What are the potential causes and necessary tests for a patient with pyrexia of unknown origin, bilateral pedal edema, and a recent history of sore throat 5 days prior?

Diagnostic Approach to Pyrexia of Unknown Origin with Bilateral Pedal Edema and Recent Sore Throat

This clinical triad—pyrexia of unknown origin, bilateral pedal edema, and recent pharyngitis—strongly suggests post-streptococcal complications, particularly acute rheumatic fever or post-streptococcal glomerulonephritis, but also requires systematic exclusion of infectious endocarditis, vasculitis (especially giant cell arteritis if age >50), and occult infections.

Immediate Priority: Rule Out Life-Threatening Causes

Cardiac Evaluation (First Priority)

• Obtain urgent echocardiography to exclude infective endocarditis, which presents with fever, new murmur, and can cause pedal edema from heart failure 1
• Perform ECG looking for conduction abnormalities, PR prolongation, or evidence of myocarditis (acute rheumatic fever complication) 2
• Measure brain natriuretic peptide (BNP) to assess for heart failure as cause of edema 2
• Blood cultures (minimum 3 sets) must be obtained before any antimicrobial therapy to maximize diagnostic yield, as viridans streptococci are the most common organisms in endocarditis following pharyngitis 3, 1

Renal Assessment (Second Priority)

• Urinalysis with microscopy looking for hematuria, proteinuria, and red blood cell casts (post-streptococcal glomerulonephritis) 2
• Serum creatinine and BUN to assess renal function 3
• If proteinuria present with edema, measure 24-hour urine protein to evaluate for nephrotic syndrome 2
• Complement levels (C3, C4) are characteristically low in post-streptococcal glomerulonephritis 1

Essential Laboratory Work-Up

Infection Markers

• Complete blood count with differential to assess for neutropenia, leukocytosis, or cytopenia 3, 4
• CRP and ESR: If ESR >40 mm/h in patient >50 years with new headache or jaw symptoms, giant cell arteritis becomes urgent consideration requiring temporal artery biopsy within 24 hours 2, 3
• Anti-streptolysin O (ASO) titer and anti-DNase B to confirm recent streptococcal infection 1

Inflammatory/Autoimmune Screening

• Antinuclear antibody (ANA), rheumatoid factor, and anti-CCP if polyarthritis develops (Still's disease presents with spiking fever, rash, arthritis, and markedly elevated CRP/ESR) 3, 1
• Antineutrophil cytoplasmic antibodies (ANCA) if vasculitis suspected, particularly with respiratory symptoms 2

Additional Critical Tests

• Liver function tests and comprehensive metabolic panel 3
• Thyroid function tests (thyroiditis can cause chronic cough and fever) 2
• Blood glucose to exclude diabetic complications if patient on thiazolidinediones (TZDs cause fluid retention and pedal edema) 2

Imaging Strategy

First-Line Imaging

• Chest radiograph to exclude pneumonia, heart failure, pulmonary infiltrates, or mediastinal masses 2, 4
• CT chest, abdomen, and pelvis as minimal imaging standard to identify occult abscesses, lymphadenopathy, or malignancy 1
• Lower extremity venous ultrasound if asymmetric edema or concern for deep vein thrombosis 2

Advanced Imaging (If Initial Work-Up Unrevealing)

• FDG-PET/CT should be performed early (within 3 days if glucocorticoids needed), demonstrating 84-86% sensitivity for identifying PUO causes with 79% high clinical impact prompting specialist referrals or antimicrobial changes 3, 4, 1
• FDG-PET/CT particularly valuable for detecting vasculitis, occult infections, inflammatory bowel disease, and malignancies 3, 1

Specific Diagnostic Considerations Based on Clinical Context

If Age >50 Years

• Giant cell arteritis is critical consideration: harsh nonproductive cough with sore throat, headache, and elevated ESR >40 mm/h warrants urgent temporal artery biopsy 2
• Prednisone 40-60 mg/day dramatically resolves symptoms if giant cell arteritis confirmed 2

If Recent Pharyngitis (5 Days Ago)

• Post-streptococcal sequelae timeline: Acute rheumatic fever develops 2-3 weeks post-pharyngitis; glomerulonephritis 1-3 weeks post-infection 1
• Look for Jones criteria: carditis, polyarthritis, chorea, erythema marginatum, subcutaneous nodules 1
• Throat culture may be negative by this timepoint; rely on ASO/anti-DNase B titers 1

If Bilateral Pedal Edema Predominates

• Exclude heart failure first: Signs include jugular venous distention, S3 gallop, pulmonary rales, orthopnea 2
• Nephrotic syndrome: Proteinuria >3.5 g/day with hypoalbuminemia and hyperlipidemia 2
• Medication-induced: Review for calcium channel blockers, TZDs, NSAIDs 2
• Venous insufficiency typically asymmetric and not associated with fever 2

Risk-Stratified Management

High-Risk Features Requiring Immediate Action

• Hemodynamic instability: Monitor every 2-4 hours with urgent infectious disease consultation 4
• Severe neutropenia (ANC <0.5 × 10⁹/L): Medical emergency requiring same-day broad-spectrum antibiotics without waiting for cultures 4, 1
• New cardiac murmur with fever: Presume endocarditis until proven otherwise 1

Moderate-Risk Stable Patient

• Complete diagnostic work-up as outlined above before empiric antibiotics 4, 5
• Serial CRP measurements more valuable than single values for monitoring 3
• If diagnosis remains elusive after comprehensive evaluation, careful clinical observation preferred over empiric antimicrobials in stable patients 5

Critical Pitfalls to Avoid

• Do not attribute edema to TZDs or calcium channel blockers without excluding CHF and nephrotic syndrome first 2
• CRP >10 mg/L warrants thorough evaluation, but 20% of smokers have elevated CRP from smoking alone; obesity, age, sex affect baseline 3
• Single normal CRP does not rule out infection; CRP has 31.4% false-negative rate in high pretest probability scenarios 3
• Prior antibiotic use significantly reduces culture positivity; withhold antibiotics ≥48 hours in stable patients with negative cultures to improve diagnostic yield 1
• Do not delay FDG-PET/CT with prolonged empiric antibiotic trials; early use prevents missed diagnoses by identifying inflammation before suppression by extended therapy 3, 1
• In resource-limited settings, always assume and treat infection when fever cannot be explained—do not label as "PUO" and observe 1

Specific Infectious Causes to Consider

Bacterial

• Tuberculosis (extrapulmonary manifestations including lymphadenitis) requires mycobacterial cultures 3, 1
• Occult abscesses (hepatic, splenic, psoas) identified by CT or FDG-PET/CT 3, 1
• Lemierre syndrome (septic thrombophlebitis post-pharyngitis) in young adults—potentially fatal 1

Atypical Organisms

• Mycoplasma and Legionella can cause pleural effusion; check urinary Legionella antigen 1
• Brucellosis, Q fever, leptospirosis if relevant occupational/travel exposure 3

Opportunistic Infections

• MAC or M. kansasii in immunocompromised patients presenting with disseminated disease 3, 1

When Diagnosis Remains Elusive

• Up to 50% of PUO cases remain undiagnosed despite adequate investigation 6, 7
• Reassuringly, undiagnosed PUO cohort has good prognosis 6
• Continue clinical observation for new symptoms/signs rather than multiple antimicrobial courses in stable patients 5
• Repeat comprehensive history and physical examination focusing on travel, occupational exposures, animal contacts, medications, and family history 1, 7