What are the differential diagnoses for a non-smoker with severe limb pain and recent febrile illness?

Differential Diagnoses for Severe Limb Pain Following Febrile Illness in a Non-Smoker

In a non-smoker with severe bilateral limb pain, inability to move limbs due to pain, and recent febrile illness, the primary differential diagnoses are post-infectious inflammatory conditions (reactive arthritis, post-infectious myositis), infectious myositis/pyomyositis, tuberculous arachnoiditis, deep vein thrombosis with venous vasculitis, and acute limb ischemia from embolic sources (particularly cardiac).

Immediate Life-Threatening Considerations

Acute Limb Ischemia

• Cardiac embolism is the most common cause of acute limb ischemia, particularly in patients with atrial fibrillation, and emboli typically lodge at arterial bifurcation points causing profound ischemia 1
• The classic presentation includes the "5 Ps": pain, paralysis, paresthesias, pulselessness, and pallor—though this patient lacks documented sensory loss or upper motor neuron signs, severe pain on passive movement suggests threatened limb viability 2
• Critical pitfall: In non-smokers without atherosclerotic disease, consider cardiac sources (atrial fibrillation, patent foramen ovale, ventricular dysfunction) or proximal arterial aneurysms as embolic sources 3, 1
• Immediate systemic anticoagulation is mandatory even before definitive diagnosis, as low-flow states encourage thrombus propagation 1

Deep Vein Thrombosis with Complications

• DVT must be excluded immediately using proximal compression ultrasound of common femoral and popliteal veins 4
• Venous vasculitis can present with severe febrile lower limb pain and major wall swelling of proximal deep veins, confirmed by color Doppler ultrasound showing unilateral halo sign 5
• Bilateral involvement with severe pain suggests possible vena cava thrombosis, which can present with massive pain, congestion, and daily fever up to 39.5°C 6

Post-Infectious/Inflammatory Conditions

Infectious Myositis and Pyomyositis

• Pyomyositis complicating dengue hemorrhagic fever presents with persistent fever and severe limb pain, with multiple intramuscular hematomas requiring 6 weeks of antibiotics and aspiration 7
• Prolonged fever with severe musculoskeletal pain and focal tenderness warrants radiographic testing (ultrasonography or MRI) to differentiate hematoma, myositis, or pyomyositis 7
• Systemic antibiotics should be initiated promptly if infection is suspected with evidence of limb involvement 3

Tuberculous Arachnoiditis

• Disseminated tuberculosis with tuberculous arachnoiditis can present with severe pain over bilateral lower and upper limbs following low-grade fever, progressing to bed-ridden state 8
• Key features include severe neck rigidity, generalized tenderness, generalized hyperalgesia, hyporeflexia, and bilateral extensor plantar response 8
• MRI brain and spine shows enhancement and clumping of nerve roots in conus and cauda equina; CECT chest may reveal necrotic mediastinal lymph nodes 8
• Treatment requires ATT, pulse methylprednisolone followed by maintenance oral corticosteroids 8

Systemic Inflammatory/Autoimmune Conditions

Still's Disease (Adult-Onset Still's Disease)

• Alternative diagnoses such as malignancies, infectious diseases, other immune-mediated inflammatory diseases should be carefully considered in patients with fever and limb pain 3
• Highly elevated levels of IL-18 and S100 proteins (serum calprotectin) can identify Still's disease with high sensitivity and specificity 3
• Critical consideration: Glucocorticoids or immunomodulating agents are potentially deleterious if Still's disease is misdiagnosed, particularly in presence of malignancies or infections 3

Inflammatory Myopathies

• Idiopathic inflammatory myopathies can present with proximal muscle weakness and pain, though typically not as acute as described 3
• Anti-SRP antibody-associated necrotizing myopathy presents acutely with poor response to standard immunosuppression 3
• EMG and muscle biopsy are essential to confirm myopathic process and differentiate inflammatory from noninflammatory myopathy 3

Diagnostic Algorithm

Initial Urgent Evaluation

1. Vascular assessment: Check bilateral pulses, capillary refill, skin temperature, and color; perform ankle-brachial index if feasible 3, 9
2. Immediate anticoagulation: If acute limb ischemia suspected based on history and physical examination, administer heparin and obtain vascular surgery consultation 9
3. DVT exclusion: Proximal compression ultrasound of bilateral lower extremities; if positive, initiate DVT treatment immediately 4
4. Infection markers: CBC with differential, ESR, CRP, blood cultures if febrile 3

Secondary Investigations Based on Initial Findings

• If vascular compromise suspected: CT angiography or conventional angiography to identify embolic or thrombotic occlusion 3, 9
• If infection suspected: Ultrasound or MRI of affected limbs to identify abscess, pyomyositis, or muscle hematoma 7
• If neurologic signs present: MRI brain and spine with contrast to evaluate for arachnoiditis; consider CECT chest for mediastinal lymphadenopathy 8
• If systemic inflammation suspected: IL-18, S100 proteins (calprotectin), ferritin, autoantibody panel including anti-synthetase antibodies 3

Critical Pitfalls to Avoid

• Never assume "just musculoskeletal pain" without excluding DVT when bilateral limb involvement and recent fever are present 4
• Do not delay anticoagulation if acute limb ischemia is suspected—prompt systemic anticoagulation prevents thrombus propagation regardless of embolic versus thrombotic etiology 1
• In non-smokers, cardiac evaluation is mandatory to identify embolic sources (echocardiography, ECG for atrial fibrillation) 3, 1
• Patients at risk who develop acute limb symptoms represent potential vascular emergencies and should be assessed immediately by a specialist competent in treating vascular disease 3
• Fever with limb pain may represent infection requiring urgent surgical consultation for drainage or debridement, especially if abscess or necrotizing infection suspected 3
• Tuberculous arachnoiditis requires high index of suspicion in endemic areas or immunocompromised patients, as delayed diagnosis leads to permanent neurologic damage 8