Chapter 019. Fever of Unknown Origin (Part 2) Infections, especially extrapulmonary tuberculosis, remain the leading diagnosable cause of FUO. Prolonged mononucleosis syndromes caused by Epstein-Barr virus, cytomegalovirus (CMV), or HIV are conditions whose consideration as a cause of FUO is sometimes confounded by delayed antibody responses. Intraabdominal abscesses (sometimes poorly localized) and renal, retroperitoneal, and paraspinal abscesses continue to be difficult to diagnose. Renal malacoplakia, with submucosal plaques or nodules involving the urinary tract, may cause FUO and is often fatal if untreated. It is associated with intracellular bacterial infection, is seen most often in patients with defects of intracellular bacterial killing, and is treated with fluoroquinolones or trimethoprim-sulfamethoxazole. Occasionally, other organs may be involved. Osteomyelitis, especially where prosthetic devices have been implanted, and infective endocarditis must be considered. Although true culture-negative infective endocarditis is rare, one may be misled by slow-growing organisms of the HACEK group (Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae; Chap. 140), Bartonella spp. (previously Rochalimaea), Legionella spp., Coxiella burnetii, Chlamydophila psittaci, and fungi. Prostatitis, dental abscesses, sinusitis, and cholangitis continue to be sources of occult fever. Fungal disease, most notably histoplasmosis involving the reticuloendothelial system, may cause FUO. FUO with headache should prompt examination of spinal fluid for Cryptococcus neoformans. Malaria (which may result from transfusion, the failure to take a prescribed prophylactic agent, or infection with a drug-resistant strain) continues to be a cause, particularly of asynchronous FUO. A related protozoan infection, babesiosis, may cause FUO and is increasing in geographic distribution and in incidence, especially among the elderly and immunosuppressed. In most earlier series, neoplasms were the next most common cause of FUO after infections (Table 19-1). In more recent series, a decrease in the percentage of FUO cases due to malignancy was attributed to improvement in diagnostic technologies—in particular, high-resolution tomography, MRI, PET scanning, and tumor antigen assays. This observation does not diminish the importance of considering neoplasia in the initial diagnostic evaluation of a patient with fever. A number of patients in these series had temporal arteritis, adult Still's disease, drug-related fever, and factitious fever. In recent series, ~25–30% of cases of FUO have remained undiagnosed. The general term noninfectious inflammatory diseases applies to systemic rheumatologic or vasculitic diseases such as polymyalgia rheumatica, lupus, and adult Still's disease as well as to granulomatous diseases such as sarcoidosis and Crohn's and granulomatous hepatitis. In the elderly, multisystem disease is the most frequent cause of FUO, giant-cell arteritis being the leading etiologic entity in this category. In patients >50 years of age, this disease accounts for 15–20% of FUO cases. Tuberculosis is the most common infection causing FUO in the elderly, and colon cancer is an important cause of FUO with malignancy in this age group. Many diseases have been grouped in the various studies as "miscellaneous." On this list are drug fever, pulmonary embolism, factitious fever, the hereditary periodic fever syndromes (familial Mediterranean fever, hyper-IgD syndrome, tumor necrosis factor receptor–associated periodic syndrome, familial cold urticaria, and the Muckle-Wells syndrome), and Fabry disease. A drug-related etiology must be considered in any case of prolonged fever. Any febrile pattern may be elicited by a drug. Virtually all classes of drugs cause fever, but antimicrobial agents (especially β-lactam antibiotics), cardiovascular drugs (e.g., quinidine), antineoplastic drugs, and drugs acting on the central nervous system (e.g., phenytoin) are particularly common causes. It is axiomatic that, as the duration of fever increases, the likelihood of an infectious cause decreases, even for the more indolent infectious etiologies (e.g., brucellosis, paracoccidioidomycosis, malaria due to Plasmodium malariae). In a series of 347 patients referred to the National Institutes of Health from 1961 to 1977, only 6% had an infection (Table 19-2). A significant proportion (9%) had factitious fevers—i.e., fevers due either to false elevations of temperature or to self-induced disease. A substantial number of these factitious cases were in young women in the health professions. It is worth noting that 8% of the patients with prolonged fevers (some of whom had completely normal liver function studies) had granulomatous hepatitis, and 6% had adult Still's disease. After prolonged investigation, 19% of cases still had no specific diagnosis. A total of 27% of patients had no actual fever during inpatient observation or had an exaggerated circadian temperature rhythm without chills, elevated pulse, or other abnormalities. Table 19-2 Causes of FUO Lasting >6 Months Cause Cases, % None identified 19 Miscellaneous causes 13 Factitious causes 9 Granulomatous hepatitis 8 Neoplasm 7 Still's disease 6 Infection 6 Collagen vascular disease 4 Familial Mediterranean fever 3 No fever a 27 a No actual fever observed during 2–3 weeks of inpatient observation. Includes patients with exaggerated circadian rhythm. . Chapter 019. Fever of Unknown Origin (Part 2) Infections, especially extrapulmonary tuberculosis, remain the leading diagnosable cause of FUO. Prolonged mononucleosis. series of 347 patients referred to the National Institutes of Health from 1961 to 1977, only 6% had an infection (Table 19 -2). A significant proportion (9%) had factitious fevers—i.e., fevers. had temporal arteritis, adult Still's disease, drug-related fever, and factitious fever. In recent series, ~25–30% of cases of FUO have remained undiagnosed. The general term noninfectious