Fever of unknown origin (Proceedings)

Dogs that present with the vague client complaint of "ain't doin' right" can be a particularly difficult diagnostic challenge when the only significant finding on a routine physical examination is fever. The cryptic fever becomes even more challenging when the results of routine diagnostic laboratory work fail to localize the disease process. The veterinarian is then faced with the dilemma of determining which diagnostic test to choose to uncover the etiology of the fever. The dilemma, however, is also financial as the risk of high cost/low yield tests becomes greater with advancing diagnostics.

Cryptic fever, or fever of unknow origin, is defined in the human medical field as either a fever of greater than 3 weeks duration and an undetermined cause after one week of extensive in-hospital evaluation or a fever of greater than 2 weeks duration with no apparent diagnosis after routine diagnostics. For an immunosuppressed individual, the duration of fever is reduced to 3 days before it is described as a FUO. In the veterinary medical field, FUO is defined as any fever in which the cause is not readily apparent and has no response to empirically chosen antibiotics.

It is important to understand that inflammation is responsible for most abnormally elevated rectal temperatures and the 3 main categories of inflammatory disease are infectious disease, immune-mediated disease, and neoplasia. Sterile inflammatory processes, such as acute pancreatitis, can produce significant fever, as can drugs in some patients (hopefully easily identified from the medical history). Overly tight catheter wraps and other bandages are a common cause of recently developing fever in a hospitalized patient and should be the first thing evaluated when the patient did not initially have a febrile illness. Anxiety is a surprising cause of markedly elevated rectal temperatures, sometimes exceeding 104 F (40 C). These dogs may present for some other clinical problem but the "fever" results in a diagnostic work-up and differential diagnoses list that is off-track from the original problem. Re-taking the rectal temperature throughout the day while hospitalized or having the owner take the temperature at home later that day are valuable tools in deciding the significance of the fever.

Among infectious causes of cryptic fever, many will evidence some abnormality on physical examination or routine screening laboratory work. However, even diskospondylitis, pyelonephritis, leptospirosis, brucellosis, and the deep mycoses my present with no specific abnormalities. A recently detected cardiac murmur is a good clue for bacterial endocarditis, although the murmur may be missed early on in the course of disease. Urine culture, blood culture, and, in some cases, arthrocentesis are good sources of culture specimens. Serology and PCR assays are available for many of the unculturable agents such as leptospirosis, bartonellosis, and neosporosis.

Sterile inflammatory diseases to consider include the immune-mediated diseases such as systemic lupus erythematosus, aseptic meningitis, and immune-mediated polyarthritis. Dogs with immune-mediated polyarthritis may have relatively subtle lameness, presenting with more of a generalized stiffness and discomfort, but lameness can be uncovered by hyperflexing a limb and having the dog walk immediately after. Sterile inflammatory diseases of a non-immune basis to consider include pansteatitis, nodular panniculitis, granulomatosis, juvenile cellulitis, Shar-pei fever, hypertrophic osteodystrophy, panosteitis, and pancreatitis.

Any neoplasia can create fever, although common causes included lymphoma, leukemia, mulitple myeloma, hepatic neoplasia, and necrotic tumor masses. Hypothalamic disease, either neoplastic or granulomatous, could result in an elevated rectal temperature due to resetting of the thermostat. Drugs that have been reported to cause fever include penicillins, sulfas, quinidine, phenobarbital, levamisole, ketamine, and organophosphates.

The diagnostic approach should include a thorough history, especially to uncover an unexpected travel history, but also for evidence of previous diseases; physical examination, which should also include a fundic exam, oral exam, orthopedic and neurological evaluation, and otic exam; a minimum data base, which would include CBC, serum chemistry profile, blood smear, urinalysis, and urine culture. When the diagnosis is not readily apparent at that point the clinician is faced with the option of therapeutic trial or continued diagnostics. A therapeutic trial should have the goal of being diagnostic, so antibiotics should not be combined with antipyretics, such as NSAIDs or corticosteroids. The next level of diagnostics will include imaging, where thoracic and abdominal radiographs are the first line but abdominal ultrasound, echocardiography, CT or MRI, and dental radiographs are all possible options; serology for infectious disease, which is often based on regional prevalence; anti-nuclear antibody testing; cytology, including lymph node aspirates, joint taps, bone marrow aspirate, and CSF tap; blood culture; bronchoscopy; and a bone scan.

The question that needs to be asked and answered at every step of the way is "Do I have reasonable information for a diagnosis and treatment plan?" Antibiotic trials are given up to 72 hours to evaluate a response, but some reduction in fever should be evidenced early in that period. Reasonable antibiotics to try include Clavamox, cephalexin, doxycycline, and the fluoroquinolones. Clindamycin has utility when protozoal disease is suspected and azithromycin would be the drug of choice for bartonellosis. When the clinician has exhausted the diagnostics, or at least reached a reasonable confidence level that infectious disease is not present and there is no evidence of neoplasia, the default diagnosis is immune-mediated fever. Corticosteroid trials must be aggressive, starting at 2 mg/kg/day for a minimum of 3 weeks with gradual reduction by 25% every 3-4 weeks after that. If infectious disease is to be uncovered shortly after starting a corticosteroid regimen, most dogs will deteriorate within 3-5 days.