What is the likely cause of fatigue in a patient with a past Epstein‑Barr virus infection, elevated vitamin D, normal calcium, and elevated vitamin B12 levels?

Post-Viral Fatigue Following EBV Infection with Abnormal Laboratory Values

The fatigue in this patient is most likely post-infectious fatigue syndrome following EBV infection, potentially meeting criteria for post-acute sequelae of viral infection (PASC-like syndrome) or chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), while the elevated vitamin B12 and vitamin D levels are likely incidental findings unrelated to the fatigue etiology. 1, 2

Understanding the Clinical Picture

The constellation of past EBV infection with persistent fatigue represents a well-documented post-infectious syndrome. Post-infectious fatigue following EBV can persist for 2 years or more, characterized by weakness and fatigue in the absence of significant physical findings or laboratory abnormalities. 3 This patient's presentation aligns with established patterns:

• Approximately 30% of patients with documented EBV infection report persistent fatigue at 6 months post-infection, similar to patterns seen in other post-viral syndromes 1
• The fatigue mechanism involves mitochondrial dysfunction, altered fatty acid metabolism, and persistent immune activation even after viral clearance 4, 2
• Gene expression studies show alterations in mitochondrial function genes including those affecting fatty acid metabolism and cell cycle regulation in patients who develop post-EBV fatigue 4

Evaluating the Laboratory Abnormalities

Elevated Vitamin D

The elevated vitamin D is not causally related to fatigue—in fact, vitamin D deficiency (not elevation) is typically associated with fatigue. This finding is likely incidental or reflects supplementation. [@General Medicine Knowledge]

Elevated Vitamin B12

Similarly, elevated B12 levels do not cause fatigue and are commonly seen with supplementation or certain dietary patterns. While very high B12 can occasionally indicate myeloproliferative disorders or liver disease, these would present with additional clinical features beyond isolated fatigue. [@General Medicine Knowledge]

Normal Calcium

This effectively rules out hypercalcemia as a fatigue contributor. [@General Medicine Knowledge]

Diagnostic Considerations for Post-EBV Fatigue

Consider whether this patient meets criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which requires:

• Substantial functional impairment lasting >6 months [@8@]
• Profound fatigue not alleviated by rest [@8@]
• Postexertional malaise (worsening after physical or cognitive exertion) 1
• Unrefreshing sleep [@8@]
• Either orthostatic intolerance or cognitive impairment 1

Assess for autonomic dysfunction, specifically Postural Orthostatic Tachycardia Syndrome (POTS):

• Heart rate increase >30 beats per minute after 5-10 minutes of standing without orthostatic hypotension [@8@]
• Associated symptoms include palpitations, lightheadedness, weakness, and exercise intolerance [@5@]
• In one study, 42% of POTS cases were preceded by viral infection 2

Pathophysiologic Mechanisms

The fatigue likely stems from multiple interconnected mechanisms:

• Persistent immune activation with elevated inflammatory markers including interleukin-1 receptor antagonist and soluble TNF receptor II [@7@]
• Mitochondrial dysfunction affecting energy metabolism, particularly impaired fatty acid metabolism [@10@, 2]
• Subtle autonomic dysregulation with sympathetic predominance over parasympathetic tone [@11@]
• Possible herpesvirus reactivation as EBV and other herpesviruses are associated with chronic fatigue states [@1@, 2]

Notably, laboratory markers in post-EBV fatigue patients show only subtle alterations: slightly elevated C-reactive protein (0.48 vs 0.43 mg/L), higher total T cell counts, and elevated plasma catecholamines [@11@]

Management Approach

Initial Assessment

• Evaluate for postexertional malaise specifically—ask about symptom worsening 12-48 hours after physical or cognitive exertion [@8@]
• Perform orthostatic vital signs: measure heart rate and blood pressure supine, then after 5-10 minutes of standing [@8@]
• Screen for depression and anxiety, which commonly coexist but do not fully explain the fatigue [@11@, @9@]

Treatment Strategy

Critical: Do NOT prescribe standard exercise programs or graded exercise therapy if postexertional malaise is present, as physical activity worsened the condition in 75% of Long COVID patients with similar presentations. [@8@]

For patients with orthostatic intolerance or POTS features:

• Aggressive hydration: 3 liters of water or electrolyte-balanced fluids daily [@8@]
• Increase salt intake to 5-10 grams per day [@8@]
• Waist-high compression stockings [@8@]
• Elevate head of bed with 4-6 inch blocks 1
• Low-dose beta-blockers or nondihydropyridine calcium-channel blockers titrated to control excessive tachycardia 1
• Consider fludrocortisone up to 0.2 mg at night combined with salt loading, or midodrine 2.5-10 mg for orthostatic symptoms 1

For general fatigue management:

• Minimize upright activity during acute symptom flares [@8@]
• Avoid complete bedrest as this worsens deconditioning 1
• Provide emotional support, reassurance, and explanation of the condition [@9@]
• Consider physical therapy consultation for reconditioning protocols only if postexertional malaise is absent [@3@]

Common Pitfalls

• Do not attribute the fatigue to the elevated vitamin D or B12—these are not causative [@General Medicine Knowledge]
• Do not assume psychological etiology alone, though psychological susceptibility may influence symptom expression 3
• Do not order extensive EBV viral load testing or antibody panels repeatedly—chronic active EBV infection (CAEBV) is rare and requires >102.5 copies/mg DNA in peripheral blood mononuclear cells plus specific clinical features like fever, lymphadenopathy, or hepatosplenomegaly 2
• Recognize that standard diagnostic tests may appear normal despite significant functional impairment 2, 5

Prognosis

Post-infectious fatigue following EBV typically persists for 2 years or more but may eventually resolve. 3 However, some patients develop chronic symptoms meeting ME/CFS criteria. The illness pattern can be persistent or relapsing. 3