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Uncovering the Cause of Fever in Dogs

Uncovering the Cause of
Fever in Dogs
Kenneth R. Harkin, DVM, Diplomate ACVIM (Small Animal Internal Medicine)Kansas State University

The term fever of unknown origin (FUO) is often
overused in veterinary medicine, as the number ofpatients in which a true cause of fever cannot be
uncovered is relatively small.
In 1961, Petersdorf and Beeson first defined FUO
in humans as a fever ≥ 101°F (38.3°C) that persists
for greater than 3 weeks, with the diagnosis uncertain
after one week of study in the hospital. This definition
has remained mostly intact today except for therequirement of in-hospital study.1,2 The duration ofgreater than 3 weeks was intended to eliminate casesof acute self-limited infectious disease (often viral)from the retrospective analysis of FUO cases.1
When describing FUO in dogs, fever is usually
defined as greater than 103.5°F to 104°F (39.7–
40°C), with no duration of fever specified.3,4 In
animals, the path to revealing the cause of persistent
fever can be lengthy and expensive but, in mostpatients, an etiology can be eventually identified (seeFUO in Animals: Often a Misnomer).
CLINICAL CHALLENGES
When a patient presents with an elevatedtemperature, it is important to distinguish from

FUO inAnimals: Oftena Misnomer

30

Veterinary patients are often describedincorrectly as having FUO when routine
diagnostic testing—which can usually becompleted over the course of a day—yields
negative results. In these cases, the designationof FUO is often applied prematurely. The term
should be reserved for patients in which no
etiology is revealed after an extensive workup.
Another commonly used, yet erroneous,criterion for defining FUO is a fever that does
not respond to empiric antibiotics. A responseto antibiotics does not prove a bacterial cause
for fever because a transient response may be
associated with an anti-inflammatory effect of
the antibiotic or the waxing and waning courseof disease. Thus, the cause of fever remains
unknown.

the outset whether the increase is due to fever
or nonfebrile hyperthermia (see Is It Fever orHyperthermia?).
Most dogs that present with fever have someabnormality on physical examination that helps
guide the diagnostic process. Abnormal findingsthat present with fever may include, among
others, lymphadenomegaly, joint effusion, spinalor paraspinal pain or discomfort, low-grade
cough, abnormal findings on thoracic auscultation,
enlarged and painful prostate or swollen testicles inintact dogs, resistance to manipulation of the neckand head, red and swollen gums, or abdominal
discomfort on palpation.
A dog that presents only with vague client
complaints of lethargy and hyporexia can be aparticularly difficult diagnostic challenge when
the only significant finding on routine physicalexamination is fever. Cryptic fever becomes evenmore challenging when:• Routine diagnostic laboratory work fails to
localize the disease process• The only abnormal finding on routine diagnostics
is inaccessible (eg, enlarged peribronchial lymph
nodes)• Evaluation of identified abnormalities (such as
an aspirate of an enlarged lymph node) fails tosuggest a definitive disease process (eg, reactive
lymph node).
The veterinarian is then faced with the dilemmaof determining which additional diagnostic tests topursue, and pursuit of more advanced diagnostics
can be curtailed by owner financial concerns thatarise with high-cost/low-yield tests and ownercompliance (or lack thereof).
DIFFERENTIAL DIAGNOSISFever often results from an immune or inflammatory
response, and most causes of fever can be classified
as infectious, immune-mediated, or neoplastic(Table).2,5

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Uncovering the Cause of Fever in Dogs

Fever implies an internal resetting of the
hypothalamic set point, whereas the elevated
body temperature in hyperthermia resultsfrom outside causes. Many veterinarians
have embarked on misguided diagnostic ortherapeutic pathways due to the presumptionthat an elevated rectal temperature is associatedwith inflammatory disease.
In my experience, it is not uncommon to see
dogs with elevated rectal temperatures associatedwith anxiety, environmental conditions, exercise,drugs, and catheters/wraps. In fact, I have seen
dogs that have presented with rectal temperaturesin the 103°F to 104°F range (even as high as 105°F)
as a consequence of anxiety.
The presence of fever can be confirmed either
by hospitalizing the dog for several hours or
instructing the owner to take the dog’s temperature at home when the pet is relaxed. Likewise,
when a dog that is being treated in the hospitalfor a noninflammatory disease suddenly develops
an elevated rectal temperature but no other signs(eg, cough), the first step should be removal oftight bandages and removal/replacement of
intravenous catheters before investigation for a
nosocomial infection or other source of fever.

Infectious CausesWith infectious causes of cryptic fever, many animals
have evidence of some abnormality on physicalexamination or routine laboratory screening.
However, even diskospondylitis, pyelonephritis,
leptospirosis, and the deep mycoses may present withno specific abnormalities.4,6-10
A recently detected cardiac murmur can indicate
bacterial endocarditis, although the murmur may
be missed early in the course of disease. However,
it is just as likely the murmur has been present andundetected for some time and is not part of thecurrent febrile disease.

commonly lymphoma, leukemia, multiple myeloma,
hepatic neoplasia, and necrotic tumor masses. One
would expect hematologic abnormalities on thecomplete blood count (CBC), but these changes
can often be subtle and/or misleading. Unexplained
hematologic abnormalities should be viewed as aninvitation to perform a bone marrow examination—
aspiration or biopsy—which often yields a diagnosis.

Immune-Mediated Causes
Sterile inflammatory diseases are most commonly
immune-mediated, and include immune-mediatedpolyarthritis (IMPA), steroid-responsive meningitisarteritis (SRMA), and systemic lupus erythematosus.
In some dogs, IMPA and SRMA can be more difficult
to diagnose because:
1. Laboratory changes are often restricted to an
inflammatory leukogram
2. Dogs with IMPA may have relatively subtle
lameness and minimal joint effusion, presenting
with more generalized stiffness and discomfort(which can also be confused as SRMA).11
Lameness can sometimes be uncovered byhyperflexing a limb; then having the dog walk
immediately afterward.
Some sterile inflammatory processes are notimmune-mediated but can produce significant fever;these diseases include acute pancreatitis, pansteatitis,
nodular panniculitis, granulomatosis, juvenile
cellulitis, shar-pei fever, hypertrophic osteodystrophy,
and panosteitis.3,4,12,13

Table.
Causes of Persistent Fever in Dogs

Neoplastic Causes
Fever may be seen with various cancers, mostPeer Reviewed

Is It Fever orHyperthermia?

DIAGNOSTIC APPROACH
Initial Diagnostics
The initial diagnostic approach in a dog with
unexplained fever should begin with signalment,

Infectious

Bronchopneumonia
Deep mycoses
Diskospondylitis
Leptospirosis
Pyelonephritis
Pyothorax
Soft tissue abscessTick-borne disease
Toxoplasmosis or neosporosis

ImmuneMediatedGranulomatous
meningoencephalitis
Panniculitis
Polyarthritis
Steroid-responsive fever
Steroid-responsive meningitisarteritis
Systemic lupus erythematosus

Neoplastic

Lymphoid leukemia
Lymphoma
Myeloma
Other leukemias

MiscellaneousHypertrophic osteodystrophy
Intervertebral disk disease3
Pancreatitis, acute or chronic
Panosteitis
Portosystemic shunt1

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UNCOVERING THE CAUSE OF FEVER IN DOGS

patient history, physical examination, and laboratory
diagnostics (see Diagnosing Fever: A Stepwise
Approach, page 34). When the diagnosis is notreadily apparent following the initial diagnostic
approach, the clinician is faced with the option of atherapeutic trial or continued diagnostics.

Ask
Yourself…
The question thatneeds to be asked
and answered at every
step of the way is: Do
I have reasonable
information fora diagnosis andtreatment plan? This
question should always
be re-evaluated justbefore and after anantibiotic trial (either
failure or success).

Therapeutic Trial
The goal of the therapeutic trial should be diagnosis(or, at least, elimination of a disease category);
therefore, antibiotics should not be combined with
antipyretics, such as nonsteroidal anti-inflammatory
drugs (NSAIDs) or corticosteroids. Artificial
resolution of fever due to antipyretic administration
may improve the patient’s demeanor but is rarely
required and tends to delay and confuse thediagnosis.
Antibiotic selection is empiric and often basedon prior experience or suspicions (eg, doxycycline
in a dog with high tick exposure). Depending on
the patient’s condition, most antibiotic trials areadministered for 48 to 72 hours before declaring
failure and considering either an alternate antibiotic
choice or the next step in diagnostics.
During this trial period, the patient can bestabilized with IV fluids and other supportive care,
if required, or discharged to the client if relatively
stable.
Further Diagnostics
Presuming there is no response to the therapeutic
trial(s) and no distinctive localized findings toprompt more specific diagnostic tests, the next levelof diagnostics should be pursued.
These tests, some of which may require referral tospecialty practitioners, include:• Cytology and blood cultures• Serology or polymerase chain reaction (PCR)• Antinuclear antibody testing• Imaging, such as radiography and ultrasound• Bone scan
• Bronchoscopy.
Cytology & Other Testing
Random cytologic sampling is often not valuable,
but simple collections, such as peripheral lymph node
aspirates, can be obtained easily. There are a variety ofsites from which to sample, some more challenging
than others, and diagnostics can include aspirates
of apparently normal lymph nodes, joint taps, bonemarrow aspirate, and cerebrospinal fluid (CSF) tap.
Serology or PCR may be indicated for certain

32

infectious diseases, and the specific selection of tests isoften based on regional prevalence of such diseases.
Imaging
Abdominal radiographs and ultrasound (if available)
are commonly pursued because it is difficult to
palpate the abdomen in many dogs, especiallythose that are particularly deep chested. Abdominal
radiographs are also important in the diagnosis
of diskospondylitis. In the absence of identifiable
abdominal pain or abnormalities on palpation,
thoracic radiographs often have more value thanabdominal radiographs.
Computed tomography or magnetic resonanceimaging of the brain rarely has value in the absenceof neurologic abnormalities; CSF analysis has
surprisingly greater benefit and is less expensive.
DEFAULT DIAGNOSISWhen the clinician has exhausted the diagnostics
or, at least, reached a reasonable confidence levelthat infectious disease is not present and there isno evidence of neoplasia, the default diagnosis isimmune-mediated fever.
Corticosteroid trials must be administeredappropriately; my protocol is to administer
prednisone at 2 mg/kg Q 24 H (or 60 mg/M2 forlarger dogs) for a minimum of 3 weeks (presuming
the patient’s response is good), with gradualreduction by 25% every 3 to 4 weeks. If infectious
disease is present, most dogs will deteriorate within 3
to 5 days of initiating a corticosteroid regimen.
LITERATURE REVIEW
Three large retrospective studies of fever in dogs offer
a valuable perspective on the outcome of diagnostic
investigations into fever.3,4,14 Although the studies
were conducted in Europe, where prevalence andtype of infectious diseases may differ from those seenin the United States, the general findings are relevant
across canine populations.
Inclusion Criteria
Inclusion criteria for these studies were fairly
straightforward. Two studies included dogs that had
a recurrent or persistent fever (> 40°C [104°F] on
at least one occasion) documented for 1 week orlonger.3,14 In the other study, investigators searchedpatient records for the term FUO or fever of unknown
origin in the letter from the referring veterinarianas well as documentation of a fever (> 39.7°C[103.5°F]).4

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Uncovering the Cause of Fever in Dogs

Diagnostic Results
The records of 217 dogs with fever were evaluated.
The most common final diagnostic category was
immune-mediated disease, which was present in 32%(69/217) of the dogs. This category included IMPA
and SRMA, both of which commonly have localizing
signs.
Diagnostic Approach
When additional diagnostic tests were performed,
presumably based on an abnormal finding on physicalexamination or routine screening laboratory tests(CBC, serum biochemistry profile, urinalysis),

Over the past 6 to 8 years, clinicians at Kansas
State University Veterinary Health Center haveidentified more than 50 dogs with fever and avariety of clinical signs, including facial cellulitis,
lymphadenomegaly, polyarthritis, hematologic
abnormalities, hepatic enzyme elevation, andgeneral malaise.
Diagnostic Findings
The most common cytologic finding fromaspirates of the affected organ or tissue in thesepatients was pyogranulomatous (sometimes
just suppurative) inflammation with no visibleorganism.
These findings led to a consideration ofseveral diagnoses—fungal disease, systemic
lupus erythematosus, or IMPA. However, theantinuclear antibody tests were negative and thepolyarthropathy did not respond as expected tocorticosteroids (although, often with very little
detrimental effect other than the disease did not
resolve completely).
The pursuit of this disease as infectious
began when a holiday delayed an exploratory
surgery on a febrile dog with pyogranulomatous
hepatitis (from a liver aspirate). The dog was
serendipitously administered enrofloxacin andazithromycin and responded completely to thiscombination, with no surgery needed.
Use of Two Antibiotics
Subsequently, it was discovered that otherdogs with pyogranulomatous inflammation of
no apparent cause responded completely to a
combination of:`` A fluoroquinolone (enrofloxacin, 7.5–10 mg/
kg PO Q 24 H or 5 mg/kg PO Q 12 H) or`` Ciprofloxacin, 15–20 mg/kg PO Q 24 H and`` Azithromycin, 5 mg/kg Q 24 H.
When dogs respond (eg, resolution or reduction of fever, cellulitis) to this antibiotic combina-

Peer Reviewed

the diagnostic yield was fairly high. For instance,
cytology (which was poorly defined in these studies
but included aspirates of masses or enlarged lymph
nodes, CSF or synovial fluid analysis, and evaluationof bronchoalveolar lavage samples) provided, or was
crucial to, the diagnosis in 56% to 62% of the dogs, andbone marrow aspiration yielded a diagnosis in 64%.
However, diagnostics that are often performed
as screening tests and not always chosen based ona specific identified abnormality had a much lower
yield. Radiographs revealed a diagnosis in 48% of
patients (22/46 dogs) in the study by Dunn and
Dunn3 but in only 9.5% and 3.3% of the patients intion, they show dramatic improvement within 48
hours and the typical protocol is to proceed witha 6-week course; then carefully monitor the dog
over the following 6 months for relapse. As withall antibiotic trials, if dogs do not respond within
72 hours, the trial should not be continued.
Ongoing Investigation
This treatment approach is based on theassumption that patients likely have bartonellosis
or are infected with an unidentified unculturable
organism even though:`` Bartonellosis has not been confirmed with
PCR or serology testing in these dogs`` Use of this antibiotic combination varies
from other treatment recommendations forbartonellosis.
Bartonellosis has been reported in dogs withfever and pyogranulomatous inflammation invarious organs,15-18 and the investigation into thedogs at Kansas State University continues.

UnpublishedObservations
from Kansas
State University:
Dual Therapy for
Antibiotic Trials

Note on Ciprofloxacin
Some veterinary professionals feel that
ciprofloxacin has unpredictable absorption
and pharmokinetics and, therefore, should not
be used in dogs due to the results of a 2012
study.19 That study was conducted on 6 beagles
that were fasted for 18 hours; 4 demonstrated
high levels of absorption when administeredciprofloxacin, while 2 had poor absorption.
A study comparing oral ciprofloxacin andnorfloxacin in 4 beagles also noted inconsistentabsorption of ciprofloxacin.20 In contrast, a 1990
study on 4 mixed breed dogs (range, 16.4–27.3kg) did not demonstrate large variations inpharmacokinetic variables.21 Therefore, a study
involving a larger number of dogs receiving
ciprofloxacin in real-world conditions (ie, withfood) is needed to understand the prevalence ofvariable absorption among dogs.

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Peer Reviewed

Uncovering the Cause of Fever in Dogs

Diagnosing Fever: A Stepwise Approach
Consider signalment• Age• Neuter status• BreedObtain a thorough patient and environmental history, which may uncover:+ Unexpected travel history or recent boarding or recreational activities (eg,lake swimming)+ Evidence of previous diseases+ Prior treatments for the presenting complaint (especially with clients who may
be pursuing a second or third opinion)+ Response to prior therapy, which often provides the greatest clues to apotential diagnosis (or at least category of disease)

Perform a careful physical examination:• Orthopedic and neurologic assessments and evaluation• Fundic, oral, and otic examinations• Digital rectal, spinal, and paraspinal palpation

Direct diagnostics based on physical examination findings(eg, aspirates of enlarged lymph nodes, radiographs of abdomen or thorax)

Undertake laboratory diagnostics:+ Complete blood count+ Serum biochemical profile+ Urinalysis and urine culture (often performed regardless of the urine sediment)+ Screening for vector-borne disease (eg, SNAP 4Dx Plus [idexx.com]), depending on disease prevalence, time of year, and hematologic abnormalities

Conduct additional directed diagnostics
based on initial laboratory work(eg, bone marrow with bi- or pancytopenia)

If no diagnosis, consider first antibiotic trial or additional
nondirected diagnostics:+ Abdominal and thoracic radiographs (including spine)+ Abdominal ultrasound+ Echocardiogram+ Urine or blood culture+ Aspirates of normal lymph nodes+ PCR screening for infectious organisms+ Antinuclear antibody testing

If no response, consider second antibiotic trial or
additional nondirected diagnostics (see list above)
Repeat antibiotic trial with different targeting of spectrum

If antibiotic trials have failed, and no additional diagnostics seemreasonable, consider corticosteroid trial for immune-mediated disease34

the studies by Battersby et al4 and Chervier et al,14
respectively.
Although thoracic and abdominal radiographs
were reportedly obtained in almost all dogs in
the studies by Dunn and Dunn and Battersby
et al, diagnoses were most commonly acquired
from lesions identified on bony structures (eg,osteomyelitis, diskospondylitis, hypertrophic
osteodystrophy).3,4 Chervier et al did not specify what
type of radiographs were obtained.14
Likewise, abdominal ultrasonography, PCR
testing for vector-borne disease, and serology fortoxoplasmosis and neosporosis infrequently yielded adiagnosis.4 These methods failed to yield a diagnosis
in 19/1013, 15/664, and 14/5014 dogs.
Effect of Therapy
In the study by Battersby et al, therapy administeredin the 24 hours before referral increased the timenecessary to obtain a diagnosis.4 Chervier et al also
looked at the effect of prior treatment, and although
the mean time to diagnosis was longer in the groupthat had received prior treatment (12.75 versus 9.2
days in those that had not received prior treatment),
this finding was not statistically significant.14
The findings by Battersby et al emphasize theneed to resist the knee-jerk response to administeranti-inflammatories (NSAIDs or glucocorticoids)
in response to fever4—a reaction often referred toas fever phobia in human medicine.22 Although fever
may be a marker for a serious and life-threatening
disease process, no evidence demonstrates that fever
itself will result in organ damage or other serious
consequences.23
Although an antibiotic trial is often recommended
and frequently employed in the workup of fever,antibiotics should be administered only aftertarget areas have been sampled (eg, blood, urine,or abdominal fluid for culture or PCR). It is
important that no additional antimicrobials or antiinflammatories that may confuse the interpretation of
the response be administered concurrently.
Outcomes
Outcomes for dogs with FUO were discussed inonly one of these studies, with nearly half the dogs
(7/15) demonstrating resolution of fever without
treatment, 3 responding to antibiotics, and 2
requiring glucocorticoids.4 Chervier et al highlighted
the importance of client compliance in obtaining
a diagnosis: of 14 dogs in which a diagnosis was
not obtained, failure of clients to pursue diagnostic

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UNCOVERING THE CAUSE OF FEVER IN DOGS

investigation was the reason for lack of diagnosis in 13
patients.14
IN SUMMARY
Uncovering the cause of fever in dogs is usually astraightforward process. For those in which the etiology
is not easily uncovered, however, an ordered and logicaldiagnostic and treatment protocol helps categorize the
etiology (ie, infectious, immune-mediated, neoplastic)—even
if the ultimate diagnosis is vague (eg, immune-mediatedfever).
CBC = complete blood count; CSF = cerebrospinal fluid;
FUO = fever of unknown origin; IMPA = immunemediated polyarthritis; NSAID = nonsteroidal antiinflammatory drug; PCR = polymerase chain reaction;
SRMA = steroid-responsive meningitis-arteritis
References
1.

Petersdorf RG, Beeson PB. Fever of unexplained origin: Report on 100
cases. Medicine 1961; 40:1-30.
2. Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: A clinicalapproach. Amer J Med 2015; 128:1138e1-1138e15.
3. Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of
unknown origin. J Small Anim Pract 1998; 39:574-580.
4. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of fever indogs: Laboratory testing, diagnoses and influence of prior treatment. J
Small Anim Pract 2006; 47:370-376.
5. Flier JS, Underhill LH. The neurological basis of fever. New Engl J Med
1994; 330(26):1880-1885.
6. Burkert BA, Kerwin SC, Hosgood GL, et al. Signalment and clinicalfeatures of diskospondylitis in dogs: 513 cases (1980-2001). JAVMA 2005;
227(2):268-275.
7. Harkin KR, Roshto YM, Sullivan JT. Clinical application of a polymerase
chain reaction assay for diagnosis of leptospirosis in dogs. JAVMA 2003;
222:1224-1229.
8. Bromel C, Sykes JE. Histoplasmosis in dogs and cats. Clin Tech Small Anim
Pract 2005; 20:227-232.
9. Graupmann-Kuzma A, Valentine BA, Shubitz LF, et al. Coccidioidomycosisin dogs and cats: A review. JAAHA 2008; 44:226-235.
10. Bromel C, Sykes JE. Epidemiology, diagnosis, and treatment of
blastomycosis in dogs and cats. Clin Tech Small Anim Pract 2005; 20:233239.
11. Rondeau MP, Walton RM, Bissett S, et al. Suppurative, nonseptic
polyarthropathy in dogs. J Vet Intern Med 2005; 19:654-662.
12. Safra N, Johnson EG, Lit L, et al. Clinical manifestations, response totreatment, and clinical outcome for Weimaraners with hypertrophic
osteodystrophy: 53 cases (2009-2011). JAVMA 2013; 242(9):1260-1266.
13. Hess RS, Saunders HM, Van Winkle TJ, et al. Clinical, clinicopathologic,
radiographic, and ultrasonographic abnormalities in dogs with fatal acutepancreatitis: 70 cases (1986-1995). JAVMA 1998; 213:665-670.
14. Chervier C, Chabanne L, Godde M, et al. Causes, diagnostic signs, and theutility of investigations of fever in dogs: 50 cases. Can Vet J 2012; 53:525530.
15. Drut A, Bublot I, Breitschwerdt EB, et al. Comparative microbioligicalfeatures of Bartonella henselae infection in a dog with fever of unknown
origin and granulomatous lymphadenitis. Med Microbiol Immunol 2014;
203:85-91.
16. Breitschwerdt E, Blann KR, Stebbins ME, et al. Clinicopathologicalabnormalities and treatment response in 24 dogs seroreactive to Bartonella
vinsonii (berkhofﬁi) antigens. JAAHA 2004; 40:92-101.
17. Friedenberg SG, Balakrishnan N, Guillaumin J, et al. Splenic vasculitis,
thrombosis, and infarction in a febrile dog infected with Bartonella henselae.
J Vet Emerg Crit Care 2015; 25(6):789-794.
18. Tucker MD, Sellon RK, Tucker RL, et al. Bilateral mandibular
pyogranulomatous lymphadenitis and pulmonary nodules in a dog with

Peer Reviewed

KENNETH R. HARKIN

Kenneth R. Harkin, DVM, Diplomate ACVIM (Small
Animal Internal Medicine), is a professor and head of
the Section of Medicine in the College of Veterinary
Medicine at Kansas State University. His researchinterests include infectious diseases and immunology,
with a special interest in leptospirosis. He currently
lectures on gastroenterology, hematology, hepatology,
and neurology.

Bartonella henselae bacteremia. Can Vet J 2014; 55:970-974.
19. Papich MG. Ciprofloxacin pharmacokinetics and oral
absorption of generic ciprofloxacin tablets in dogs. Am J Vet
Res 2012; 73(7):1085-1091.
20. Albarellos GA, Montoya L, Waxman S, et al. Ciprofloxacin andnorfloxacin pharmacokinetics and prostatic fluid penetration indogs after multiple oral dosing. Vet J 2006; 172:334-339.
21. Walker RD, Stein GE, Hauptmam JG, et al. Serum andtissue cage fluid concentrations of ciprofloxacin after oral
administration of the drug to healthy dogs. Am J Vet Res
1990; 51(6):896-900.
22. Purssell E, Collin J. Fever phobia: The impact of time andmortality—A systematic review and meta-analysis. Int J Nurs
Stud 2016; 56:81-89.
23. Neto AS, Pereira VGM, Colombo G, et al. Should we treat
fever in critically ill patients? A summary of the current
evidence from three randomized controlled trials. Einstein
2014; 12(4):518-523.

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