What work‑up and differential diagnosis are appropriate for a 19‑year‑old with profound fatigue and generalized weakness after a viral illness, normal complete blood count, comprehensive metabolic panel, thyroid‑stimulating hormone, creatine kinase, erythrocyte sedimentation rate, C‑reactive protein, and adrenocorticotropic hormone, positive antinuclear antibody 1:160 with negative extractable nuclear antigen panel, past Epstein‑Barr virus infection (viral capsid antigen IgG positive, IgM negative), and meeting criteria for fibromyalgia?

Post-Viral Fatigue and Weakness: Diagnostic Approach

Primary Diagnosis: Post-Viral Fatigue Syndrome with Possible ME/CFS

This 19-year-old most likely has post-viral fatigue syndrome following a recent viral illness, with features overlapping myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and the workup should now focus on excluding cardiac involvement, evaluating for dysautonomia, and screening for malignancy given the positive ANA. 1

Critical Next Steps in Workup

Immediate Cardiac Evaluation (Priority #1)

• Obtain troponin and 12-lead ECG immediately to exclude myocarditis, which can present with profound fatigue and normal CK but carries significant mortality risk 2
• Consider echocardiogram if any cardiac symptoms, palpitations, or chest discomfort are present 1
• Post-viral myocarditis can occur with normal inflammatory markers and must be ruled out before attributing symptoms solely to fatigue syndrome 1

Autonomic Testing (Priority #2)

• Perform 3-minute active stand test (or 10-minute if postural tachycardia suspected): measure lying and standing blood pressure and heart rate to evaluate for postural orthostatic tachycardia syndrome (POTS) or orthostatic hypotension 1
• Up to 75% of ME/CFS patients have orthostatic intolerance, and this is a cardinal feature that guides management 1
• Document presence of postexertional malaise (PEM)—worsening of symptoms 12-48 hours after minimal physical or cognitive exertion—as this is the hallmark of ME/CFS and occurs in approximately 50% of post-viral fatigue patients 1

Additional Laboratory Testing

• Cortisol level (8 AM): Low cortisol without compensatory ACTH elevation suggests hypothalamic-pituitary-adrenal axis dysfunction, documented in long COVID and ME/CFS patients more than 1 year into illness 1
• Complete muscle enzyme panel: Although CK is normal, obtain aldolase, AST, ALT, and LDH to definitively exclude inflammatory myopathy, as hypomyopathic dermatomyositis can present with normal CK 3, 2
• Vitamin D, B12, ferritin: Common deficiencies that exacerbate fatigue 1
• Repeat ESR/CRP if not recently checked, as these can fluctuate 1

Imaging

• Chest X-ray: Obtain if not already done and respiratory symptoms persist, though normal imaging does not exclude post-viral pulmonary involvement 1

Differential Diagnosis Analysis

Most Likely: Post-Viral Fatigue/ME/CFS

• Profound fatigue following viral illness lasting >4 weeks is characteristic of post-viral fatigue syndrome 1, 4
• The EBV serology (IgG positive, IgM negative) indicates past infection, not acute or reactivated disease, and does not explain current symptoms 5, 6
• Historical studies show EBV serologies have little clinical usefulness in evaluating chronic fatigue, with no consistent differences between fatigued patients and controls 5, 6
• Meeting fibromyalgia criteria is common in ME/CFS, as both conditions share central sensitization mechanisms 1

Low Probability but Must Exclude:

Inflammatory Myopathy (Dermatomyositis/Polymyositis)

• Normal CK makes typical inflammatory myopathy unlikely, but hypomyopathic dermatomyositis can present with normal or minimally elevated CK 3, 7
• The positive ANA at 1:160 with negative ENA is non-specific but warrants consideration of autoimmune disease 7
• Key distinguishing features to assess: Look for Gottron's papules, heliotrope rash, periungual telangiectasias, V-sign, shawl sign, or mechanic's hands on careful skin examination 7
• If any rash present or aldolase elevated, proceed to MRI of thigh muscles and consider muscle biopsy 7, 2

Systemic Lupus Erythematosus or Other Connective Tissue Disease

• ANA 1:160 is a low titer and can occur in healthy individuals (5-10% of population) 7
• Negative ENA panel makes SLE, Sjögren's, and mixed connective tissue disease less likely
• Monitor for development of specific symptoms: malar rash, photosensitivity, oral ulcers, serositis, arthritis, renal involvement 7
• Do not pursue further rheumatologic workup unless new symptoms develop

Occult Malignancy

• Age 19 makes malignancy unlikely, but dermatomyositis (if present) has strong cancer association, particularly in patients >40 years 7
• Given young age and absence of dermatomyositis features, defer comprehensive cancer screening unless constitutional symptoms worsen or new findings emerge 7

Endocrine Disorders

• TSH and ACTH normal, but consider 8 AM cortisol as noted above 1
• If cortisol low without elevated ACTH, this supports central HPA axis dysfunction seen in ME/CFS rather than primary adrenal insufficiency 1

Management Framework

If Cardiac and Dysautonomia Testing Normal:

Diagnosis: Post-Viral Fatigue Syndrome/ME/CFS

• Provide education and validation: Explain that post-viral fatigue is a recognized medical condition with biological basis, not psychological weakness 1
• Emphasize pacing and energy envelope theory: Avoid pushing through fatigue, as this worsens PEM and prolongs recovery 1
• Medical documentation: Provide work/school excuse as protracted fatigue is justified medical reason for reduced activity 1
• Avoid deconditioning trap: Once acute phase resolves (typically several months), refer to physical therapy for gradual reconditioning protocol specifically designed for post-viral fatigue, not standard exercise programs 1
  • Standard graded exercise therapy can worsen ME/CFS; PT must understand PEM and use adaptive pacing 1
• Symptom journal: Have patient track daily symptoms to recognize gradual improvement that may not be apparent day-to-day 1
• Monitor for improvement: Reassess every 2-4 weeks initially, then monthly 1
• Expected timeline: Most post-viral fatigue improves over 6-24 months, though some patients develop chronic ME/CFS 1, 8

If Dysautonomia Confirmed:

• Increase fluid intake to 2-3 liters daily and salt intake to 6-10 grams daily 1
• Consider compression stockings 1
• Pharmacologic management (fludrocortisone, midodrine, beta-blockers) if non-pharmacologic measures insufficient 1

Red Flags Requiring Urgent Re-evaluation:

• Development of ascending weakness (Guillain-Barré syndrome) 1
• Chest pain, palpitations, syncope (myocarditis) 1, 2
• Fever, weight loss, night sweats (malignancy, systemic disease) 1
• New rash (dermatomyositis) 7
• Worsening weakness with rising CK (delayed-onset inflammatory myopathy) 3, 2

Common Pitfalls to Avoid

• Do not attribute all symptoms to fibromyalgia and stop investigating: Fibromyalgia is a clinical diagnosis of exclusion and frequently overlaps with other conditions 1
• Do not order repetitive EBV serologies: Past EBV infection (IgG+/IgM-) is present in >90% of adults and does not indicate active disease or explain chronic fatigue 5, 6
• Do not miss cardiac involvement: Post-viral myocarditis can be subtle and fatal if unrecognized 1, 2
• Do not prescribe graded exercise therapy without understanding PEM: Standard exercise programs can severely worsen ME/CFS patients 1
• Do not dismiss patient concerns as "just depression": While psychiatric comorbidity is common (>50%), this does not negate the biological basis of post-viral fatigue 1, 6
• Do not rely solely on normal CK to exclude myositis: Hypomyopathic variants exist 3, 7