Uncovering the Cause of Fever in Dogs

The term fever of unknown origin (FUO) is often overused in veterinary medicine, as the number of patients 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 the requirement of in-hospital study.^1,2 The duration of greater than 3 weeks was intended to eliminate cases of 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 most patients, an etiology can be eventually identified.

Clinical Challenges

When a patient presents with an elevated temperature, it is important to distinguish from the outset whether the increase is due to fever or nonfebrile hyperthermia (see Is It Fever or Hyperthermia?).

Most dogs that present with fever have some abnormality on physical examination that helps guide the diagnostic process. Abnormal findings that present with fever may include, among others, lymphadenomegaly, joint effusion, spinal or paraspinal pain or discomfort, low-grade cough, abnormal findings on thoracic auscultation, enlarged and painful prostate or swollen testicles in intact dogs, resistance to manipulation of the neck and 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 a particularly difficult diagnostic challenge when the only significant finding on routine physical examination is fever. Cryptic fever becomes even more 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 to suggest a definitive disease process (eg, reactive lymph node).

The veterinarian is then faced with the dilemma of determining which additional diagnostic tests to pursue, and pursuit of more advanced diagnostics can be curtailed by owner financial concerns that arise with high-cost/low-yield tests and owner compliance (or lack thereof).

Differential Diagnosis

Fever 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

Infectious Causes
With infectious causes of cryptic fever, many animals have evidence of some abnormality on physical examination or routine laboratory screening. However, even diskospondylitis, pyelonephritis, leptospirosis, and the deep mycoses may present with no 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 and undetected for some time and is not part of the current febrile disease.

Immune-Mediated Causes

Sterile inflammatory diseases are most commonly immune-mediated, and include immune-mediated polyarthritis (IMPA), steroid-responsive meningitis-arteritis (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 by hyperflexing a limb; then having the dog walk immediately afterward.

Some sterile inflammatory processes are not immune-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

Neoplastic Causes

Fever may be seen with various cancers, most commonly lymphoma, leukemia, multiple myeloma, hepatic neoplasia, and necrotic tumor masses. One would expect hematologic abnormalities on the complete blood count (CBC), but these changes can often be subtle and/or misleading. Unexplained hematologic abnormalities should be viewed as an invitation to perform a bone marrow examination—aspiration or biopsy—which often yields a diagnosis.

Diagnostic Approach

Initial Diagnostics

The initial diagnostic approach in a dog with unexplained fever should begin with signalment, patient history, physical examination, and laboratory diagnostics (see Diagnosing Fever: A Stepwise Approach). When the diagnosis is not readily apparent following the initial diagnostic approach, the clinician is faced with the option of a therapeutic trial or continued diagnostics.

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 the diagnosis.

Antibiotic selection is empiric and often based on prior experience or suspicions (eg, doxycycline in a dog with high tick exposure). Depending on the patient’s condition, most antibiotic trials are administered 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 be stabilized 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 to prompt more specific diagnostic tests, the next level of diagnostics should be pursued.

These tests, some of which may require referral to specialty 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 of sites from which to sample, some more challenging than others, and diagnostics can include aspirates of apparently normal lymph nodes, joint taps, bone marrow aspirate, and cerebrospinal fluid (CSF) tap.

Serology or PCR may be indicated for certain infectious diseases, and the specific selection of tests is often 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, especially those 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 than abdominal radiographs.

Computed tomography or magnetic resonance imaging of the brain rarely has value in the absence of neurologic abnormalities; CSF analysis has surprisingly greater benefit and is less expensive.

Default Diagnosis

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 administered appropriately; my protocol is to administer prednisone at 2 mg/kg Q 24 H (or 60 mg/M² for larger dogs) for a minimum of 3 weeks (presuming the patient’s response is good), with gradual reduction 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 and type of infectious diseases may differ from those seen in 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 or longer.^3,14 In the other study, investigators searched patient records for the term FUO or fever of unknown origin in the letter from the referring veterinarian as well as documentation of a fever (> 39.7°C [103.5°F]).⁴

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 physical examination or routine screening laboratory tests (CBC, serum biochemistry profile, urinalysis), 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 evaluation of bronchoalveolar lavage samples) provided, or was crucial to, the diagnosis in 56% to 62% of the dogs, and bone marrow aspiration yielded a diagnosis in 64%.

However, diagnostics that are often performed as screening tests and not always chosen based on a 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 in 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 for toxoplasmosis and neosporosis infrequently yielded a diagnosis.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 administered in the 24 hours before referral increased the time necessary 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 group that 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 the need to resist the knee-jerk response to administer anti-inflammatories (NSAIDs or glucocorticoids) in response to fever⁴—a reaction often referred to as 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 after target areas have been sampled (eg, blood, urine, or abdominal fluid for culture or PCR). It is important that no additional antimicrobials or anti-inflammatories that may confuse the interpretation of the response be administered concurrently.

Outcomes

Outcomes for dogs with FUO were discussed in only 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 investigation was the reason for lack of diagnosis in 13 patients.¹⁴

In Summary

Uncovering the cause of fever in dogs is usually a straightforward process. For those in which the etiology is not easily uncovered, however, an ordered and logical diagnostic and treatment protocol helps categorize the etiology (ie, infectious, immune-mediated, neoplastic)—even if the ultimate diagnosis is vague (eg, immune-mediated fever).

CBC = complete blood count; CSF = cerebrospinal fluid; FUO = fever of unknown origin; IMPA = immune-mediated polyarthritis; NSAID = nonsteroidal anti-inflammatory drug; PCR = polymerase chain reaction; SRMA = steroid-responsive meningitis-arteritis