Fever of Unknown Origin: Introduction

In both veterinary and human patients, fever may indicate infectious, inflammatory, immune-mediated, or neoplastic disease. In most cases, the history and physical examination reveal the cause of the fever, or the fever resolves spontaneously or in response to antibiotic therapy. However, in a small percentage of patients, the cause of fever is not readily apparent, and the problem becomes persistent or recurrent. These patients are said to have fever of unknown origin (FUO).

In human medicine, classical FUO is defined as fever >101ºF (38.3ºC) on several occasions over a period >2-3 wk with no diagnosis established after 3 outpatient visits or 3 days in the hospital. There is no recognized definition of this syndrome in veterinary medicine, making it difficult to determine its true prevalence. FUO is probably less prevalent now than 20 years ago due to improved diagnostic technology (eg, imaging, labortory tests).

Body Temperature Regulation:

Body temperature is regulated by the hypothalamus. This area of the brain acts as a thermostat to maintain temperature as close as possible to a normal set-point. The hypothalamus receives input from internal and external thermoreceptors, and it activates physiologic and behavioral activities that influence heat production, heat loss, and heat gain. Hyperthermia refers to any increase in body temperature above the normal range. Fever is a particular form of hyperthermia in which the heat loss and heat gain mechanisms are adjusted to maintain body temperature at a higher hypothalamic set-point; thus, fever is essentially a regulated hyperthermia. In nonfebrile cases of hyperthermia (eg, heat stroke, exercise-induced hyperthermia, malignant hyperthermia, seizure), body temperature is elevated by abnormal and unregulated heat loss, heat gain, or heat production, and the hypothalamic set-point is not altered. Depending on their severity, these conditions can potentially result in body temperatures ³106ºF (41.1ºC). In comparison, most patients with true fever have body temperatures in the range of 103-106ºF (39.5-41.1ºC). Elevation of the hypothalamic set-point may be initiated by exogenous pyrogens, which include drugs, toxins, and viral or bacterial products (eg, endotoxin). These pyrogenic stimuli lead to the release of cytokines, termed endogenous pyrogens, from inflammatory cells. Ultimately, locally synthesized prostaglandin E2 in the hypothalamus is responsible for elevating the set-point, resulting in fever.

Etiology and Pathogenesis:

FUO may be defined as fever that does not resolve spontaneously in the period expected for self-limited infection and for which a cause cannot be found despite considerable diagnostic effort. This excludes patients that respond to antibiotic therapy (and do not relapse) and patients in which the cause of fever is determined from initial history, physical examination, or laboratory tests, or in which fever resolves spontaneously. Infectious, immune-mediated, and neoplastic disease are the most common causes of FUO in dogs. In a study of 101 dogs with fever, 22% had immune-mediated diseases, 22% primary bone marrow abnormalities, 16% infectious diseases, 9.5% neoplasia, 11.5% miscellaneous conditions, and 19% had genuine FUO. In cats, the cause is more likely to be infectious, but there are fewer published data on feline cases compared with canine cases. In a case series of horses with FUO, 43% had infectious disease, 22% had neoplasia, 6.5% had immune-mediated disease, 19% had miscellaneous causes, and in 9.5% the cause was not determined. In farm animals, the most likely causes of FUO are infectious or inflammatory diseases such as pneumonia, peritonitis, abscesses, endocarditis, metritis, mastitis, polyarthritis, and pyelonephritis.

Diagnosis:

The key to diagnosis of FUO is to develop and follow a systematic plan that allows for the detection of both common and uncommon causes of fever. Clients should be informed that diagnosis of FUO may require considerable time and patience and may demand more advanced or expensive diagnostic tests. Nevertheless, simple and inexpensive tests may also reveal diagnostic clues that eventually point to the cause of the fever. A staged or tiered approach to diagnosis can assist in choosing appropriate tests. The first stage should include history, physical examination, ophthalmic and neurologic examinations, CBC, fibrinogen, serum chemistry profile, urinalysis and urine culture, feline leukemia virus and feline immunodeficiency virus tests (cats), and usually thoracic and abdominal radiographs in small animals. In the second stage, some first-stage tests may be repeated (particularly the physical examination) and additional specialized tests are performed. These may be dictated by abnormal findings in the first stage of testing or may be determined by consideration of the most common known causes of FUO. Tests included in this stage include blood cultures, arthrocentesis, abdominal ultrasound, lymph node aspiration, aspiration of other organs or masses, analysis of body fluids (eg, fluid from body cavities, milk samples, reproductive tract secretions), fecal culture, echocardiography (in the presence of a murmur), long-bone and joint radiographs, contrast radiographs, and serology. The third stage again may repeat earlier tests, as well as additional specialized procedures. These procedures are most likely to be chosen on the basis of previous findings, but may also be considered when all previous testing has been unrewarding. Examples include echocardiography (in the absence of a murmur), dental radiographs, bone marrow aspiration, bronchoscopy and bronchoalveolar lavage, CSF analysis, computed tomography (CT), MRI, laparoscopy, thoracoscopy, biopsies, exploratory surgery, or trial therapy. History and Physical Examination: Epidemiologic characteristics such as vaccination, parasite control, and travel history should always be reviewed. The response to previous medications should be determined, as well as the presence of illness in other animals or humans. Clients should be questioned carefully about specific clinical signs as these may help localize the source of the fever. The physical examination should be detailed and repeated frequently. CBC and Serum Chemistry Profile: The CBC and chemistry changes in FUO patients are often nonspecific, but may suggest further diagnostic tests. The CBC should always be accompanied by blood smear evaluation to detect parasites or morphologic changes. Urine Culture: This test is always indicated to evaluate FUO in small animals, regardless of the appearance of the urine sediment. Radiography and Advanced Imaging: Thoracic and abdominal radiographs are useful screening tools for the early localization of fever. Skeletal radiographs and contrast radiographs may subsequently be considered, depending on initial findings. For example, myelography may be used to investigate back pain. The use of advanced techniques such as CT and MRI is determined by the results of initial diagnostic testing or by consideration of the body system of interest, eg, MRI is particularly useful for evaluating the CNS. Ultrasonography and Echocardiography: Abdominal ultrasound may reveal a source of fever in the abdomen, such as neoplasia, peritonitis, pancreatitis, or abscesses. The thoracic cavity, limbs, and retrobulbar areas may also be examined by ultrasound. Echocardiography is indicated at the early stages of evaluation of the FUO patient with a murmur. This may aid in the detection of endocarditis, although this diagnosis should also be based on signalment, onset of the heart murmur, and blood culture results. Bone Marrow Evaluation: Bone marrow cytology and histology should be evaluated in any patient with unexplained CBC abnormalities. Bone marrow disease is a common cause of FUO in small animals; therefore, bone marrow aspiration should also be included in the second stage of diagnostic testing in these patients. Arthrocentesis: Because immune-mediated polyarthritis is a common cause of FUO in dogs, arthrocentesis is included in the second stage of diagnostic testing in this species, even if the joints are normal on palpation. Some dogs with steroid-responsive meningitis-arteritis also have concurrent immune-mediated polyarthritis; therefore, arthrocentesis should be performed in dogs with spinal pain. Infectious polyarthritis is more commonly recognized in large animals, in which arthrocentesis is an important diagnostic test. Blood Culture: Blood cultures are recommended in all patients with unexplained fever. The techniques used should allow the collection of adequately large volumes of blood under aseptic conditions. If the size of the patient allows collecting more than one blood culture set, using appropriately sized aerobic and anaerobic bottles increases the sensitivity and specificity of the test. Serology: Serologic tests are available for the diagnosis of many infectious diseases and some immune-mediated disorders. Selection should be based on the signalment, clinical signs, and epidemiologic characteristics of the patient. Interpretation of test results requires an understanding of disease prevalence, vaccination history, and sensitivity and specificity of the test. The use of immune panels or autoantibody screens in small animal patients with FUO is discouraged. Neither antinuclear antibody or rheumatoid factor titers alone are sensitive or specific enough to diagnose systemic lupus erythematosus or rheumatoid arthritis, respectively. Microbiology, Cytology, and Histology: Fine-needle aspirates are safe and simple to obtain from effusions, masses, nodules, organs, tissues, and body fluids. Fluids should be examined cytologically and also submitted for microbiologic testing. Tissue biopsies are generally obtained in the second or third stages of diagnostic testing, after clinical signs or initial diagnostic tests have localized the fever. When biopsies are obtained, sufficient samples should be submitted for histopathology, appropriate culture (aerobic and anaerobic, fungal, mycoplasmal, mycobacterial, etc), and special stains. If exploratory surgery is performed, biopsies should be obtained from several sites.

Treatment:

In some FUO cases a specific diagnosis is not reached, or diagnostic testing is discontinued, leading to consideration of therapy in the absence of a diagnosis. Options include antibiotics, antifungal agents, and anti-inflammatory or immunosuppressive therapy (usually with corticosteroids). Trial therapy may resolve the patient’s clinical signs or may confirm a presumptive diagnosis, but it is also associated with significant risk. Before pursuing a therapeutic trial, the client should be informed of the potential risks and should be committed to careful monitoring of the patient for an appropriate length of time. The therapeutic trial should be based on a tentative diagnosis and should define the parameters to be followed and the criteria used to determine treatment success or failure. In true fever, the elevation in body temperature is regulated; therefore, cooling methods such as water baths work against the body’s own regulatory mechanisms. It is also likely that fever itself has some beneficial effects, particularly in infectious diseases. However, fever can lead to anorexia, lethargy, and dehydration. Thus, FUO patients may benefit from IV fluid therapy or from the use of antipyretic medications. Examples include NSAID such as aspirin, carprofen, ketoprofen, and meloxicam (small animals) and flunixin meglumine or phenylbutazone (large animals).