What additional investigations and differential diagnoses should be considered for a 61-year-old man with multiple sclerosis who presents with diffuse myalgias, fatigue, worsening cough, normal complete blood count and basic metabolic panel, negative COVID‑19 and influenza tests, clear chest radiograph, urinalysis showing protein, 2+ blood and elevated bilirubin, and pending creatine kinase level?

Workup and Differential Diagnosis for 61-Year-Old MS Patient with Myalgias, Fatigue, and Abnormal Urinalysis

Order a comprehensive metabolic panel, liver function tests, aldolase, myoglobin, and urinary myoglobin immediately, and strongly consider repeating COVID-19 testing given the clinical picture of possible viral-induced rhabdomyolysis despite initial negative results.

Immediate Additional Laboratory Testing

Essential tests to order now:

• Comprehensive metabolic panel (if not already complete) to assess renal function, electrolytes, and calcium—critical for evaluating rhabdomyolysis complications 1
• Liver function tests (AST, ALT, LDH)—elevated transaminases often accompany muscle injury and help differentiate hepatic from muscle sources of elevated CK 1
• Aldolase—more specific for muscle injury than CK alone and helps confirm myositis 2
• Serum and urine myoglobin—direct markers of muscle breakdown; urine myoglobin causes the elevated bilirubin and blood on urinalysis without RBCs 1
• Inflammatory markers (ESR, CRP)—elevated in inflammatory myopathies and severe viral infections 2, 3
• Repeat SARS-CoV-2 testing (PCR and/or antigen)—COVID-19 can present with isolated myalgias and elevated CK without respiratory symptoms initially 1

Secondary priority tests:

• Thyroid function tests (TSH, free T4)—hypothyroidism causes myopathy with elevated CK 2
• Vitamin D level—deficiency associated with myalgias and weakness
• Influenza PCR (if rapid test was used initially)—influenza causes hyperCKemia in 28% of hospitalized patients 3

Primary Differential Diagnosis

1. Viral-Induced Rhabdomyolysis (Most Likely)

COVID-19 remains high on the differential despite negative testing. Rhabdomyolysis can be the sole initial presentation of SARS-CoV-2 infection with no respiratory symptoms, and patients may have bilateral infiltrates on chest X-ray with isolated weakness and elevated CK 1. The combination of body aches, fatigue, proteinuria, hematuria (from myoglobinuria), and elevated bilirubin (from myoglobin breakdown) strongly suggests muscle injury 1.

• HyperCKemia occurs in 27% of hospitalized COVID-19 patients and correlates with disease severity and inflammatory markers 3
• Influenza causes similar presentations with hyperCKemia in 28% of cases, often with higher CK levels than COVID-19 3
• Consider repeat COVID-19 testing as initial tests can be falsely negative, especially early in infection 1

2. Drug-Induced Myopathy

Although the patient reports no daily medications, specifically inquire about:

• Recent statin use (even if discontinued)—statins are the most common cause of drug-induced myopathy 2
• Over-the-counter medications, supplements, or herbal products
• Any recent medication changes or exposures 2

3. Inflammatory Myositis

• Polymyositis or dermatomyositis can present with proximal muscle weakness, elevated CK, and systemic symptoms 2
• Order anti-Jo-1, anti-Mi-2, and anti-SRP antibodies if CK is markedly elevated (>1000 U/L) 2
• Consider EMG and muscle biopsy if CK remains elevated without clear viral etiology 2

4. MS Exacerbation vs. Pseudoexacerbation

• Infections trigger MS exacerbations in 57% of cases, with new symptoms developing during viral illness 4
• However, true MS relapses do not cause elevated CK or myoglobinuria—this presentation suggests concurrent pathology 5, 6
• The clear chest X-ray argues against typical MS-related respiratory complications 6

5. Hypothyroid Myopathy

• Can present with myalgias, fatigue, elevated CK, and generalized weakness
• More common in patients with autoimmune conditions like MS

6. Paraneoplastic Syndrome

• Consider in a 61-year-old with new-onset myopathy
• Order paraneoplastic antibody panel (ANNA-1, anti-CRMP5) if other causes excluded 2

Critical Diagnostic Pitfalls to Avoid

Do not assume negative COVID-19 and influenza tests exclude viral infection. COVID-19 can present with isolated rhabdomyolysis and elevated CK as the sole initial manifestation, with respiratory symptoms developing later or not at all 1. The presence of bilateral infiltrates on chest X-ray despite lack of respiratory symptoms is consistent with this presentation 1.

Do not attribute all symptoms to MS exacerbation. While infections can trigger MS symptoms, the combination of elevated urinary bilirubin, hematuria (likely myoglobinuria), and pending elevated CK indicates acute muscle injury that is not explained by MS pathophysiology alone 5, 4, 6.

Myoglobinuria appears as "blood" on urinalysis dipstick but shows few or no RBCs on microscopy—this is the key to recognizing rhabdomyolysis 1. The elevated bilirubin represents myoglobin breakdown products 1.

Immediate Management Considerations

While awaiting CK results:

• Aggressive IV hydration if CK is elevated to prevent acute kidney injury from myoglobin precipitation 1
• Monitor renal function closely—rhabdomyolysis can rapidly progress to acute renal failure 1
• Avoid nephrotoxic agents until rhabdomyolysis is excluded 1
• Repeat COVID-19 testing given high clinical suspicion despite initial negative result 1

Follow-Up Testing Based on CK Level

If CK >1000 U/L:

• Admit for IV hydration and renal monitoring 1
• Order autoimmune myositis panel 2
• Consider EMG and muscle biopsy if no viral etiology identified 2

If CK 200-1000 U/L:

• Outpatient management possible with close follow-up
• Repeat CK in 24-48 hours to assess trend 3
• Continue diagnostic workup for underlying cause 3

If CK normal or mildly elevated (<200 U/L):

• Reconsider diagnosis
• Evaluate for other causes of proteinuria and hematuria
• Consider MS-related complications or alternative diagnoses 5, 6