In a patient with unilateral leg swelling, erythema, a measurable fluid collection, markedly elevated C‑reactive protein and no fever, what are the likely diagnoses and how should I work up and manage it?

Unilateral Leg Swelling with Erythema, Fluid Effusion, and Elevated CRP Without Fever

The most critical first step is to obtain duplex ultrasound within 24 hours to exclude deep vein thrombosis (DVT), which presents identically with unilateral leg swelling, erythema, and elevated inflammatory markers. 1

Differential Diagnosis Priority

1. Deep Vein Thrombosis (Primary Concern)

• Unilateral leg swelling, pain, erythema, and tenderness are the classic presenting features of DVT, occurring in approximately 80%, 75%, and 26% of cases respectively 2, 3
• The presence of a measurable fluid collection does not exclude DVT; edema is the hallmark of venous obstruction 3
• Approximately one-third of DVT patients are asymptomatic or have atypical presentations, making clinical diagnosis unreliable 3
• The absence of fever is common in DVT, as systemic inflammatory response is typically absent unless complicated by septic thrombophlebitis 2

2. Cellulitis/Soft Tissue Infection

• Cellulitis presents with erythema, warmth, swelling, and tenderness with elevated CRP and ESR 1
• Fever is absent in up to 50% of soft tissue infections, even when severe 2
• Elevated CRP (>13 mg/L) significantly increases likelihood of bacterial infection, though normal white blood cell count does not exclude it 2, 1
• CRP levels distinguish infectious from inflammatory causes of erythema in leg conditions 4

3. Superficial Vein Thrombosis

• SVT presents with pain, erythema, and a palpable tender cord along the affected vein 2
• Approximately 10% of SVT cases develop DVT or pulmonary embolism within 3 months 2
• SVT and DVT occur simultaneously in a significant proportion of cases 2

Immediate Diagnostic Workup

Mandatory First-Line Testing

• Duplex venous ultrasonography of the entire affected limb within 24 hours to evaluate for DVT 2, 1
• Complete blood count with differential 2
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT) 2
• Serum creatinine and bicarbonate 2
• Blood cultures if systemic signs present (tachycardia, hypotension, altered mental status) 2

Clinical Assessment Parameters

• Measure the extent of erythema from the wound/affected area margin (>2 cm extension suggests severe infection requiring hospitalization) 2
• Assess for warmth, induration, tenderness, and purulent drainage 2
• Palpate all peripheral pulses (dorsalis pedis, posterior tibial, popliteal, femoral) 2
• Evaluate for signs of critical ischemia: dependent rubor, pallor on elevation, capillary refill >3 seconds 5
• Document presence of any skin breakdown, ulceration, or necrotic tissue 2

Management Algorithm

If DVT is Confirmed

• Initiate anticoagulation immediately per standard DVT protocols 2
• Evaluate for underlying malignancy if unprovoked DVT 2
• Assess for concurrent infection requiring antibiotics 2

If DVT is Excluded and Cellulitis is Diagnosed

Mild Cellulitis (Outpatient Management)

• Oral beta-lactams are first-line (cephalexin, dicloxacillin) in areas with low community-acquired MRSA prevalence 2, 1
• Consider trimethoprim-sulfamethoxazole or doxycycline if MRSA risk is high 2
• Mandatory reassessment within 24-48 hours to ensure clinical improvement 1

Severe Cellulitis (Hospitalization Criteria)

• Admit if systemic toxicity present: fever/hypothermia, tachycardia (>100 bpm), hypotension (SBP <90 mmHg), altered mental status 2
• Admit if CRP >13 mg/L with marked left shift or creatinine elevation 2
• Parenteral antibiotics are first choice for severe infections 1
• Obtain blood cultures and consider tissue aspiration/biopsy for Gram stain and culture 2

If Fluid Collection is Identified

• Ultrasound-guided aspiration for diagnostic purposes can differentiate cellulitis from DVT 6
• Edema fluid protein >19 g/L suggests cellulitis; <6 g/L suggests DVT 6
• Surgical consultation if abscess, compartment syndrome, or necrotizing infection suspected 2, 5

Critical Pitfalls to Avoid

• Never assume DVT is excluded based on clinical examination alone; duplex ultrasound is mandatory 2, 1
• Do not delay imaging for 24-48 hours if clinical suspicion is high; obtain ultrasound immediately 1
• Absence of fever does not exclude serious infection; up to 50% of severe soft tissue infections are afebrile 2
• Normal white blood cell count does not rule out cellulitis or DVT 2, 1
• Palpable pulses do not exclude significant arterial disease in diabetic patients or those with vascular risk factors 2, 5
• If no improvement or worsening after 24-48 hours of antibiotics, broaden coverage to include MRSA and obtain imaging to exclude deeper infection or abscess 1

Special Populations Requiring Enhanced Vigilance

Diabetic Patients

• Evaluate for diabetic foot infection if any skin breakdown present 2
• Probe-to-bone test if ulcer present (positive test has likelihood ratio of 7.2 for osteomyelitis) 2
• Assess vascular status with ankle-brachial index; ABI <0.6 indicates significant ischemia requiring urgent vascular consultation 2, 5

Patients with Lymphedema

• High prevalence and recurrence rate of cellulitis in this population 1
• Lower threshold for hospitalization due to rapid progression risk 1