Commonly Missed Infectious Diseases in Fever of Unknown Origin
Most Frequently Missed Infections
Tuberculosis, infective endocarditis, and atypical bacterial infections (Brucella, Q fever, Bartonella) represent the most commonly missed infectious causes of FUO, with tuberculosis accounting for 17.6% of infectious FUO cases and often presenting atypically without classic pulmonary symptoms. 1, 2
Key Infectious Etiologies by Frequency
- Tuberculosis is the single most common infectious cause of FUO in endemic regions, representing 40% of all infectious FUO cases and 17.6% of total FUO diagnoses 1, 2
- Infective endocarditis presents as subacute disease with low-grade fever and non-specific symptoms that confuse initial assessment, making it particularly difficult to verify 3, 4
- Atypical bacterial infections including Brucella (0.1-2.8% of cases), Q fever/Coxiella (0.2-0.9%), and Bartonella are frequently overlooked due to their requirement for specific serologic testing 3
- Intra-abdominal abscesses (renal, splenic, hepatic, vertebral) of unknown cause should trigger suspicion for occult infection 3
Tuberculosis Evaluation in FUO Patients
Order region-specific tuberculosis serologic testing and chest radiography as mandatory first-line investigations in all FUO patients, particularly those from endemic areas or with travel history to high-prevalence regions. 5, 6, 7
Specific Diagnostic Approach
- Obtain chest radiography as the only first-line imaging study recommended by the American College of Radiology, particularly when there is concern for tuberculosis, atypical bacterial infection, or HIV 3, 6
- Order tuberculosis-specific serologic testing as part of region-specific workup, especially in patients with travel history or immigration status 5, 6
- Consider CT chest with IV contrast if chest radiography is non-diagnostic but clinical suspicion remains high 6
- Perform FDG-PET/CT (sensitivity 84-86%, diagnostic yield 56%) if initial workup is unrevealing, as it can identify extrapulmonary tuberculosis sites 5, 6
Critical Risk Factors to Elicit
- Travel history with specific countries visited, as Central/Western Africa has higher tuberculosis rates 5
- Immigration status or visiting friends/relatives abroad, as these individuals are less likely to seek pre-travel advice and have higher infection rates 5
- Duration of fever and hospital stay, which are significantly prolonged in tuberculosis cases (mean 44 days fever duration) 2
Suspecting Endocarditis Despite Negative Cultures
Suspect culture-negative endocarditis when fever is accompanied by new regurgitant heart murmur, embolic events of unknown origin, or peripheral abscesses (renal, splenic, cerebral, vertebral), even with negative blood cultures. 3
Specific Clinical Triggers for Suspicion
- New regurgitant heart murmur on cardiac auscultation (present in up to 85% of endocarditis cases) 3, 6
- Embolic events of unknown origin including stroke, splenic infarct, or peripheral emboli 3
- Intracardiac prosthetic material (prosthetic valve, pacemaker, implantable defibrillator, surgical baffle/conduit) 3
- Previous history of infective endocarditis or previous valvular/congenital heart disease 3
- Immunologic phenomena: Roth spots, splinter hemorrhages, Janeway lesions, Osler's nodes 3
- Positive serology for chronic Q fever, as microbiological findings may precede cardiac manifestations 3
Diagnostic Algorithm for Culture-Negative Cases
- Perform transthoracic echocardiography (TTE) as first-line imaging in all suspected cases 3
- Follow with transesophageal echocardiography (TEE) in patients with high clinical suspicion and normal TTE, owing to better sensitivity and specificity for abscess diagnosis and vegetation measurement 3
- Repeat TTE and TEE within 7-10 days if initially negative but clinical suspicion remains high 3
- Order Q fever serology specifically, as chronic Q fever can cause culture-negative endocarditis 3
Important Caveats
- Fever may be absent in elderly patients, after antibiotic pre-treatment, in immunocompromised patients, and with less virulent organisms 3
- Endocarditis may present as subacute or chronic disease with low-grade fever rather than acute sepsis, leading to delayed diagnosis 3, 4
- Never start empiric antibiotics before obtaining at least 3 sets of blood cultures, as this obscures diagnosis 5, 6
Role of Atypical Infections (Brucella, Q Fever, Bartonella)
Test for atypical bacterial infections with specific serologic assays when patients have relevant animal exposures, occupational risks, or travel to endemic regions, as these organisms require targeted testing and are not detected by routine blood cultures. 3, 5, 6
Specific Testing Indications
- Brucella serology: Order when patient has exposure to unpasteurized dairy products, livestock contact, or travel to Mediterranean/Middle Eastern regions (prevalence 0.1-2.8% in FUO) 3, 6
- Q fever (Coxiella burnetii) serology: Test for both acute and chronic Q fever when patient has farm animal exposure, particularly sheep/goats, or works in veterinary/agricultural settings (prevalence 0.2-0.9%) 3
- Bartonella serology: Consider in patients with cat exposure (especially scratches), homelessness, or body lice exposure 6
When to Suspect These Infections
- Obtain targeted history focusing on animal exposures (livestock, cats, unpasteurized dairy) and occupational risks (farming, veterinary work, slaughterhouse employment) 6
- Consider atypical infections when routine blood cultures remain negative despite clinical sepsis picture 3
- Remember that chronic Q fever specifically causes culture-negative endocarditis and requires serology for diagnosis 3
Treatment Considerations
- Avoid empiric antibiotics in stable patients, as they obscure diagnosis without improving outcomes 5, 6
- Consider empiric therapy only for suspected tickborne rickettsial diseases or critically ill patients when specific atypical infection is strongly suspected 5
- Treat confirmed diagnoses according to established pathogen-specific guidelines once serology returns positive 5