What conditions should be ruled out in a patient presenting with fever and bilateral joint pain?

Differential Diagnosis for Fever with Bilateral Joint Pain

Immediate Life-Threatening Conditions to Exclude

Septic arthritis must be ruled out first in any patient with fever and joint pain, as it represents an orthopedic emergency requiring immediate intervention to prevent permanent cartilage damage. 1, 2, 3

Septic Arthritis Assessment

• Examine for monoarticular involvement initially, as septic arthritis typically affects a single joint, though polyarticular involvement can occur in immunocompromised patients or with hematogenous seeding 3
• Check for risk factors: age >80 years, diabetes mellitus, rheumatoid arthritis, recent joint surgery, prosthetic joints, skin infection, immunosuppressive medications, or intravenous drug use 3, 4
• Perform joint aspiration immediately if any single joint appears more inflamed than others—synovial fluid analysis with Gram stain and culture is mandatory before antibiotics 3
• Note that Staphylococcus aureus is the most common pathogen, but consider Neisseria gonorrhoeae in sexually active patients, Kingella kingae in children <4 years, and Salmonella in sickle cell disease 2, 3

Major Rheumatologic Syndromes to Consider

Adult-Onset Still's Disease (AOSD)

AOSD should be strongly suspected when high-spiking quotidian fever (>39°C with late afternoon/evening peaks) occurs with bilateral joint involvement, as this pattern is 95.7% sensitive for the diagnosis. 1

• Look for the classic triad: high-spiking quotidian fever, evanescent salmon-pink maculopapular rash (often appearing with fever spikes), and arthritis/arthralgia—this triad is 93.5% sensitive 1
• Examine for symmetric polyarthritis affecting wrists, knees, and ankles specifically 1
• Order ferritin with glycosylated fraction, markedly elevated ferritin with low glycosylated fraction is characteristic 1
• Check for marked leukocytosis and elevated ESR/CRP 1
• Obtain wrist radiographs to evaluate for characteristic erosions 1

Acute Rheumatic Fever (ARF)

Consider ARF when fever duration exceeds 5 days and migratory polyarthritis affects large joints, particularly in patients with recent streptococcal infection. 1

• Apply the revised Jones Criteria: evidence of preceding Group A Streptococcal infection (throat culture, rapid antigen test, or elevated anti-streptolysin O/anti-DNase B titers) PLUS either 2 major criteria OR 1 major + 2 minor criteria 1
• Major criteria include: carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules 1
• Minor criteria include: polyarthralgia, fever, elevated ESR or CRP, prolonged PR interval on ECG 1
• Perform echocardiography immediately if ARF is suspected to evaluate for carditis 1
• Examine for migratory pattern of joint involvement, though strict migration may not always be present 1

Infectious Etiologies Beyond Septic Arthritis

Bacterial Endocarditis

• Auscultate carefully for new cardiac murmurs, particularly in patients with risk factors for endocarditis 1
• Obtain blood cultures (at least 3 sets from different sites) before antibiotics if endocarditis is suspected 3
• Consider echocardiography (transesophageal preferred over transthoracic) for vegetations 1

Disseminated Fungal Infections

• Consider Blastomyces dermatitidis in endemic areas when fever, joint pain, and pulmonary symptoms occur together, particularly with skin lesions 5
• Examine skin thoroughly for nodules or ulcerations that may indicate disseminated fungal infection 5
• Order urine and blood antigen testing for Blastomyces if clinical suspicion exists 5

Viral Syndromes

• Recognize that viral arthritis typically resolves within 3 months and is usually self-limited 1
• Consider parvovirus B19, hepatitis B/C, HIV, and arboviral infections based on exposure history 3

Autoinflammatory Syndromes

Familial Mediterranean Fever (FMF)

• Look for self-limited episodes of peritonitis, pleuritis, and acute monoarthritis in patients of Mediterranean ancestry 1
• Episodes typically last 12-72 hours and resolve spontaneously 1

TNF Receptor-Associated Periodic Syndrome (TRAPS)

• Identify longer fever attacks (>7 days), ocular involvement (conjunctivitis/periorbital edema), and centrifugal erythematous patches 1

Essential Initial Workup Algorithm

Mandatory First-Line Laboratory Tests

• Complete blood count with differential: leukocytosis suggests infection or AOSD; marked elevation (>14,000) indicates potential septic arthritis or ischemia 1, 3
• ESR and CRP: elevated in most inflammatory conditions, but nonspecific; normal values do NOT exclude serious pathology 1, 3
• Blood cultures: obtain before antibiotics if septic arthritis or endocarditis suspected 1, 3
• Joint aspiration with synovial fluid analysis: cell count, Gram stain, culture (bacterial, fungal, mycobacterial) if any joint appears disproportionately affected 3

Second-Line Serologic Testing

• ANA, rheumatoid factor, anti-CCP antibodies: to evaluate for underlying autoimmune disease 1
• Ferritin with glycosylated fraction: markedly elevated with low glycosylated fraction suggests AOSD 1
• Streptococcal serology (ASO, anti-DNase B): if ARF suspected 1

Imaging Studies

• Plain radiographs of affected joints: exclude metastases, evaluate for erosions, assess prosthetic joints 1
• Wrist radiographs specifically if AOSD suspected 1
• Echocardiography: mandatory if ARF or endocarditis suspected 1
• Chest radiograph: evaluate for pulmonary involvement in systemic infections or AOSD 5

Critical Clinical Pitfalls

• Never delay joint aspiration if septic arthritis is in the differential—permanent cartilage damage can occur within hours to days 2, 3
• Do not rely on absence of fever to exclude infection—elderly or immunocompromised patients may not mount febrile responses 3
• Avoid starting antibiotics before obtaining cultures unless patient is hemodynamically unstable or has signs of septic shock 3
• Remember that bilateral involvement does NOT exclude septic arthritis—polyarticular septic arthritis occurs in 10-20% of cases, particularly with hematogenous seeding 3
• Consider prosthetic joint infection even years after surgery—Streptococcus gordonii and other oral flora can seed prosthetic joints from dental sources 6
• Do not dismiss atypical presentations—sternoclavicular joint involvement should raise suspicion for IV drug use and unusual pathogens 4