Diagnostic approach to fuo
Certain basic procedures should be followed to try to establish a specific cause for fever (figure 1). Many times the initial evaluation leads to the correct diagnosis and the patient's condition does not fit the definition of FUO, which requires at least 1 week of evaluation that has not led to a diagnosis.
History taking, physical examinationObtaining a thorough history is the most important step toward establishing a cause for FUO. Information should be obtained about current symptoms and their onset, duration, and periodicity. In-depth questioning should elicit information about medications, including over-the-counter drugs, diet pills, and herbal remedies; occupational exposures; alcohol and drug use; pets; hobbies; travel and former residences; and sexual activities. Known familial disorders, previous surgical procedures (especially ones involving a foreign material), and other past medical history should also be explored.
Repeated physical examination is very important in FUO cases, because key findings can be missed on the initial examination and new signs often develop over time. For example, Osler's nodes, Janeway lesions, and conjunctival petechiae may not be present initially in a patient with endocarditis. The rash associated with Still's disease is evanescent and easily missed. Slight tenderness or enlargement of the thyroid gland; periodontal disease or tooth pain elicited by gentle tapping; sinus tenderness; thickening or tenderness of the temporal artery; and a boggy, tender, or nodular prostate gland are examples of easily elicited but often missed physical signs that can point to a specific cause of FUO (8,13).
Initial laboratory and radiologic investigation Certain tests should be obtained at a patient's initial visit before a diagnosis of FUO is established. These assessments include a complete blood cell count with differential, erythrocyte sedimentation rate (ESR), routine chemistry tests (including liver enzymes), urinalysis, urine culture, two sets of blood cultures, and a chest radiograph. Subsequent workup should be guided by abnormalities noted on physical examination, the age of the patient, historical information obtained from the patient, and results of the initial laboratory tests. Use of antibiotics to treat fever with no known source is discouraged, because antibiotics may obscure the diagnosis of a variety of different infectious diseases.
Subsequent screening diagnostic tests, procedures For a patient who is taking drugs that have been described as a cause of FUO (see table 2), an important early maneuver is to discontinue the likely offending agent or agents and discover whether the fever disappears after 3 to 4 days. This step may spare the patient a costly workup. Even medications that the patient has taken for months or years can cause drug-related fever (8).
Several imaging procedures have proved useful in defining the cause of fever early in a workup; in many instances, they allow a diagnosis to be established before the actual definition of FUO is met. Abdominal ultrasound is a low-cost test that can detect abnormalities of the hepatobiliary and genitourinary systems as well as fluid collections elsewhere in the abdomen. CT of the chest, abdomen, and pelvis is helpful in patients who have abscesses, hematomas, or malignancies or lymphadenopathy related to either lymphoma or granulomatous diseases. In most situations, findings on ultrasound and CT are not definitive, but they allow subsequent biopsy or aspiration that can give a definitive diagnosis. These imaging procedures should be part of the routine workup for patients suspected of having an FUO.
When patients have an illness suggesting a systemic viral disease (especially if a blood smear shows atypical lymphocytes), EBV and CMV immunoglobulin G (IgG) and immunoglobulin M (IgM) antibody assays should be ordered. It is helpful to remember that the presence of IgG antibodies usually reflects only prior disease and does not establish the cause of FUO. HIV antibody tests should be obtained early in a workup for fever, even in patients who deny high-risk behaviors. Often, patients are not willing to share with their physician information about certain risky behaviors. When elevated liver enzyme levels are noted on initial screening tests, antibody assays for hepatitis A, B, and C viruses should be ordered.
For patients who have symptoms that suggest a collagen vascular or granulomatous disease, tests for antinuclear (ANA) and anti-DNA antibodies, complement, antineutrophil cytoplasmic antibodies (ANCAs), cryoglobulins, and rheumatoid factor should be performed. Results of thyrotropin (TSH) and free thyroxine (T4) assays can establish an early diagnosis of hyperthyroidism in a patient who has fever, loose stools, and weight loss. Any patient with a prosthetic device who has an FUO should undergo an imaging procedure to assess the integrity of both the device and the tissues surrounding the device (14), no matter how long the device has been in place.
Further targeted diagnostic tests and procedures For patients in whom a diagnosis of FUO has been established but the previously mentioned tests have not led to a diagnosis, more detailed testing is required and should be done in consultation with a specialist.
Temporal arteritis, one of the most common causes of FUO in older adults, has no specific serologic marker. Almost all patients have a markedly elevated ESR (ESR, usually >50 mm/hr and often >100 mm/hr), and many of these patients have symptoms suggesting primarily polymyalgia rheumatica without headaches or visual complaints. Diagnosis often requires a temporal artery biopsy and should be made in consultation with a rheumatologist. Similarly, diagnosis of Still's disease may be difficult, and consultation is recommended.
A high index of suspicion for infective endocarditis should be maintained, particularly in a patient in whom a murmur is discovered. If initial blood cultures yield no pathogen, cultures should be repeated and the laboratory asked to hold them longer than is customary. Echocardiography should be performed to look for valvular vegetations and myocardial abscesses (15). Transthoracic echocardiography is much less sensitive (sensitivity, 65% to 70%) than transesophageal echocardiography (sensitivity, about 90%) for visualizing vegetations and is markedly inferior for determining the presence of myocardial abscesses. These studies should be done in consultation with an infectious diseases specialist.
Nuclear scanning using autologous white blood cells labeled with either technetium Tc 99m or indium In 111 can be helpful in localizing abscesses, phlegma, and osteoarticular infections in areas not viewed by routine CT. Scanning with gallium citrate Ga 67 is helpful in detecting infectious and inflammatory processes as well as tumors (16), but it has been supplanted in many centers by white blood cell scanning.
Miliary tuberculosis can be difficult to diagnose on initial presentation. The first chest radiograph may be normal, but subsequent films often show the typical miliary pattern. Disseminated histoplasmosis and nontuberculous mycobacterial infection, especially that of Mycobacterium avium complex, mimic tuberculosis and must be excluded. Lysis centrifugation techniques for culturing blood and biopsy samples of involved organs are important diagnostic procedures for establishing a diagnosis of disseminated mycobacterial or fungal infection.
For patients in whom elevated levels of alkaline phosphatase or transaminases, or both, have been documented, liver biopsy can provide evidence for a variety of malignancies and granulomatous processes. Patients with pancytopenia should undergo a bone marrow biopsy for both histologic testing and culture. Histoplasmosis and mycobacterial infections often cause fever and pancytopenia, and malignancies also can be documented by bone marrow biopsy.