level	Benzodiazepines Supportive care, e.g., thiamine supplementation See “Management of alcohol withdrawal” for details.
Sedative-hypnotic drug overdose	Altered mental status Cerebellar symptoms Respiratory depression	Clinical diagnosis Toxicology screen in selected patients	Supportive care, e.g., fluids, airway protection Antidote (e.g., flumazenil) if indicated See “Management of sedative-hypnotic drug overdose” for details.
Cardiovascular drug poisoning	Hypotension Bradycardia Altered mental status	Clinical diagnosis ECG: arrhythmias, heart blocks Measurement of drug levels, e.g., digoxin	Antidotes for cardiovascular drug poisoning See “Initial approach to cardiovascular drug poisoning” for details.
Opioid overdose	Altered mental status Respiratory depression Pinpoint pupils	Clinical diagnosis Toxicology screen in selected patients	Naloxone for opioid overdose See “Management of opioid overdose” for details.
CO poisoning	Headache Altered mental status Inhalation injury in fire-related exposure Cherry-red skin	Normal SpO₂ CO-oximetry	100% oxygen via NRB Hyperbaric oxygen therapy See “Acute management checklist for CO poisoning.”
Cholinergic poisoning	Bronchospasm Bradycardia Muscle weakness Agitation, seizures	Clinical diagnosis based on, e.g., exposure to pesticides, nerve agents, or parasympathomimetic drugs Cholinesterase activity assays if the diagnosis is uncertain	PPE and surface decontamination if indicated Antidotes, e.g., atropine, pralidoxime See “Management of cholinergic poisoning” for details.
Acetaminophen overdose	Nausea, vomiting Abdominal pain Jaundice	Serum acetaminophen levels LFTs Coagulation panel	N-acetylcysteine Liver function monitoring See “Management of acetaminophen overdose” for details.
Salicylate poisoning	Tinnitus Tachypnea Altered mental status	Salicylate levels BMP: high anion gap Blood gas analysis: mixed respiratory alkalosis and metabolic acidosis	IV sodium bicarbonate Hemodialysis See “Acute management checklist for salicylate poisoning.”

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Subacute/chronic-onset or gradually progressive causes

Chronic noninfectious causes

Noninfectious causes of chronic malaise and fatigue ^[1]
	Distinguishing clinical features	Diagnostics	Management
Major depression	Clinical features of major depression, e.g., anhedonia, feeling hopeless	Depression screening Exclusion of organic causes	Antidepressants Psychotherapy See “Treatment of major depressive disorder” for details.
IDA	Pallor Shortness of breath See “Clinical features of IDA.”	CBC: microcytic, hypochromic anemia Iron studies: ↓ serum ferritin	Iron supplementation See “Treatment of IDA” for details.
Hypothyroidism	Weight gain Hypothyroid myopathy See “Clinical features of hypothyroidism.”	TFTs	Levothyroxine replacement See “Management of hypothyroidism” for details.
CKD or ESRD	Pulmonary and peripheral edema Signs of uremia, e.g., nausea	Renal function tests Urine studies, e.g., UACR	Treatment of the underlying cause and complications Renal replacement therapy in advanced cases See “Treatment of CKD” for details.
OSA	Loud snoring Excessive daytime sleepiness Impaired cognitive function	Sleep studies, e.g., polysomnography	CPAP Lifestyle changes, e.g., weight loss See “Management of OSA” for details.
Diabetes mellitus	Polyuria, polydipsia Weight loss	Hyperglycemia tests, e.g., fasting plasma glucose	Antihyperglycemics, e.g., insulin Diet and lifestyle modification See “Diabetes management” for details.
Heart failure	Dyspnea Peripheral pitting edema	ECG, CXR, TTE Natriuretic peptides	Diuretics, beta blockers, RAAS inhibitors See “Treatment of heart failure” for details.
Coronary artery disease (CAD)	Chest pain Dyspnea Palpitations	ECG, TTE Cardiac stress testing Myocardial perfusion scan, CMR	Prevention of recurrent CAD, e.g., with antiplatelet agents, statins Antianginal medication See “Treatment of CAD” for details.
ME/CFS	Fatigue not relieved by rest Postexertional malaise Cognitive impairment	Diagnosis of exclusion 2015 IOM diagnostic criteria for CFS	Supportive care to alleviate symptoms See “Management of ME/CFS” for details.
Fibromyalgia	Diffuse chronic musculoskeletal pain Sleep disturbances Fibromyalgia fog	Diagnosis of exclusion	Exercise therapy Pharmacotherapy, e.g., pregabalin, duloxetine See “Management of fibromyalgia” for details.
Adrenal insufficiency	Muscle weakness Weight loss Hypotension Nausea, vomiting	Morning cortisol and ACTH levels ACTH stimulation test	Steroid replacement, e.g., corticosteroids, mineralocorticoids See “Treatment of adrenal insufficiency” for details.
Rheumatoid arthritis	Symmetrical joint pain and swelling Morning stiffness	Rheumatoid factor Anti-CCP antibodies Imaging (x-rays, MRI)	Steroids and NSAIDs for acute flares DMARDs, e.g., methotrexate Physical therapy See “Treatment of rheumatoid arthritis” for details.
SLE	Skin involvement, e.g., malar rash Joint pain, distal symmetrical polyarthritis	ANAs Anti-dsDNA Complement levels	Hydroxychloroquine Immunosuppressants See “Treatment of SLE” for details.

Chronic infectious causes

Infectious causes of chronic malaise and fatigue ^[1]
	Distinguishing clinical features	Diagnostics	Management
Atypical pneumonia	Cough Fever	CXR: diffuse reticular opacity, absent consolidation Microbiological studies, e.g., blood and sputum culture PCR	Empiric antibiotics for community-acquired pneumonia Empiric antibiotics for hospital-acquired pneumonia See “Acute management checklist for pneumonia.”
Chronic hepatitis	Hepatitis B: nausea, nonspecific abdominal pain Hepatitis C: signs of chronic liver disease, extrahepatic features of HCV	LFTs Hepatitis B diagnostics Hepatitis C diagnostics	See “Treatment of hepatitis B” for details. See “Treatment of hepatitis C” for details. See also “Management of cirrhosis.”
Disseminated Lyme disease	Early disseminated Lyme disease, e.g., Lyme carditis Late disseminated Lyme disease, e.g., neuroborreliosis	Lyme serology Depending on manifestation, e.g., ECG, LP, arthrocentesis	Antibiotics See “Treatment of Lyme disease” for details.
HIV	Prior acute retroviral syndrome Clinical features of HIV-associated conditions	HIV testing, e.g., RNA PCR	Antiretroviral therapy See “HIV treatment” and “HIV-associated conditions” for details.
TB	Chronic cough Hemoptysis Weight loss Fever and night sweats	Active TB: sputum microscopy and culture, chest imaging Latent TB: e.g., interferon-γ release assay	Antibiotics for TB, e.g., RIPE See “TB treatment” for details.
Chronic osteomyelitis	Recurrent pain Swelling and tenderness over the affected bone	Blood cultures Imaging, e.g., MRI (most sensitive) See “Diagnostics for osteomyelitis” for details.	IV antibiotics Surgery in severe cases See “Treatment of osteomyelitis” for details.

Chronic substance-related causes

Substance-related causes of chronic malaise and fatigue ^[1]
	Distinguishing clinical features	Diagnostics	Management
Lead poisoning	Cognitive impairment Severe abdominal pain Burton line	Blood lead levels CBC: anemia, basophilic stippling X-ray: lead lines	Chelation therapy Nutritional support, e.g., calcium, iron See “Lead poisoning” for details.
Mercury poisoning	Acute: gastroenteritis, airway inflammation in patients with inhalation exposure Chronic: polyneuropathy, ataxia, irritability	Blood or urine mercury levels	Chelation therapy See “Mercury poisoning” for details.
Arsenic poisoning	Acute: abdominal pain, vomiting, coma Chronic: lung and skin cancer, arsenical keratosis	Urine arsenic levels Hair analysis (for chronic exposure)	Chelation therapy See “Arsenic poisoning” for details.
Asbestosis	Exertional dyspnea Dry cough Pleural effusion	CXR or CT scan PFTs	Cessation of asbestos exposure Supportive care Monitoring and treatment of asbestos-related diseases
AUD	Signs of complications of alcohol use Signs of chronic liver disease	DSM-5 criteria for AUD Laboratory confirmation of alcohol use Evaluation for alcohol-related complications	Management of acute complications, e.g., alcohol withdrawal Counseling on AUD Pharmacotherapy for AUD See “Management of AUD” for details.
Cannabis use disorder	Impaired social and professional function Cannabis-induced disorders, e.g., cannabis-induced psychiatric disorders	Clinical diagnosis based on DSM-5 diagnostic criteria Urine drug screening	See “Management of substance use disorder” for a general approach to all substance use. See “Cannabis intoxication” and “Cannabis withdrawal” for details on these conditions.
Opioid use disorder	Craving, tolerance, and withdrawal symptoms Constipation Psychosocial dysfunction	Clinical diagnosis based on diagnostic criteria for opioid use disorder and risk factors for opioid overdose	Medication for opioid use disorder Behavioral therapy and counseling See “Management of opioid use disorder” for details.

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Management

Further evaluation

Consult a specialist as needed based on the suspected underlying cause.
Ensure follow-up to discuss the results of ongoing or pending investigations.
Avoid repeating recently performed investigations unless the patient's condition has changed significantly.

Long-term supportive care for malaise and fatigue ^[1]

The following general management steps may alleviate malaise and/or fatigue and improve functional outcomes irrespective of the cause.

Optimize sleep hygiene and nutrition.
Educate patients on stress management.
Review medications and modify or discontinue unnecessary or harmful drugs.
Encourage regular exercise if tolerated.
- Helpful for fatigue due to inflammatory disorders, neurological disorders, fibromyalgia, and malignancy.
- Avoid unstructured exercise in patients with ME/CFS; a personalized and graded approach is necessary to prevent harm. ^[1]
Ensure access to mental health services.
Optimize psychosocial supports.
Provide reassurance about serious conditions that have been excluded.
Arrange appropriate follow-up and referrals.
Consider symptomatic pharmacological treatment in selected patients. ^[1]
- Medications such as modafinil and methylphenidate are usually ineffective for fatigue secondary to chronic diseases.
- Several pharmacological options can be considered for the symptomatic management of ME/CFS.

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Disposition

Disposition varies significantly depending on the patient and underlying cause.

Consider admitting patients with red flags in malaise and fatigue.
Most older adults require admission (e.g., for workup, supportive care, rehabilitation). ^[5]
Critically ill patients (e.g., with sepsis) require admission to the ICU.
Selected low-risk patients can be referred for outpatient evaluation after critical causes have been excluded.

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Acute management checklist

Follow the ABCDE approach if the patient is unstable.
Obtain a full set of vitals.
Treat hypoglycemia if present.
Identify and treat critical causes of acute malaise and fatigue.
Conduct medical history and physical examination.
Obtain a 12-lead ECG.
Obtain laboratory studies, including:
- CBC, BMP, renal function tests, LFTs, TFTs
- Urinalysis, urine beta-hCG
Consider targeted infection screening, e.g. COVID-19 testing.
Obtain imaging guided by clinical suspicion.
Provide supportive care, e.g., analgesia, IV fluids.
Consult a specialist as needed.
Admit for inpatient management as needed.

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Malaise and fatigue

Summary

Definitions

Etiology

Infectious

Cardiovascular

Respiratory

Gastrointestinal

Endocrine and metabolic

Inflammatory or autoimmune

Neoplastic

Genitourinary

Hematologic

Toxicological and substance-related

Psychiatric and behavioral

Initial management

Approach [1]

Red flags in malaise and fatigue

Acute supportive care

Clinical evaluation

Focused history [1]

Focused examination [1]

Specific assessments and screening

Diagnosis

Routine studies [1][2][9]

Specific studies [1][2][9]

Acute-onset or rapidly progressive causes

Acute critical causes

Acute infectious causes

Acute substance-related causes

Subacute/chronic-onset or gradually progressive causes

Chronic noninfectious causes

Chronic infectious causes

Chronic substance-related causes

Management

Further evaluation

Long-term supportive care for malaise and fatigue [1]

Disposition

Acute management checklist

Approach ^[1]

Focused history ^[1]

Focused examination ^[1]

Routine studies ^[1]^[2]^[9]

Specific studies ^[1]^[2]^[9]

Long-term supportive care for malaise and fatigue ^[1]