What is the next step in managing a patient with severe knee pain 2 years after knee replacement, elevated C-Reactive Protein (CRP), normal White Blood Cell (WBC) count, and no signs of infection?

Diagnostic Workup for Suspected Periprosthetic Joint Infection

Proceed immediately with joint aspiration for synovial fluid analysis (cell count with differential and culture) to definitively rule out or confirm periprosthetic joint infection, as this is the most critical next step given the elevated CRP at 2 years post-surgery. 1, 2

Why Joint Aspiration is Essential Now

Your patient's presentation—severe knee pain 2 years after TKA with elevated CRP but normal WBC—is a classic scenario for chronic/late periprosthetic joint infection (PJI), which occurs in 21.9% of revisions performed >2 years after initial surgery. 1 The key diagnostic challenge here is that:

• Peripheral WBC counts are NOT elevated in most patients with infected prostheses, making your normal WBC count meaningless for excluding infection. 1
• CRP has 73-91% sensitivity and 81-86% specificity for prosthetic knee infection when using a cutoff of 13.5 mg/L, and since CRP returns to baseline within 2 months after surgery under normal circumstances, any elevation at 2 years is highly concerning. 1
• Pain is the most common presenting symptom of infection, though it's nonspecific; chronic infections may manifest with pain alone without fever, erythema, or warmth. 1

The Diagnostic Algorithm

Step 1: Joint Aspiration (Do This Now)

Withhold antibiotics for at least 2 weeks prior to aspiration if clinically feasible to avoid false-negative cultures. 2

The aspiration should include:

• Synovial fluid WBC count and differential - This is the single most precise test with 100% sensitivity, 98% specificity, and 99% accuracy when WBC >3,000 cells/μL. 3
• Synovial fluid culture - Critical for identifying causative organisms (most commonly Staphylococcus aureus and coagulase-negative Staphylococcus). 1
• Synovial fluid alpha-defensin - Provides 97% sensitivity and 96% specificity; when combined with synovial CRP, sensitivity remains 97% with specificity increasing to 100%. 2

Step 2: Obtain Additional Serum Markers

While arranging aspiration, obtain:

• ESR and CRP together - The AAOS strongly recommends using both markers. 1 When at least 2 of 3 tests (CRP >0.93 mg/L, ESR >27 mm/h, and fibrinogen >432 mg/dL) are abnormal, diagnostic accuracy reaches 93% sensitivity, 100% specificity, and 97% accuracy. 1
• Interleukin-6 - Provides higher predictive value than most other serologic markers and shows excellent sensitivity when combined with CRP. 1, 2

Step 3: Imaging

Obtain radiographs first as the initial imaging evaluation, looking for signs of loosening, osteolysis, or component migration that may accompany infection. 1

Critical Cutoff Values at 2 Years Post-Surgery

Since your patient is well beyond the 12-week postoperative window, use these thresholds:

• Synovial WBC ≥1,983 cells/μL suggests infection (80% sensitivity, 85% specificity). 4
• Synovial neutrophils ≥76% suggests infection (80% sensitivity, 81% specificity). 4
• Absolute neutrophil count ≥1,684 cells/μL suggests infection (80% sensitivity, 87% specificity). 4
• CRP ≥34 mg/L suggests infection (90% sensitivity, 93% specificity). 4

Important Clinical Pearls

Night pain or pain at rest is characteristic of infection, whereas pain on weight-bearing suggests mechanical loosening—ask specifically about pain patterns. 1

A large multicenter study found CRP and joint aspiration to be the most useful tools for diagnosing infection, making your combination approach optimal. 1

Do not rely on the absence of fever, erythema, or warmth to exclude infection—chronic infections frequently present with pain alone. 1

Alternative Diagnoses to Consider

If infection is definitively ruled out after comprehensive workup:

• Metal hypersensitivity/synovitis can present with persistent pain, elevated inflammatory markers, and hypertrophic synovitis despite negative infection workup; histopathology would show lymphocytic or histiocytic monocellular response. 5
• Aseptic loosening typically presents with pain on weight-bearing rather than at rest. 1
• Component malposition or instability should be assessed on radiographs and physical examination. 1