What are the differential diagnoses for a 25-year-old female with a history of bicuspid aortic valve (BAV) and supravalvular aortic stenosis, presenting with a 2-month history of fever, mild anemia, splenomegaly, and an ejection systolic murmur, without chest or abdominal complaints?

Differential Diagnoses for Prolonged Fever with Bicuspid Aortic Valve and Splenomegaly

The most critical diagnosis to exclude immediately is infective endocarditis, as bicuspid aortic valve patients have a 10-30% lifetime risk of developing this life-threatening complication, and the combination of prolonged fever, splenomegaly, anemia, and a pre-existing valvular abnormality creates a classic presentation. 1, 2, 3

Primary Differential Diagnoses

1. Infective Endocarditis (Most Urgent)

• Bicuspid aortic valves are intrinsically predisposed to endocarditis and represent the most important cardiac substrate for this infection in developed countries 3
• The 2-month fever duration, splenomegaly, mild anemia, and known valvular disease form the classic triad for subacute bacterial endocarditis 1
• The ejection systolic murmur may represent the pre-existing bicuspid valve or new/worsening valvular dysfunction from vegetations 1
• Immediate blood cultures (before antibiotics), transesophageal echocardiography, and inflammatory markers (ESR, CRP) are mandatory 1
• Even without obvious vegetations on initial imaging, endocarditis cannot be excluded as vegetations may be small or absent in 12% of cases 1

2. Q Fever (Chronic Form)

• Patients with bicuspid aortic valve are at highest risk for chronic Q fever, particularly endocarditis, which comprises 60-78% of chronic Q fever cases worldwide 1
• Chronic Q fever presents with nonspecific features including prolonged fever, fatigue, weight loss, and hepatosplenomegaly 1
• The median onset time for Q fever endocarditis is 2.5 months after acute illness, matching this patient's timeline 1
• Approximately 40% of persons with known valvulopathy who develop acute Q fever subsequently develop infective endocarditis 1
• Diagnosis requires specific serologic testing for Coxiella burnetii phase I and II antibodies 1

3. Acute Rheumatic Fever (Less Likely but Consider)

• While the patient has a bicuspid aortic valve (a congenital anomaly), acute rheumatic fever must be considered in the differential of prolonged fever with cardiac involvement 1, 4
• However, rheumatic carditis rarely presents with isolated aortic valve involvement; it primarily affects the mitral valve, and isolated aortic regurgitation is rarely the sole finding 1, 4
• The presence of a pre-existing bicuspid valve makes this diagnosis less likely, as the valve abnormality predates the current illness 1
• Fever ≥38.5°C, elevated ESR ≥60 mm/h and/or CRP ≥3.0 mg/dL would support this diagnosis if present 1
• Anti-streptolysin O titers and throat culture for group A streptococcus would be needed 1

4. Chronic Valvular Disease Complications

• Bicuspid aortic valves may develop progressive stenosis or regurgitation, with 25-42% requiring surgery for symptomatic valve disease, LV dysfunction, or endocarditis 1
• The supravalvular aortic stenosis adds complexity and may contribute to hemodynamic stress 1
• However, isolated valvular disease without infection would not typically cause prolonged fever or splenomegaly 1

Secondary Considerations

5. Hematologic/Oncologic Causes

• Mild anemia with splenomegaly and prolonged fever raises concern for lymphoproliferative disorders, though less likely given the cardiac findings 1
• Complete blood count with differential, peripheral smear, and lactate dehydrogenase levels would help evaluate this 1

6. Autoimmune/Inflammatory Conditions

• Systemic lupus erythematosus can cause valvulitis, fever, anemia, and splenomegaly, though typically presents with other systemic features 1
• Giant cell arteritis or Takayasu arteritis could affect the aorta but are less common in a 25-year-old 1

Critical Diagnostic Approach

Immediate workup must include:

• Three sets of blood cultures from different sites before any antibiotics 1
• Transesophageal echocardiography (TEE) - more sensitive than transthoracic for detecting vegetations and valvular complications 1
• Complete blood count, ESR, CRP, and cardiac biomarkers 1
• Q fever serology (Coxiella burnetii phase I and II antibodies) 1
• Anti-streptolysin O titer and throat culture 1
• Comprehensive metabolic panel and urinalysis (to assess for embolic phenomena) 1

Common Pitfalls to Avoid

• Do not dismiss the possibility of endocarditis based on a negative transthoracic echocardiogram alone; TEE is required 1
• Do not delay blood cultures while waiting for imaging studies 1
• Do not assume the ejection systolic murmur is solely from the pre-existing bicuspid valve; new or changing murmurs suggest active endocarditis 1, 3
• Do not overlook Q fever as a cause of culture-negative endocarditis in patients with valvular disease 1
• The bicuspid valve with supravalvular stenosis may mask subtle changes in murmur character that would otherwise suggest new pathology 1