What is the initial workup and treatment approach for a patient presenting with chronic fatigue?

Chronic Fatigue Workup

Initial Screening and Severity Assessment

Begin by screening all patients with fatigue using a 0-10 numeric rating scale, where scores of 0-3 (mild) require only periodic rescreening, while scores ≥4 (moderate to severe) mandate immediate comprehensive diagnostic evaluation. 1, 2, 3

• Patients with fatigue scores ≥7 typically experience marked decreases in physical functioning and require urgent attention 1
• Document the onset, pattern, duration, changes over time, associated or alleviating factors, and interference with daily activities 1, 3
• Assess the patient's self-understanding of potential causes 1

Mandatory Laboratory Evaluation for Moderate-to-Severe Fatigue

For all patients with fatigue scores ≥4, obtain the following laboratory studies immediately 2, 3:

• Complete blood count with differential to evaluate for anemia, infection, or malignancy 2, 3
• Comprehensive metabolic panel to assess liver and kidney function, electrolyte disturbances 2, 3
• Thyroid-stimulating hormone (TSH) to rule out hypothyroidism 2, 3
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to evaluate for inflammatory conditions 2, 3
• Creatine kinase (CK) to assess for myopathy or muscle disorders 2
• Consider HIV testing and tuberculosis screening if risk factors are present 3

Assessment of Treatable Contributing Factors

Pain Assessment

• Evaluate and treat pain effectively, as it commonly clusters with fatigue 1, 3

Emotional Distress Screening

• Screen for depression and anxiety, which frequently co-occur with fatigue 1, 3
• Consider cognitive behavioral therapy for chronic fatigue 3, 4

Sleep Disturbance Evaluation

• Assess sleep quality, quantity, and hygiene practices 1, 3
• Screen for sleep disorders such as sleep apnea or insomnia 3
• Evaluate sleep environment and pre-bedtime activities 3

Medication Review

• Review all current medications including over-the-counter drugs, herbal supplements, and vitamins 5, 3
• Note recent medication changes that might contribute to fatigue 5, 3
• Identify specific culprits: β-blockers causing bradycardia, combinations of narcotics/antidepressants/antiemetics/antihistamines causing excessive drowsiness, and statins causing myopathy 5, 2, 3
• Adjust dosage or dosing intervals as needed 5

Nutritional Assessment

• Evaluate weight changes, caloric intake, appetite, and impediments to nutritional intake 5, 3
• Check for fluid and electrolyte imbalances (sodium, potassium, calcium, iron, magnesium) 5
• Assess for vitamin D deficiency, low IGF-1, and magnesium deficiency 2
• Consider nutrition expert consultation if substantial abnormalities exist 5, 3

Activity Level and Deconditioning

• Assess changes in exercise or activity patterns and ability to accomplish normal daily activities 5, 3
• Determine current conditioning level before recommending exercise 5, 3

Substance Use

• Screen for alcohol or substance misuse that may contribute to fatigue 5, 3

Evaluation of Comorbidities

Review and optimize management of existing medical conditions that may contribute to fatigue 5, 3:

• Cardiac dysfunction (congestive heart failure, cardiomyopathy) 5
• Pulmonary disease 5
• Renal and hepatic dysfunction 5
• Neurologic disorders 5
• Endocrine dysfunction: hypothyroidism, hypogonadism, adrenal insufficiency, hypopituitarism 5, 2
• Infection 5

Special Considerations for Inflammatory and Autoimmune Conditions

When body aches accompany fatigue, consider 2:

• Polymyalgia rheumatica-like syndrome: severe proximal myalgia in upper/lower extremities with highly elevated inflammatory markers but normal CK levels 2
• Inflammatory arthritis: oligoarthritis of large joints or symmetrical polyarthritis, possibly with positive rheumatoid factor or anti-CCP antibodies 2

Imaging Studies (When Indicated)

• Chest X-ray as initial screening for pulmonary pathology if respiratory symptoms present 3
• CT scan if lymphadenopathy, organomegaly, or masses are suspected 3
• Further imaging based on specific clinical findings 3

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Considerations

If no alternative physical or psychiatric disorder explains symptoms after comprehensive evaluation, consider ME/CFS, but recognize that the most important distinguishing symptom is postexertional malaise. 4

• ME/CFS requires severe fatigue lasting >6 months plus ≥4 of the following: postexertional malaise, unrefreshing sleep, impaired memory/concentration, muscle pain, polyarthralgia, sore throat, tender lymph nodes, or new headaches 6
• Critical pitfall: Exercise can be harmful to ME/CFS patients because it triggers postexertional malaise—these patients should pace activity rather than follow graded exercise programs 2, 4
• ME/CFS is a diagnosis of exclusion made only when other disease processes are excluded 6, 7

Treatment Algorithm

Step 1: Treat Identified Underlying Causes

• Correct anemia, electrolyte disturbances, and endocrine abnormalities 2
• Manage depression with antidepressants 2
• Address sleep disorders with cognitive behavioral therapy for insomnia 2

Step 2: Inflammatory Conditions Require Specific Treatment

• Initiate prednisone 40 mg daily or equivalent for polymyalgia-like syndrome 2
• Use NSAIDs, corticosteroids, and disease-modifying antirheumatic drugs for inflammatory arthritis 2

Step 3: Non-Pharmacological Interventions

• Implement structured physical activity with gradual increase in intensity, except in ME/CFS patients 2, 3
• Use cognitive behavioral therapy, mindfulness-based stress reduction, and energy conservation techniques 2
• Implement good sleep hygiene practices 3

Step 4: Pharmacological Interventions for Persistent Fatigue

• Use corticosteroids for short-term use in advanced cancer or severe inflammatory conditions 2
• Target specific symptoms with antidepressants or sleep aids 2

Step 5: Ongoing Monitoring

• Reassess fatigue severity at every visit using the same numeric scale 2, 3
• Adjust management strategies based on response and clinical status changes 2, 3

Common Pitfalls to Avoid

• Do not overlook medication side effects as potential contributors to fatigue 1, 3
• Do not prescribe exercise to patients with ME/CFS, as it can worsen postexertional malaise 2, 4
• Do not assume fatigue occurs in isolation—it frequently clusters with pain, depression, and sleep disturbances 1, 3
• Do not fail to screen for occult malignancy in elderly patients with persistent fatigue 3