Differential Diagnosis of Fever with Joint Pain
Most Likely Diagnoses
The most likely diagnoses for a patient presenting with fever and joint pain are septic arthritis, acute rheumatic fever (ARF), and Adult-Onset Still's Disease (AOSD), with septic arthritis being the most critical to exclude immediately due to its potential for irreversible joint destruction within hours to days. 1, 2
Immediate Priority: Exclude Septic Arthritis
- Septic arthritis must be ruled out first in any patient with fever and joint pain, particularly if monoarticular involvement is present, as bacterial proliferation can cause irreversible cartilage damage within hours to days. 2, 3
- Classic presentation includes acute monoarticular joint pain, swelling, and fever, though this triad occurs in only approximately 50% of cases. 2
- Joint aspiration is the definitive diagnostic procedure and should be performed immediately without waiting for advanced imaging. 2
- Synovial fluid white blood cell count ≥50,000 cells/mm³ is highly suggestive of septic arthritis. 2
- Blood cultures should be obtained before initiating empiric antibiotics. 2
Key Laboratory Findings in Septic Arthritis
- ESR ≥40 mm/hour, WBC ≥12,000 cells/mm³, CRP >2.0 mg/dL, and fever >101.3°F increase likelihood approaching 100% when all criteria are met. 2
- In children with monoarthritis, serum WCC <12.1×10⁹/L actually suggests ARF over septic arthritis (counterintuitively lower in ARF). 4
Acute Rheumatic Fever (ARF)
- ARF should be strongly considered when fever duration exceeds 5 days with migratory polyarthritis affecting large joints. 5, 1
- Diagnosis requires evidence of preceding Group A Streptococcal infection PLUS either 2 major criteria OR 1 major + 2 minor criteria (revised Jones Criteria). 1
Major Criteria for ARF
- Carditis, polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. 1
- Migratory polyarthritis is classic, though strict migratory pattern may not always be present. 1
Minor Criteria for ARF
- Polyarthralgia, fever, elevated ESR or CRP, and prolonged PR interval on ECG. 1
Distinguishing Laboratory Features
- Children with ARF display significantly higher ESR (>64.5 mm/hour) and LOWER serum WCC (<12.1×10⁹/L) compared to septic arthritis. 4
- In children presenting with monoarthritis, ESR >64.5, WCC <12.1×10⁹/L, and age >8.5 years are independent predictors of ARF with 71% probability. 4
- 30% of ARF cases initially present with monoarthritis, making differentiation from septic arthritis critical. 4
Critical Pitfall
- Echocardiography is mandatory if ARF is suspected, as 74% of children with ARF presenting with monoarthritis had abnormal echocardiograms on admission. 4
Adult-Onset Still's Disease (AOSD)
- The classic triad of high-spiking quotidian fever (>39°C with late afternoon/evening peaks), evanescent salmon-pink maculopapular rash, and arthritis/arthralgia is 93.5% sensitive for AOSD. 1
- High-spiking quotidian fever occurs in 95.7% of AOSD cases. 1
Joint Involvement Pattern
- Symmetric polyarthritis with wrist, knee, and ankle involvement is characteristic. 1
- Wrist radiographs are specifically recommended in suspected AOSD. 1
Laboratory Findings
- Marked leukocytosis, elevated ESR and CRP, and markedly elevated ferritin with low glycosylated fraction (<20%). 1
- Ferritin >5 times the upper limit of normal with low glycosylated fraction is highly suggestive. 5, 1
Diagnostic Algorithm
Step 1: Initial Assessment
- Determine if monoarticular vs polyarticular involvement is present, as this fundamentally changes the differential diagnosis. 1, 2
- Assess fever pattern: quotidian (AOSD), persistent >5 days (ARF), or acute with single joint (septic arthritis). 1
- Examine for rash: salmon-pink evanescent rash suggests AOSD; erythema marginatum suggests ARF. 1
Step 2: Immediate Laboratory Workup
- Mandatory first-line tests: CBC with differential, ESR, CRP, and blood cultures if septic arthritis suspected. 1, 2
- Joint aspiration with synovial fluid analysis (cell count, Gram stain, culture, crystal analysis) for any monoarticular presentation. 2
- Throat culture or rapid strep test plus anti-streptolysin O (ASO) titer if ARF suspected. 5, 1
Step 3: Second-Line Testing Based on Initial Results
- If polyarticular with high fever and rash: ferritin with glycosylated fraction, ANA, rheumatoid factor. 1
- If monoarticular with fever: proceed directly to joint aspiration before any other testing. 2
- If suspected ARF: ECG and echocardiography are mandatory. 1, 4
Step 4: Imaging Studies
- Plain radiographs first to exclude fractures, tumors, and other bony pathology. 2
- Ultrasound for hip joints to detect effusions and guide aspiration. 2
- MRI with contrast when clinical suspicion remains high despite negative aspiration or concern for concurrent osteomyelitis exists. 2
Other Important Differential Diagnoses
Viral Arthritis
- Typically polyarticular and self-limited, resolving within 3 months. 1
- Common viral causes include parvovirus B19, hepatitis B, EBV, and emerging infections (Zika, chikungunya, COVID-19). 5, 3
Autoinflammatory Syndromes
- Familial Mediterranean Fever: self-limited episodes of peritonitis, pleuritis, and acute monoarthritis. 1
- TRAPS: longer fever attacks, ocular involvement, and centrifugal erythematous patches. 1
Crystal Arthropathies
- Gout and pseudogout can coexist with septic arthritis in up to 73% of reported cases, so crystal analysis does not exclude infection. 2
- Even if crystals are identified, Gram stain and culture must still be performed. 2
Critical Clinical Pitfalls to Avoid
- Never assume transient synovitis in a febrile child without first excluding septic arthritis. 2
- Negative synovial fluid culture does not exclude infection; if clinical suspicion remains high, consider percutaneous bone biopsy for concurrent osteomyelitis. 2
- 14% of children with ARF presenting with monoarthritis had received NSAIDs before hospital presentation, potentially masking symptoms. 4
- Normal radiographs do not exclude septic arthritis, as they may be completely normal in early infection (<14 days). 2
- Ultrasound may yield false-negative results if performed within 24 hours of symptom onset. 2
Management Based on Diagnosis
If Septic Arthritis Confirmed or Highly Suspected
- Immediate surgical drainage combined with empiric IV antibiotics after cultures obtained. 2
- Empiric IV vancomycin 15 mg/kg every 6 hours for MRSA coverage in adults. 2
- Oral antibiotics can be initiated after 2-4 days if patient is clinically improving, afebrile, and tolerating oral intake. 2
- Total antibiotic duration: 3-4 weeks for uncomplicated cases. 2
If Acute Rheumatic Fever Diagnosed
- Anti-inflammatory therapy with aspirin or NSAIDs for arthritis. 5
- Penicillin prophylaxis is mandatory for secondary prevention. 5