In human medicine, fever of unknown origin (FUO) is defined as pyrexia of greater than two to three weeks duration (i.e. sufficient
time for self-limiting infections to resolve) during which repeat physical examinations and standard diagnostic testing have
failed to reveal an underlying cause. Additional criteria are also occasionally suggested, such as presence of non-specific
signs of illness, or hospitalization to ensure patient compliance with antibiotic administration. Similar specific criteria
have not been accepted by veterinary internists; however, using similar guidelines, most internists will define patients as
having a fever of unknown origin if pyrexia persists beyond one to two weeks, physical examination prior to referral does
not reveal any abnormalities, and the minimum data base fails to localize an underlying disease process to a particular organ
system.
DIFFERENTIAL DIAGNOSIS
In theory, any inflammatory disease, including infectious, immune-mediated, and neoplastic diseases, may stimulate sufficient
tumor necrosis factor-α and interleukin-1 and -6 production to result in persistent fevers. However, diseases which result
in the official diagnosis of FUO are typically indolent, slowly progressive, or relatively occult. Two retrospective studies,
published ten years apart, have reviewed the final diagnoses ultimately made in dogs referred to veterinary teaching hospitals
for fever of unknown origin using approximately the same criteria as those mentioned above. Selected results in these populations
of dogs included:
It is important to mention that both of these studies were performed in the United Kingdom, so the relative prevalence of
various infectious diseases would be expected to alter results of similar studies in the United States; in truth, results
from different sites even within North America would likely vary widely as well. Nevertheless, despite the variation in time
and geography between these sites and the dog and cat populations most of the audience members here evaluate, it is clear
that when a diagnosis can be made, the most likely causes of fever of unknown origin are most likely immune mediated diseases
(with joint and CNS diseases predominating) or infectious diseases (with no single occult site of infection being more likely.
Neoplasia accounts for less than 10% of fever of unknown origin, with leukemia being most likely.
DIAGNOSTIC APPROACH
The most important diagnostic test in the work-up of an animal with a fever of unknown origin is the methodical, thorough
physical examination. Diagnostic testing to rule-in or –out even a small portion of the possible causes of fever is usually
beyond the financial means of most owners; therefore, targeting diagnostic tests to exclude differentials for a higher-yield
problem if at all possible is highly desirable. A full physical examination should include fundic examination, deep palpation
of long bones and the spine to see if pain can be elicited, neurologic and orthopedic examinations, rectal palpation, and
palpation of all joints. If a specific abnormality is found then a more refined problem list can be generated and work-up
proceeds from there.
If no additional abnormal clinical findings other than fever are identified, then diagnostic tests should be selected which
will help exclude large numbers of diseases, exclude diseases which are common causes of FUO, or which are over-represented
in a given geographic area. A full minimum database (i.e. complete blood count, serum chemistry panel, and urinalysis) will
help in many cases to target a specific organ system and as with the physical examination, hopefully lead to a higher-yield
problem. The CBC should include a manual differential cell count and a cytologist's assessment of cell morphology; this is
important because in some cases intra-cellular organisms (bacteria, rickettsial organisms) may be noted, or a 'leukocytosis'
may actually be a chronic leukemia. Urinalysis should include both urine dipstick and sediment examination. Next-tier diagnostic
testing most commonly includes survey thoracic and abdominal radiographs, urine culture, and FeLV and FIV testing in cats.
I prefer radiographs over ultrasonography for evaluation of the abdomen when no abnormality has been noted on physical examination
or bloodwork because the former allow for a 'one-shot,' global assessment; with abdominal ultrasound, the quality of the study
is much more dependent on operator skill, the entire abdomen cannot be assessed at once, and there is a much higher likelihood
that a focal image will never make it into the region being evaluated. Urine culture should be performed in all patients
regardless of urine sediment or specific gravity results—chronic pyelonephritis or prostatitis may result in intermittent
shedding of organisms into urine without any changes to the urinalysis, and in some cases identical bacterial isolates may
be found in urine and blood of septic animals. FeLV and FIV are rare causes of FUO, but a positive cat with a fever may be
considered more likely to be immunocompromised, and therefore secondary infections should be investigated, as well as an increased
likelihood of lymphoproliferative neoplasia and autoimmune hematologic disease.
Unfortunately, if these first- and second-tier diagnostic tests fail to identify any additional problems to work-up and as
a clinician you are still faced only with FUO on your problem list, then the third-tier list of possible diagnostic tests
becomes much less clear-cut. Choice of tests should rely on patient signalment (young vs old; breed-related diseases) and
geographic location and season (tick-borne diseases, fungal diseases, leptospirosis). Tests which should be considered based
on those results reported in the two retrospectives discussed earlier include arthrocentesis (whether or not joint effusion
or pain is present), abdominal ultrasound, blood cultures (even in the absence of a left-shift or toxic changes, and especially
if a heart murmur is present; optimally, blood should be collected at times the patient is febrile), aspiration of lymph nodes
or other parenchymal organs (perform if enlargement is suspected at all or if imaging suggests any change in echogenicity),
infectious disease testing (e.g. Lyme, Ehrlichia spp., Anaplasma spp., Leptospira sp.). The final tier of diagnostic tests would include bone marrow aspiration or biopsy, 'autoimmune panels' even though
other tests would not support IMHA, ITP, SLE, etc., echocardiogram, general anesthesia with CSF fluid collection, etc. It
cannot be stressed enough that testing should be logical and proceed in a step-wise fashion in order to prevent exhaustion
of owner funds, and the most important diagnostic test—the physical examination—cannot be repeated often enough in FUO patients.
