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Identifying the cause of a fever of unknown origin (FUO) in dogs and cats can present a considerable challenge. The diagnostic workup can be frustrating, especially when numerous tests fail to reach a definitive diagnosis, which happens in about 10% to 15% of dogs. A systematic review of human literature found that 19% of cases of FUO remain without a diagnosis.1 However, most causes of FUO can be found or treated successfully. Most FUOs are caused by a common disease presenting in an uncommon way. This article discusses common causes, diagnostic approach, and potential treatments of FUO in dogs and cats.
It is important to differentiate between fever and hyperthermia. True fever (pyrexia) is defined as an increase in body temperature due to an elevation of the thermal set point in the anterior hypothalamus secondary to the release of pyrogens.2 Dogs and cats with true fever usually have body temperatures between 103°F and 106°F (39.5°C to 41.1°C). 3 With hyperthermia, the hypothalamic set point is not adjusted. Hyperthermia occurs when heat gain exceeds heat loss, such as with inadequate heat dissipation, exercise, stress, and pathologic or pharmacologic causes. 4 Hyperthermia above 106°F is dangerous and can result in multi-organ failure, disseminated intravascular coagulation, systemic inflammatory response syndrome, and death. Temperatures less than 106°F are unlikely to be harmful and are beneficial because they present a protective response to inflammation.
The term FUO is used to describe fever that does not resolve spontaneously, does not respond to antibiotics, and for which the diagnosis is unclear despite an initial workup. In the majority of dogs and cats, febrile diseases are caused by an infection that is found during the initial workup and that responds to antibiotics; therefore, most dogs and cats do not have true FUO. 5
Possible causes of FUO in dogs and cats are summarized in Table 1. Fevers are common in cats and are usually due to an infection. Neoplasia is less common, and immune-mediated origins of FUO are even rarer. In dogs, infectious, immune-mediated, and neoplastic diseases are all common causes. In a study of 50 dogs from France, 48% were diagnosed with non-infectious inflammatory diseases.6 Another study found a 35% prevalence of immune-mediated diseases causing FUO in dogs.7
In human medicine, the frequency of fever due to non-infectious inflammatory diseases has also increased, while fever caused by infectious and neoplastic diseases has declined.
Table 1: Some of the most common causes of FUO in dogs and cats. 8,9
(FeLV = Feline leukemia virus, FIV = Feline immunodeficiency virus, FIP = Feline infectious peritonitis, FFV = Feline foamy virus, FCV = Feline calicivirus, IMHA = immune-mediated hemolytic anemia, ITP = immune thrombocytopenia, ), IMN = immune-mediated neutropenia, IMPA = immune-mediated polyarthritis, SLE = systemic lupus erythematosus, RA = rheumatoid arthritis, PSS = portosystemic shunt)
Many different bacteria can cause bacteremia, endocarditis, septic arthritis, osteomyelitis, discospondylitis, meningitis, cholangiohepatitis, pyothorax, pyelonephritis, prostatitis, pyometra or stump pyometra, peritonitis, deep pyoderma, or abscesses.
The diagnostic approach is done in three stages, and this should be communicated to the owner to set expectations from the beginning. Table 2 shows the three stages. Diagnostics start with basic, common, and non-invasive tests, and then gradually escalate to advanced and invasive tests. The baseline tests performed in the first and second stages need to be repeated as the disease tends to progress and new findings may be found.
Table 2: Staged diagnostic approach to FUO in dogs and cats.
All medications should be discontinued to rule out a drug-induced fever, which usually resolves in 72 hours from the last dose. Although any medication has the potential to cause fever in dogs, the following drugs are known to do so: albuterol, amphotericin, antihistamines, atropine, barbiturates, bleomycin, cimetidine, colchicine, nitrofurantoin, penicillins, procainamide, sulfa drugs, and tetracyclines. Drugs known to induce fever in cats include tetracycline, sulfonamides, penicillins, and opioids such as buprenorphine.
Thorough history is the first step in a successful diagnostic approach. Clients should be asked about subtle clinical signs and any travel history. Physical exam is essential, and it will need to be repeated and thorough, including a rectal exam, dilated fundic exam, neurologic exam, and orthopedic exam. CBC should be sent out for a review by a board-certified clinical pathologist to detect morphologic changes and parasites. Multiple blood smears may be needed to find infectious organisms like Histoplasma or Babesia. Blood samples should be submitted for infectious disease testing (PCR or serology) prior to antibiotic trials. A sterile urine sample should be submitted for urinalysis and urine culture in all dogs and cats with fever, even if the sediment is inactive.
Imaging should include three-view thoracic and abdominal radiographs with radiology review to look for masses, lymphadenopathy, pneumonia, osteolytic lesions, or effusions. Long bone radiographs are useful in young dogs with fever. As abdominal ultrasonography has become more available, it is usually performed in the first stage of investigation of FUO. Echocardiography should be performed in all patients with a new or diastolic murmur. Dogs with infectious endocarditis are usually medium to large breeds that do not tend to have myxomatous valve degeneration. 10 Nuclear scintigraphy can be considered if available to find “hot spots,” which are often associated with infection.
Serial blood cultures should be performed in all dogs with FUO, especially those with suspected endocarditis, discospondylitis, and polyarthritis. Special culture media and PCR testing are recommended for Bartonella identification. A paired serum bile acid test should be submitted in dogs or cats with increased liver values or a small liver on imaging, as fever has been described as the only clinical sign in some dogs and a cat with PSS.
IMPA is a common cause of FUO in dogs, and joint taps should be performed in Stage 2 of the diagnostic workup, even if no detectable joint swelling is present. IMPA tends to involve the carpi and tarsi, while infectious arthritis usually involves larger joints (e.g., stifle, elbow, shoulder).
Infectious disease testing should be tailored to the patient and endemic area, as negative antibody titers or PCR tests do not rule out infection, and positive titers could mean exposure. In some cases, paired serum antibody titers can differentiate between true infection versus exposure or vaccination such as Leptospirosis, Toxoplasma or Neospora. Muscle biopsy may be needed to diagnose Hepatozoon.
Immunodiagnostic panels (antinuclear antibodies, rheumatoid factor, Coombs) are usually unrewarding in dogs and can have false positive results11. In a study from 2005, 10 of 12 cats diagnosed with rheumatoid arthritis were strongly seropositive for rheumatoid factor. Although this test is not specific, it may be an important diagnostic test in cats with arthropathy. 12
Cytology of enlarged lymph nodes or affected organs should be performed. In one study, cytology was the test with the highest diagnostic value to determine the origin of FUO (56%). 6 If fine-needle aspiration cytology is not diagnostic, then biopsy may be helpful. In one study, biopsy samples submitted for histopathology enabled a diagnosis in 15 of 17 dogs with FUO. 7
The goal in all cases of FUO is to obtain a specific diagnosis and treat accordingly. Therapeutic trials should only be initiated when a specific diagnosis cannot be obtained.
Supportive treatments include intravenous fluids, cooling measures, and supportive therapy. Antipyretic drugs should be reserved for patients with fever over 105°F and those who have failed to respond to fluids and mechanical cooling, as they can mask the effects of other therapies and have side effects like gastrointestinal ulceration, as well as hepatic and renal toxicity.
Empirical antibiotics are chosen based on suspected bacterial agent only after all culture specimens have been collected. In severely ill patients, a combination of antibiotics effective against aerobic, anaerobic, gram-positive, and gram-negative organisms is recommended. If no response is seen within 72 hours, alternative therapies are warranted. NSAIDs, corticosteroids, and antifungal medications can be discussed with the client along with their side effects. A glucocorticoid trial should only be used when infectious diseases have been ruled out. Fever reduction should be seen in patients with immune-mediated FUO within 24-48 hours. However, there are risks of corticosteroid therapy, including dissemination of fungal or bacterial infection, decreased chance of diagnosing neoplastic diseases (especially lymphoma or immune-mediated diseases), and chemoresistance. Some immune-mediated diseases require two potent immunosuppressive medications and long-term therapy, which is cumbersome without a diagnosis.
In summary, the most common causes of FUO in dogs and cats include infectious, immune-mediated, and neoplastic causes. A logical and stepwise diagnostic approach leads to a definitive diagnosis in most patients. In some cases, repeating simple diagnostics and allowing time for more specific clinical signs to emerge is more rewarding than expensive and invasive diagnostics or “casting a broad net”. Communication with the client and setting appropriate expectations is the key. Broad knowledge of possible causative diseases and ability to interpret specific test results are essential.
