What is the approach to a comprehensive fatigue workup in a patient with persistent and unexplained fatigue, considering their demographic and medical history, including chronic medical conditions, mental health conditions, and medications?

Fatigue Workup: A Structured Approach

Initial Screening and Severity Assessment

Begin by quantifying fatigue severity using a 0-10 numeric rating scale over the past 7 days, where 0 = no fatigue and 10 = worst fatigue imaginable. 1, 2

• Scores 0-3 (mild fatigue): Provide basic education about fatigue management strategies and rescreen at regular intervals—no further workup needed 3, 1
• Scores 4-6 (moderate fatigue): Proceed immediately to focused evaluation 3, 1
• Scores 7-10 (severe fatigue): Indicates marked functional impairment requiring urgent comprehensive workup 1, 4

Focused History: Key Elements to Assess

When fatigue scores ≥4, obtain these specific details:

Symptom Characteristics:

• Onset timing, pattern, duration, and changes over time 2
• Presence of "B symptoms": fever, drenching night sweats, unintentional weight loss >10% over 6 months 4
• Associated symptoms: pain, pulmonary complaints, postexertional malaise 3, 4

Contributing Factors (Most Common Causes):

• Sleep disturbances: Assess quantity, quality, sleep hygiene behaviors, and screen time before bed 2, 5
• Depression and anxiety: Present in 18.5% of persistent fatigue cases 5
• Medications: Complete review including prescriptions, over-the-counter drugs, herbal supplements, and vitamins 1, 2
• Alcohol and substance use 1, 4
• Psychosocial stress and life circumstances 5

Special Populations:

• For new immigrants: Document country of origin and regions visited to assess tropical disease exposure 4

Physical Examination: Targeted Findings

Focus on these specific elements rather than a general examination:

• Lymph node assessment for lymphadenopathy 1, 4
• Hepatosplenomegaly evaluation 1, 4
• Skin manifestations 4
• Cardiopulmonary and neurologic examination 6

Laboratory Workup: Selective Testing

Initial screening tests (order for all patients with fatigue scores ≥4):

• Complete blood count with differential 1, 4, 2
• Comprehensive metabolic panel 1, 4, 2
• Thyroid-stimulating hormone 1, 4, 2
• Erythrocyte sedimentation rate and C-reactive protein 1, 4, 2

Additional testing based on clinical context:

• For new immigrants: Malaria testing, tuberculosis screening, HIV testing, schistosomiasis serology, dengue serology, enteric fever blood cultures, rickettsial serology 4
• Nutritional assessment if dietary deficiencies suspected 2

Important caveat: Laboratory results affect management in only 5% of patients, and if initial results are normal, repeat testing is generally not indicated 7. Previously undiagnosed cancer accounts for only 0.6% of fatigue cases 5.

Imaging Studies: Only When Red Flags Present

Do not routinely order imaging. Reserve chest X-ray, CT chest/abdomen/pelvis with contrast, or PET/CT only when red flags are present, such as:

• B symptoms (fever, night sweats, significant weight loss) 4
• Abnormal physical examination findings 1, 4
• Concerning laboratory abnormalities 1

Treatment Approach: Evidence-Based Interventions

Regardless of the underlying cause, initiate a structured physical activity program as a Category 1 recommendation:

• Stretching and aerobic exercise (such as walking) 2-3 times weekly for 30-60 minutes 1, 2, 7
• This improves functional capacity, decreases anxiety and depression, and increases activity tolerance 3

Exception: Do not prescribe exercise for patients meeting criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), as it can trigger postexertional malaise and cause harm 6

Treat identified contributing factors:

• Sleep disorders: Cognitive behavioral therapy for insomnia and sleep hygiene optimization 2
• Depression/anxiety: Selective serotonin reuptake inhibitors (fluoxetine, paroxetine, or sertraline) 7
• Anemia: Appropriate treatment per guidelines 3
• Hypothyroidism: Levothyroxine 3
• Pain: Effective pain management strategies 2
• Nutritional deficiencies: Appropriate supplementation 2

Avoid ineffective treatments:

• Do not prescribe psychostimulants or dietary supplements—they lack efficacy for fatigue management 1, 4
• Methylphenidate may provide some benefit but evidence remains limited 3

Follow-Up Strategy

Schedule regular follow-up visits rather than sporadic urgent appointments for effective long-term management 7:

• Rescreen fatigue severity at each visit 3
• If diagnosis remains unclear after initial workup, pursue watchful waiting with regularly scheduled follow-up rather than extensive additional testing 1, 2, 5
• This approach prevents overdiagnosis and excessive focus on somatic causes 5

Key pitfall to avoid: Fatigue symptoms can persist for 6-12 months after completion of cancer therapy and do not warrant extensive workup unless other symptoms develop or fatigue worsens during this period 3