This patient has classic fever of unknown origin (FUO), defined as a temperature greater than 38.3 °C (100.9 °F) for at least 3 weeks that remains undiagnosed after two visits in the ambulatory setting or 3 days of in-hospital assessment. She has undergone a reasonable evaluation for the most common causes of FUO, which include infection (endocarditis, tuberculosis, abscesses, complicated urinary tract infection), neoplasm, and connective tissue disease; therefore, she should be observed carefully, and further diagnostic or therapeutic interventions should be based on changes in history or physical examination. Histopathologic examination of tissue obtained by aspiration or biopsy can provide a definitive diagnosis in some cases of FUO if the clinical evaluation suggests disease in a particular organ. An exception to performing blind biopsies is biopsy of the temporal artery, which may be indicated in older adult patients with FUO and an elevated erythrocyte sedimentation rate even if localizing signs are absent.

A bone marrow aspirate and biopsy would be indicated if hematologic abnormalities were seen and are helpful in diagnosing disseminated granulomatoses, such as tuberculosis and histoplasmosis, or malignancies, such as leukemia and lymphoma. Because the patient's blood counts are normal and she has no other clinical findings suggesting a process with bone marrow involvement, performing a bone marrow aspirate and biopsy is not indicated.

Therapeutic trials of antibiotics, glucocorticoids, or NSAIDs are rarely indicated in patients with FUO. They may be successful in eliminating fever, or fever may remit spontaneously, and the correct diagnosis may be delayed. Empiric therapy should be reserved for patients who are seriously ill or when a specific diagnosis is reasonably likely. In general, this occurs most often when disseminated tuberculosis is suspected and an empiric therapeutic trial of antibiotics is indicated.

In the absence of any new localizing signs or symptoms, repeat or more extensive imaging is likely to be low-yield and not cost-effective. The longer the duration of FUO, the less likely it is to have an infectious cause.