Diagnostic Approach to Intermittent Fever

Initial Diagnostic Workup

The American College of Physicians recommends beginning with targeted laboratory testing, including complete blood count with differential, inflammatory markers, blood cultures, and thick/thin blood smears for malaria, followed by chest radiography and serologic testing based on epidemiologic risk factors 1
Complete blood count with differential is essential to assess for lymphopenia, thrombocytopenia, or leukocytosis that may suggest specific etiologies 2, 1
Inflammatory markers, such as ESR and CRP, are used as first-line screening tests for ongoing inflammation 1
Thick and thin blood smears for malaria parasites are mandatory if there is any travel history to endemic areas, as malaria is a predominant cause of systemic febrile illness in returned travelers 3
Travel history within the past 3 months, particularly to malaria-endemic regions, is crucial to elicit 3
Animal exposures, such as livestock, pets, or unpasteurized dairy, suggesting Q fever risk, should be assessed 4, 5
Underlying cardiac conditions, including valvular disease, prosthetic valves, or vascular grafts, increase the risk for endocarditis 4, 1
Immunosuppressive conditions or medications should be evaluated 1

Chest radiography is the initial screening tool for all patients with prolonged fever 1
Contrast-enhanced CT of chest, abdomen, and pelvis may be performed if the initial workup is unrevealing 1
Echocardiography, preferably transesophageal, is recommended if there is suspicion of endocarditis or valvular disease 1

If there is a travel history to malaria-endemic areas, immediate thick and thin blood smears are mandatory, as delayed diagnosis of P. falciparum malaria can cause preventable deaths 3
Repeat blood smears every 12-24 hours if initial smears are negative but clinical suspicion remains high 3
Look for thrombocytopenia, anemia, elevated bilirubin, and elevated lactate dehydrogenase as supportive findings for malaria 2, 3
Q fever serologic testing using immunofluorescent assay for phase I and II IgG and IgM antibodies is recommended for patients with animal exposure or rural/farm contact 4, 1
Phase I IgG titer ≥1:1024 with clinical evidence of organ infection suggests chronic Q fever 4, 7, 1

For suspected malaria, do not delay treatment if blood smears are positive for P. falciparum, even with low parasitemia 3
Uncomplicated malaria can be treated with oral artemisinin-based combination therapy 3
Severe malaria requires intravenous artesunate with ICU admission 3
For suspected Q fever, acute Q fever can be treated with doxycycline 100 mg twice daily, while chronic Q fever requires doxycycline 100 mg twice daily plus hydroxychloroquine 200 mg three times daily for 18-24 months 6, 7, 4, 5, 8
A mandatory baseline ophthalmologic examination is required before starting hydroxychloroquine, then every 6 months due to retinal toxicity risk 4, 8