Fever of unknown origin refers generally to any persistent fever (ie, that does not resolve spontaneously or with empirical antimicrobial treatment) for which the underlying cause is not revealed from the case history, physical examination, and initial diagnostic testing. A variety of causes are possible, including infectious, immune-mediated, and neoplastic disease. A systematic, staged approach can assist with diagnosis. In the absence of a diagnosis, trial treatment may be attempted.
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 antimicrobial treatment. 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). When the fever persists and a diagnosis is not obvious, these cases can become a challenge for both the veterinarian and the animal's owner. Fortunately, a logical stepwise approach can lead to a diagnosis in most cases.
Body Temperature Regulation in Animals
Fever is measured by body temperature, which is regulated by the hypothalamus. This area of the brain acts to maintain temperature as close as possible to a normal set point (comparable to a thermostat). 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, heatstroke, exercise-induced hyperthermia, malignant hyperthermia, and seizure), body temperature is increased by abnormal and unregulated heat loss, heat gain, or heat production. The hypothalamic set point is not altered. Depending on severity, these conditions can potentially result in body temperatures of ≥41.1°C (106°F). In comparison, most patients with true fever have body temperatures in the range of 39.5°–41.1°C (103°–106°F).
An increase in 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 increasing the set point, resulting in fever.
Etiology and Pathogenesis of Fever of Unknown Origin in Animals
Fever of unknown origin 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 antimicrobial treatment (and do not relapse) and patients in which the cause of fever is determined from history, physical examination, or initial laboratory tests or in which fever resolves spontaneously. In human medicine, classic FUO is defined as fever >38.3°C (101°F) on several occasions over >2–3 weeks with no diagnosis established after three outpatient visits or 3 days in the hospital. However, there is no universally recognized definition of this syndrome in veterinary medicine, making it difficult to compare estimates of disease frequency. Cases of FUO are probably less frequent than in the past because of improved diagnostic technology (eg, imaging and molecular diagnostic tests).
In dogs, noninfectious inflammatory disease (including immune-mediated disease), infectious disease, and neoplastic disease are the most common causes of fever. In a retrospective 2012 study of 50 dogs with fever, 24 (48%) had noninfectious inflammatory disease, 9 (18%) infectious disease, and 3 (6%) neoplasia; in the remaining 14 (28%) cases, no definitive diagnosis was reached (albeit, the owner decided not to proceed with investigation in 13 of those cases). In a 1998 study of 101 dogs with fever, 22% had immune-mediated diseases, 22% primary bone marrow abnormalities, 16% infectious diseases, 11.5% miscellaneous conditions, 9.5% neoplasia, and 19% undetermined causes.1
In cats, the cause is more likely to be infectious. In a 2017 cases series of 106 cats with fever, 41 (38.7%) had infectious disease, 19 (17.9%) inflammatory disease, 13 (12.3%) neoplasia, 11 (10.4%) miscellaneous conditions, and 6 (5.7%) immune-mediated disease.2 No diagnosis was reached in 16 (15.0%) cases. Feline infectious peritonitis (FIP) was the most common cause of fever (22/106 [20.8%]).
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. In a 1989 case series of 63 horses with FUO, 27 (43%) had infectious disease, 14 (22%) neoplasia, 4 (6.5%) immune-mediated disease, 12 (19%) miscellaneous causes, and 9.5% undetermined causes.3
References
Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of unknown origin. J Small Anim Pract. 1998;39(12):574-580. doi:10.1111/j.1748-5827.1998.tb03711.x
Spencer SE, Knowles T, Ramsey IK, Tasker S. Pyrexia in cats: Retrospective analysis of signalment, clinical investigations, diagnosis and influence of prior treatment in 106 referred cases. J Feline Med Surg. 2017;19(11):1123-1130. doi:10.1177/1098612X17733624
Mair TS, Taylor FG, Pinsent PJ. Fever of unknown origin in the horse: a review of 63 cases. Equine Vet J. 1989;21(4):260-265. doi:10.1111/j.2042-3306.1989.tb02163.x
Diagnosis of Fever of Unknown Origin in Animals
History, physical examination, and initial diagnostic tests
Repeated physical examinations and reiterative stepwise approach
Diagnostic imaging, cytopathologic findings, and microbial culture of appropriate tissue/fluid samples
In cases of FUO, a systematic diagnostic plan that allows for detection of both common and uncommon causes of fever is key. The plan should include repetition of relevant tests because findings can change over time. Owners should be informed that reaching a diagnosis may require considerable time and patience and may require 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. In one retrospective study of fever in dogs, radiography, cytologic evaluation, and bacterial or fungal cultures of tissues or fluids were found to be the most useful diagnostic tests.
A staged or tiered approach to diagnosis can assist in choosing appropriate tests.
Stage 1: This stage includes simple steps and tests that often are repeated or reevaluated during the investigation of a FUO case. Most of the tests are readily available, relatively inexpensive, simple to perform, and easy to interpret:
Thorough history, including diet, preventives, medications, and supplements; medications that could induce fever should be discontinued
Physical examination
Ophthalmic and neurologic examinations
CBC with fibrinogen concentration (depending on species)
Serum biochemical analysis
Urinalysis
Bacteriologic culture of urine (particularly with a view to beginning antimicrobial treatment)
Feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV) tests (in cats)
Thoracic and abdominal radiography (particularly in small animals)
Stage 2: In this stage, some first-stage tests may be repeated (particularly 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. Examples include the following:
Bacteriologic culture of blood
Arthrocentesis (for cytologic evaluation and microbial culture, if indicated)
Abdominal ultrasonography
Lymph node aspiration (for cytologic evaluation and microbial culture, if indicated)
Fine needle aspiration of other organs or masses (for cytologic evaluation and microbial culture, if indicated)
Analysis of body fluids (eg, fluid from body cavities, milk samples, and reproductive tract secretions)
Rectal scrape cytologic evaluation
Bacteriologic culture of feces
Echocardiography (in the presence of a heart murmur)
Long-bone, spinal, and joint radiography
Contrast radiography (depending on other findings)
Serologic evaluation and molecular diagnostic tests
Stage 3: In the third stage, earlier tests may be repeated and additional specialized procedures introduced. These procedures are most likely to be chosen on the basis of previous findings. However, they may also be considered when all previous testing has been unrewarding, particularly if there are clinical signs that point towards a specific body system. Examples of testing at this stage include the following:
Echocardiography (in the absence of a heart murmur)
Dental radiography
Bone marrow aspiration and analysis
Bronchoscopy and bronchoalveolar lavage
CSF analysis
CT
MRI
Laparoscopy
Thoracoscopy
Biopsies
Exploratory surgery
Trial treatment
History and Physical Examination
Epidemiological characteristics such as vaccination, parasite control, exposure to vectors, and travel history should be reviewed. Response to previous medications should be determined as well as the presence of illness in other animals or humans. Owners should be questioned carefully about specific clinical signs, which may help localize the source of the fever. The physical examination should be detailed, including fundic, neurologic, and rectal examinations, and should be repeated frequently.
CBC and Serum Biochemical Analysis
Findings on CBC and serum biochemical analysis in animals with FUO are often nonspecific but may suggest further diagnostic tests. For example, bile acids assay may be indicated in an animal with changes suggestive of hepatic dysfunction. The CBC should be accompanied by blood smear evaluation to detect parasites or morphological changes.
Bacteriologic Culture of Urine
Bacteriologic culture of urine is always indicated to evaluate FUO in small animals, regardless of the appearance of the urine sediment.
Radiography and Advanced Imaging
Thoracic radiography and abdominal radiography are useful screening tools for the early localization of fever. Skeletal radiography and contrast radiography may subsequently be considered, depending on initial findings. For example, myelography may be used to investigate back pain. Advanced imaging, such as CT or MRI, may be indicated based on results of initial diagnostic testing or by consideration of the body system of interest (eg, MRI is particularly useful to evaluate the CNS). Nuclear scintigraphy and positron emission tomography are used in human patients with FUO but not yet widely used in veterinary medicine.
Ultrasonography and Echocardiography
Abdominal ultrasonography may reveal sources of fever such as neoplasia, peritonitis, pancreatitis, or abscesses. The thoracic cavity, limbs, and retrobulbar areas may also be examined by ultrasonography. Echocardiography is indicated at the early stages of evaluation of a patient with a heart murmur. This may aid in the detection of endocarditis, although this diagnosis should also be based on signalment, characteristics of the heart murmur, and results of bacteriologic culture of blood.
Bone Marrow Evaluation
Bone marrow cytologic evaluation and histologic evaluation should be performed in any patient with unexplained CBC abnormalities. Bone marrow disease is a common cause of FUO in small animals; therefore, bone marrow aspiration and biopsy, if possible, should also be included in the second stage of diagnostic testing if indicated by CBC findings. When obtaining bone marrow aspirates from cats, a sample should be saved for possible molecular diagnostic testing for FeLV.
Arthrocentesis
Because immune-mediated polyarthritis is a common cause of FUO in dogs, arthrocentesis of multiple joints 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 signs of spinal pain. Infectious polyarthritis is more commonly recognized in large animals, in which arthrocentesis is an important diagnostic test.
CSF Analysis
Sampling of CSF is recommended for dogs with FUO if less invasive tests do not reveal the cause of the fever. Fluid should be submitted for cytologic evaluation, protein concentration measurement, and microbial culture.
Bacteriologic Culture of Blood
Bacteriologic culture of blood is recommended in all animals with unexplained fever. The techniques used should allow the collection of adequately large volumes of blood under aseptic conditions. If the size of the animal allows collecting more than one set of samples for culture, use of appropriately sized aerobic and anaerobic bottles increases the sensitivity and specificity of the test. Special enrichment culture methods may be considered for certain organisms (eg, Bartonella spp).
Infectious Disease Testing
Tests available for the diagnosis of infectious diseases include assays for detection of antibodies or antigens in blood, urine, other body fluids, or tissues. Molecular diagnostic tests detect nucleic acid, with PCR assay being the most common in this category. Selection of these tests should be based on the signalment, clinical signs, and epidemiological characteristics (eg, vaccination, parasite control, exposure to vectors, and travel history) of the animal. Interpretation of test results requires an understanding of disease prevalence, vaccination history, and sensitivity and specificity of the test. When requesting PCR assays, it is important to use laboratories that have quality management programs that address test performance and consistency and that control for sample contamination.
Other Serologic Tests
The value of immune panels or autoantibody screens in small animal patients with FUO is unclear. Neither antinuclear antibody nor rheumatoid factor titers alone should be used to diagnose systemic lupus erythematosus or rheumatoid arthritis, respectively.
Microbiological, Cytopathologic, and Histologic Evaluation
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 microbiological or molecular diagnostic 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), molecular diagnostics, and special stains. If exploratory surgery is performed, biopsies should be obtained from several sites.
Treatment of Fever of Unknown Origin in Animals
External cooling not recommended for patients with true fever
IV fluid treatment and NSAIDs can be beneficial
For therapeutic trial with antimicrobials, collect samples for culture first
In some cases, either no specific diagnosis is reached or diagnostic testing is discontinued, leading to consideration of treatment in the absence of a diagnosis. Options include antifungal agents and other antimicrobials along with anti-inflammatory or immunosuppressive treatment (usually with corticosteroids).
Trial treatment may resolve the clinical signs or confirm a presumptive diagnosis; however, it is also associated with considerable risk. Before pursuing a therapeutic trial, the owner should be informed of the potential risks and should be committed to careful monitoring of the animal 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. If an animal is likely to be referred for in-depth investigation of FUO, trial treatment should not be started because it may affect the results of further testing.
In true fever, the increase 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, animals with FUO may benefit from IV fluid therapy or antipyretic medications. Examples include NSAIDs (eg, aspirin, carprofen, ketoprofen, or meloxicam in small animals; flunixin meglumine or phenylbutazone in large animals).
Key Points
Reaching a final diagnosis for FUO presents challenges but can usually be accomplished with a stepwise approach
Repeated physical examinations and simple tests often reveal diagnostic clues that can be followed with more focused or specialized testing to achieve a diagnosis.
In most cases of FUO in dogs and cats, infectious or inflammatory diseases are ultimately diagnosed. Polyarthritis is an important cause in dogs, and infectious diseases, particularly FIP, are noteworthy causes in cats.
Trial treatment is sometimes necessary but is most likely to be helpful if based on a tentative diagnosis, so that the response to treatment can be interpreted.
For More Information
Flood J. The diagnostic approach to fever of unknown origin in dogs. Compend Contin Educ Vet. 2009;31(1):14-E3.
Flood J. The diagnostic approach to fever of unknown origin in cats. Compend Contin Educ Vet. 2009;31(1):26-E4.
Chervier C, Chabanne L, Godde M, Rodriguez-Piñeiro MI, Deputte BL, Cadoré JL. Causes, diagnostic signs, and the utility of investigations of fever in dogs: 50 cases. Can Vet J. 2012;53(5):525-530.
Battersby IA, Murphy KF, Tasker S, Papasouliotis K. Retrospective study of fever in dogs: laboratory testing, diagnoses and influence of prior treatment. J Small Anim Pract. 2006;47(7):370-376. doi:10.1111/j.1748-5827.2006.00042.x
