What is the differential diagnosis for a 19-year-old patient with extreme fatigue, weakness, and weight loss after a viral illness, with normal hemoglobin (Hgb) and platelet counts?

Differential Diagnosis for Post-Viral Fatigue, Weakness, and Weight Loss in a 19-Year-Old

The most likely diagnosis is post-acute sequelae of viral infection (PASC/Long COVID if COVID-19, or post-viral chronic fatigue syndrome if another virus), with the normal hemoglobin and platelet counts effectively ruling out acute hematologic malignancy, severe anemia, or thrombocytopenia-related disorders. 1

Primary Diagnostic Considerations

Post-Acute Sequelae of Viral Infection (PASC)

• 10-30% of individuals experience prolonged symptoms following viral infection, with fatigue being the most common manifestation 1
• The hemoglobin of 17.4 g/dL is actually elevated (normal range ~13.5-17.5 g/dL for males, ~12-16 g/dL for females), which may suggest dehydration from weight loss rather than anemia 2
• Platelet count of 159,000/μL is within normal range (150,000-400,000/μL), making thrombocytopenia-related conditions unlikely 2
• Consider PASC when symptoms persist beyond 4 weeks after acute infection, rather than waiting 12 weeks 1

Key Mechanistic Features to Assess

• Deconditioning occurs rapidly after viral illness, resulting in compensatory tachycardia, reduced stroke volume, and exercise intolerance 1
• Immune activation and inflammation persist beyond acute infection, contributing to ongoing fatigue 1
• Endothelial dysfunction, latent viral persistence, and impaired exercise metabolism may all contribute 1

Critical Differential Diagnoses to Exclude

Infectious Etiologies

• Tuberculosis reactivation: Weight loss, fatigue, and weakness are classic presenting symptoms; consider especially if any immunosuppression or endemic exposure 2
• Disseminated histoplasmosis: Presents with fever, fatigue, and weight loss in immunocompromised patients, though less likely in a previously healthy 19-year-old 2
• HIV infection: Can present with prolonged fatigue and weight loss; testing is essential in the workup 2
• Infectious mononucleosis complications: Epstein-Barr virus can cause prolonged fatigue lasting months 3

Endocrine Disorders

• Hyperthyroidism: Weight loss with fatigue and weakness; check TSH, free T4
• Adrenal insufficiency: Fatigue, weight loss, weakness; check morning cortisol and ACTH
• Type 1 diabetes mellitus: Weight loss despite normal or increased appetite; check glucose and HbA1c

Hematologic Malignancies (Lower Probability Given Labs)

• Hairy cell leukemia: Can present with fatigue and weight loss, but typically shows cytopenias (hemoglobin <11 g/dL, platelets <100,000/μL, neutropenia) 2
• The normal-to-elevated hemoglobin and normal platelet count make acute leukemia or lymphoma less likely 2

Autoimmune/Inflammatory Conditions

• Inflammatory bowel disease: Weight loss, fatigue; may have gastrointestinal symptoms 2
• Systemic lupus erythematosus: Fatigue, weight loss, multisystem involvement
• Celiac disease: Weight loss, fatigue, malabsorption

Recommended Diagnostic Workup

Essential Initial Laboratory Tests

• Complete metabolic panel: Assess for electrolyte abnormalities, renal function, liver function, and albumin (hypoalbuminemia suggests chronic illness) 2
• C-reactive protein and erythrocyte sedimentation rate: Elevated markers suggest ongoing inflammation or infection 2, 4
• TSH and free T4: Screen for thyroid dysfunction
• HIV antibody/antigen test: Essential in any patient with unexplained weight loss and fatigue 2
• Hemoglobin A1c and fasting glucose: Screen for diabetes

Additional Testing Based on Clinical Context

• Chest X-ray: Essential to exclude tuberculosis or other pulmonary pathology, especially given weight loss 2
• Tuberculin skin test or interferon-gamma release assay: If any risk factors for TB exposure 2
• Epstein-Barr virus serologies: If infectious mononucleosis suspected, though viral serologies are generally not useful for chronic fatigue evaluation 3
• Morning cortisol and ACTH stimulation test: If adrenal insufficiency suspected

Assessment for Post-Viral Syndromes

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

• Criteria include substantial functional impairment lasting >6 months with profound fatigue not alleviated by rest, postexertional malaise, unrefreshing sleep, and either orthostatic intolerance or cognitive impairment 1
• Postexertional malaise is a key distinguishing feature 1

Postural Orthostatic Tachycardia Syndrome (POTS)

• Assess for heart rate increase >30 beats per minute after 5-10 minutes of standing without orthostatic hypotension 1
• Common in post-viral syndromes and contributes to fatigue and exercise intolerance 1

Critical Pitfalls to Avoid

• Do not dismiss symptoms as "just deconditioning" without excluding serious underlying conditions 1
• Do not prescribe standard exercise programs if postexertional malaise is present, as physical activity worsened the condition in 75% of Long COVID patients 1
• A near-normal or elevated hemoglobin may actually suggest dehydration rather than reassurance 2
• Viral serologies are generally not useful in evaluating chronic fatigue and should not be routinely ordered 3
• Psychiatric morbidity and attributional style are associated with chronic post-viral fatigue, but organic causes must be excluded first 5

Management Approach if Post-Viral Syndrome Confirmed

Initial Supportive Measures

• Aggressive hydration with 3 liters of water or electrolyte-balanced fluids daily, increase salt intake to 5-10 grams per day 1
• Use waist-high compression stockings and elevate the head of the bed with 4-6 inch blocks 1
• Minimize upright activity during acute symptom flares to reduce orthostatic stress 1

Pharmacological Options

• Low-dose beta-blockers or nondihydropyridine calcium-channel blockers can be titrated to control excessive tachycardia 1
• Fludrocortisone up to 0.2 mg at night combined with salt loading can increase blood volume 1
• Midodrine 2.5-10 mg can be used for orthostatic intolerance 1

Critical Management Principle

• Exercise therapy is crucial to recovery, but standard upright exercise may worsen symptoms; avoid complete bedrest as this worsens deconditioning 1