Start with a focused history, exam, and a limited, high-yield lab panel to rule out common, reversible causes; then use symptom-directed testing.

According to American Academy of Family Physicians guidance, only about 8–12% of patients with chronic fatigue have an abnormal test that changes the diagnosis, so keep the initial workup targeted and avoid indiscriminate testing.

Essential initial steps

• History: onset/duration (6 months vs subacute), sleep quantity/quality (OSA, insomnia), mood/anxiety, pain/fibromyalgia features, post‑exertional symptom exacerbation, orthostatic intolerance, medications/substances (sedatives, antihistamines, alcohol), infection exposure, autoimmune features, weight change, fever, night sweats, cancer red flags, menstruation/pregnancy, social stressors and deconditioning.
• Physical exam: vitals including orthostatics, BMI, thyroid, HEENT (pallor, adenopathy), cardiac/pulmonary, abdominal, neurologic (focal deficits), musculoskeletal (tender points, joint swelling), skin (rashes), and mood/affect.
• Baseline labs (high yield): CBC with differential, CMP (electrolytes, renal, hepatic), TSH, fasting glucose or HbA1c, ESR and/or CRP, ferritin (especially if heavy menses or RLS), vitamin B12 as indicated, pregnancy test when relevant, urinalysis; consider HIV and hepatitis C screening based on risk. Abnormalities leading to alternate diagnoses occur in up to 8%, and any lab abnormality appears in ~12%.
• Sleep evaluation: screen for OSA (STOP-BANG) and RLS; consider home sleep test/polysomnography if indicated.
• Mental health: screen with PHQ-9/GAD-7; depression and anxiety are common and treatable contributors.

When to broaden testing

• Guided by red flags or specific syndromic clues. Examples: morning stiffness/joint swelling (ANA/RF/anti-CCP), polyuria/polydipsia (diabetes testing), heat/cold intolerance/weight change (thyroid antibodies if autoimmune suspicion), orthostasis/brain fog (POTS evaluation with active stand test/tilt), malignancy signs (age-appropriate cancer screening, imaging), chronic infection risk (TB, EBV/CMV only if acute features; routine EBV serology is low yield), celiac serology if GI symptoms or iron deficiency.

Diagnosing myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

• Consider ME/CFS when fatigue is unexplained, lasts ≥6 months, is not substantially alleviated by rest, and causes substantial activity reduction, with hallmark symptoms such as post-exertional malaise and unrefreshing sleep, plus either cognitive impairment or orthostatic intolerance, after exclusion of alternative diagnoses. Diagnosis is clinical; there is no definitive lab test.

Management pearls while workup proceeds

• Address identified contributors (sleep disorders, mood, pain, anemia/iron deficiency, thyroid disease, medication effects).
• Exercise: regular, structured physical activity improves fatigue in many chronic conditions; moderate aerobic activity (e.g., 30‑minute walk daily) has the most consistent benefit for general chronic fatigue, tailored to tolerance. For ME/CFS, emphasize activity management/pacing to avoid post‑exertional exacerbation; CBT or graded, supervised activity can be adjuncts but are not curative.
• Pharmacologic options target comorbidities: treat depression (e.g., SSRIs), pain (NSAIDs or low‑dose tricyclics at night), sleep disorders; stimulants generally lack benefit for disease‑related fatigue in most chronic conditions.

Key evidence and guidance

• Initial labs yield any abnormality in ~12% and alternate diagnoses in up to 8%, supporting a concise panel rather than broad screening.
• AAFP guidance emphasizes targeted evaluation of secondary causes and nonpharmacologic interventions (exercise therapy, CBT) across conditions; stimulants show little benefit for most disease‑related fatigue.
• For ME/CFS, diagnosis is symptom-based with exclusion; CBT and graded exercise may help some patients but are adjunctive and not curative; pacing is central to symptom control.

Follow-up

• Reassess symptoms and functional status after addressing reversible causes and initiating sleep/mood/pain management.
• If persistent, disabling fatigue with red flags or unclear diagnosis, proceed with directed testing (endocrine, inflammatory, sleep, autonomic) based on evolving findings, rather than expansive one-time panels.

Sources

1. Chronic Fatigue Syndrome: Diagnosis and Treatment – https://www.aafp.org/pubs/afp/issues/2012/1015/p741.html
2. Chronic Fatigue Syndrome – https://www.ncbi.nlm.nih.gov/books/NBK557676/
3. Fatigue: An Overview – https://www.aafp.org/pubs/afp/issues/2008/1115/p1173.html
4. Fatigue in Adults: Evaluation and Management – https://www.aafp.org/pubs/afp/issues/2023/0700/fatigue-adults.pdf
5. Chronic Fatigue Syndrome: Evaluation and Treatment – https://www.aafp.org/pubs/afp/issues/2002/0315/p1083.html