APPROACH TO THE PATIENT: Fever of Unknown Origin FIRST-STAGE DIAGNOSTIC TESTS
Figure 13-1 shows a structured approach to patients presenting with FUO. The most important step in the diagnostic workup is the search for potentially diagnostic clues (PDCs) through complete and repeated history-taking and physical examination and the obligatory investigations listed above. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis. Although PDCs are often misleading, only with their help can a concise list of probable diagnoses be made. The history should include information about the fever pattern (continuous or recurrent) and duration, previous medical history, present and recent drug use, family history, sexual history, country of origin, recent and remote travel, unusual environmental exposures associated with travel or hobbies, and animal contacts. A complete physical examination should be performed, with special attention to the eyes, lymph nodes, temporal arteries, liver, spleen, sites of previous surgery, entire skin surface, and mucous membranes. Before further diagnostic tests are initiated, antibiotic and glucocorticoid treatment, which can mask many diseases, should be stopped. For example, blood and other cultures are not reliable when samples are obtained during antibiotic treatment, and the size of enlarged lymph nodes usually decreases during glucocorticoid treatment, regardless of the cause of the lymphadenopathy. Despite the high number of false-positive ultrasounds and the relatively low sensitivity of chest x-rays, the performance of these simple, low-cost diagnostic tests remains obligatory in all patients with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are not. Abdominal ultrasound is preferred to abdominal CT as an obligatory test because of relatively low cost, lack of radiation burden, and absence of side effects.
Only rarely do biochemical tests (beyond the obligatory tests needed to classify a patient’s fever as FUO) lead directly to a definitive diagnosis in the absence of PDCs. The diagnostic yield of immunologic serology other than that included in the obligatory tests is relatively low. These tests more often yield false-positive rather than true-positive results and are of little use without PDCs pointing to specific immunologic disorders. Given the absence of specific symptoms in many patients and the relatively low cost of the test, investigation of cryoglobulins appears to be a valuable screening test in patients with FUO.
Multiple blood samples should be cultured in the laboratory long enough to ensure ample growth time for any fastidious organisms, such as HACEK organisms. It is critical to inform the laboratory of the intent to test for unusual organisms. Specialized media should be used when the history suggests uncommon microorganisms, such as Histoplasma or Legionella. Performing more than three blood cultures or more than one urine culture is useless in patients with FUO in the absence of PDCs (e.g., a high level of clinical suspicion of endocarditis). Repeating blood or urine cultures is useful only when previously cultured samples were collected during antibiotic treatment or within 1 week after its discontinuation. FUO with headache should prompt microbiologic examination of cerebrospinal fluid (CSF) for organisms including herpes simplex virus (HSV; especially HSV-2), Cryptococcus neoformans, and Mycobacterium tuberculosis. In CNS tuberculosis, the CSF typically has elevated protein and lowered glucose concentrations, with a mononuclear pleocytosis. CSF protein levels range from 100 to 500 mg/dL in most patients, the CSF glucose concentration is <45 mg/dL in 80% of cases, and the usual CSF cell count is between 100 and 500 cells/μL.
Microbiologic serology should not be included in the diagnostic workup in patients without PDCs for specific infections. A TST is included in the obligatory investigations, but it may yield false-negative results in patients with miliary tuberculosis, malnutrition, or immunosuppression. Although the interferon γ release assay is less influenced by prior vaccination with bacille Calmette-Guérin or by infection with nontuberculous mycobacteria, its sensitivity is similar to that of the TST; a negative TST or interferon γ release assay therefore does not exclude a diagnosis of tuberculosis. Miliary tuberculosis is especially difficult to diagnose. Granulomatous disease in liver or bone marrow biopsy samples, for example, should always lead to a (re)consideration of this diagnosis. If miliary tuberculosis is suspected, liver biopsy for acid-fast smear, culture, and PCR probably still has the highest diagnostic yield; however, biopsies of bone marrow, lymph nodes, or other involved organs also can be considered.
The diagnostic yield of echocardiography, sinus radiography, radiologic or endoscopic evaluation of the gastrointestinal tract, and bronchoscopy is very low in the absence of PDCs. Therefore, these tests should not be used as screening procedures.
After identification of all PDCs retrieved from the history, physical examination, and obligatory tests, a limited list of the most probable diagnoses should be made. Since most investigations are helpful only for patients who have PDCs for the diagnoses sought, further diagnostic procedures should be limited to specific investigations aimed at confirming or excluding diseases on this list. In FUO, the diagnostic pointers are numerous and diverse but may be missed on initial examination, often being detected only by a very careful examination performed subsequently. In the absence of PDCs, the history and physical examination should therefore be repeated regularly. One of the first steps should be to rule out factitious or fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, including nonprescription drugs and nutritional supplements, should be discontinued early in the evaluation to exclude drug fever. If fever persists beyond 72 h after discontinuation of the suspected drug, it is unlikely that this drug is the cause. In patients without PDCs or with only misleading PDCs, funduscopy by an ophthalmologist may be useful in the early stage of the diagnostic workup. When the first-stage diagnostic tests do not lead to a diagnosis, scintigraphy should be performed, especially when the ESR or CRP level is elevated.
Recurrent Fever In patients with recurrent fever, the diagnostic workup should consist of thorough history-taking, physical examination, and obligatory tests. The search for PDCs should be directed to clues matching known recurrent syndromes (Table 13-3). Patients should be asked to return during a febrile episode so that the history, physical examination, and laboratory tests can be repeated during a symptomatic phase. Further diagnostic tests, such as scintigraphic imaging (see below), should be performed only during a febrile episode because abnormalities may be absent between episodes. In patients with recurrent fever lasting >2 years, it is very unlikely that the fever is caused by infection or malignancy. Further diagnostic tests in that direction should be considered only when PDCs for infections, vasculitis syndromes, or malignancy are present or when the patient’s clinical condition is deteriorating.
Scintigraphy Scintigraphic imaging is a noninvasive method allowing delineation of foci in all parts of the body on the basis of functional changes in tissues. This procedure plays an important role in the diagnosis of patients with FUO in clinical practice. Conventional scintigraphic methods used in clinical practice are 67Ga-citrate scintigraphy and 111In- or 99mTc-labeled leukocyte scintigraphy. Focal infectious and inflammatory processes can also be detected by several radiologic techniques, such as CT, MRI, and ultrasound. However, because of the lack of substantial pathologic changes in the early phase, infectious and inflammatory foci cannot be detected at this time. Furthermore, distinguishing active infectious or inflammatory lesions from residual changes due to cured processes or surgery remains critical. Finally, CT and MRI routinely provide information only on part of the body, while scintigraphy readily allows whole-body imaging.
Fluorodeoxyglucose Positron Emission Tomography 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has become an established imaging procedure in FUO. FDG accumulates in tissues with a high rate of glycolysis, which occurs not only in malignant cells but also in activated leukocytes, and thus permits the imaging of acute and chronic inflammatory processes. Normal uptake may obscure pathologic foci in the brain, heart, bowel, kidneys, and bladder. In patients with fever, bone marrow uptake is frequently increased in a nonspecific way due to cytokine activation, which upregulates glucose transporters in bone marrow cells. Compared with conventional scintigraphy, FDG-PET offers the advantages of higher resolution, greater sensitivity in chronic low-grade infections, and a high degree of accuracy in the central skeleton. Furthermore, vascular uptake of FDG is increased in patients with vasculitis. The mechanisms responsible for FDG uptake do not allow differentiation among infection, sterile inflammation, and malignancy. However, in patients with FUO, since all of these disorders are causes of FUO, FDG-PET can be used to guide additional diagnostic tests (e.g., targeted biopsies) that may yield the final diagnosis. Improved anatomic resolution by direct integration with CT (FDG-PET/CT) has further improved the accuracy of this modality.
Overall rates of helpfulness in final diagnosis of FUO are 40% for FDG-PET and 54% for FDG-PET/CT. In one study, FDG-PET was never helpful in diagnosing FUO in patients with a normal CRP level and a normal ESR. In two prospective studies in patients with FUO, FDG-PET was superior to 67Ga-citrate scintigraphy, with a similar or better diagnostic yield and results that were available within hours instead of days. In one study, the sensitivity of FDG-PET was greater than that of 111In-granulocyte scintigraphy (86% vs 20%) in patients with FUO.
Although scintigraphic techniques do not directly provide a definitive diagnosis, they often identify the anatomic location of a particular ongoing metabolic process and, with the help of other techniques such as biopsy and culture, facilitate timely diagnosis and treatment. Pathologic FDG uptake is quickly eradicated by treatment with glucocorticoids in many diseases, including vasculitis and lymphoma; therefore, glucocorticoid use should be stopped or postponed until after FDG-PET is performed. Results reported in the literature and the advantages offered by FDG-PET indicate that conventional scintigraphic techniques should be replaced by FDG-PET/CT in the investigation of patients with FUO at institutions where this technique is available. FDG-PET/CT is a relatively expensive procedure whose availability is still limited compared with that of CT and conventional scintigraphy. Nevertheless, FDG-PET/CT can be cost-effective in the FUO diagnostic workup if used at an early stage, helping to establish an early diagnosis, reducing days of hospitalization for diagnostic purposes, and obviating unnecessary and unhelpful tests.
LATER-STAGE DIAGNOSTIC TESTS In some cases, more invasive tests are appropriate. Abnormalities found with scintigraphic techniques often need to be confirmed by pathology and/or culture of biopsy specimens. If lymphadenopathy is found, lymph node biopsy is necessary, even when the affected lymph nodes are hard to reach. In the case of skin lesions, skin biopsy should be undertaken. In one study, pulmonary wedge excision, histologic examination of an excised tonsil, and biopsy of the peritoneum were performed in light of PDCs or abnormal FDG-PET results and yielded a diagnosis.
If no diagnosis is reached despite scintigraphic and PDC-driven histologic investigations or culture, second-stage screening diagnostic tests should be considered (Fig. 13-1). In three studies, the diagnostic yield of screening chest and abdominal CT in patients with FUO was ~20%. The specificity of chest CT was ~80%, but that of abdominal CT varied between 63% and 80%. Despite the relatively limited specificity of abdominal CT and the probably limited additional value of chest CT after normal FDG-PET, chest and abdominal CT may be used as screening procedures at a later stage of the diagnostic protocol because of their noninvasive nature and high sensitivity. Bone marrow aspiration is seldom useful in the absence of PDCs for bone marrow disorders. With addition of FDG-PET, which is very sensitive in detecting lymphoma, carcinoma, and osteomyelitis, the value of bone marrow biopsy as a screening procedure is probably further reduced. Several studies have shown a high prevalence of giant cell arteritis among patients with FUO, with rates up to 17% among elderly patients. Giant cell arteritis often involves large arteries and in most cases can be diagnosed by FDG-PET. However, temporal artery biopsy is still recommended for patients ≥55 years of age in a later stage of the diagnostic protocol: FDG-PET will not be useful in vasculitis limited to the temporal arteries because of the small diameter of these vessels and the high levels of FDG uptake in the brain that overlies them. In the past, liver biopsies have often been performed as a screening procedure in patients with FUO. In each of two recent studies, liver biopsy as part of the later stage of a screening diagnostic protocol was helpful in only one patient. Moreover, abnormal liver tests are not predictive of a diagnostic liver biopsy in FUO. Liver biopsy is an invasive procedure that carries the possibility of complications and even death. Therefore, it should not be used for screening purposes in patients with FUO except in those with PDCs for liver disease.
In patients with unexplained fever after all of the above procedures, the last step in the diagnostic workup—with only a marginal diagnostic yield—comes at an extraordinarily high cost in terms of both expense and discomfort for the patient. Repetition of a thorough history-taking and physical examination and review of laboratory results and imaging studies (including those from other hospitals) are recommended. Diagnostic delay often results from a failure to recognize PDCs in the available information. In these patients with persisting FUO, waiting for new PDCs to appear probably is better than ordering more screening investigations. Only when a patient’s condition deteriorates without providing new PDCs should a further diagnostic workup be performed.