Another febrile dog (Proceedings)

Fever of unknown origin (FUO) is defined in human medicine as a temperature elevation for 3 weeks or longer, the cause of which is not diagnosed after 1 week of intensive in-hospital investigation. This definition selects a group of illnesses, which is important for diagnostic purposes. The criteria implicit in the definition also eliminate all of the acute causes of fever. In veterinary medicine, FUO is more loosely defined as a fever that does not respond to routinely used antibiotics and for which a diagnosis is not obvious after the initial work-up is performed.

Traditionally, infectious diseases represent the largest group of illnesses causing FUO in dogs, followed by non-infectious inflammatory disease. Neoplasias continue to increase in old dogs and are fever associated with tumors is becoming more common. Drug fever is uncommon and may present with no manifestation other than prolonged unexplained fevers. When associated with skin disease, drug fevers are more properly termed drug hypersensitivity reactions. Liver disease is a frequently overlooked cause of FUO.

Causes of FUO

Infections

• Localized
• Pyometra, discospondilitys, bacterial endocarditis, abscesses, pneumonia, pyelonephritis, osteomyelitis, septic arthritis
• avitary infections
• Pyothorax, peritonitis
• Protozoal disease
• Babesiosis, toxoplasmosis, neosporosis, hepatozoonosis, Leishmaniasis, Chagas' disease
• Specific bacterial diseases
• Ehrlichiosis, anaplasmosis, brucellosis, tuberculosis, Lyme borreliosis, RMSF, leptospirosis, bartonellosis
• Fungal disease
• Histoplasmosis, coccidioidomycosis, blastomycosis
• Returning traveler
• Exotic infectious diseases

Immune-mediated disease

• SLE, polyarthritis, vasculitis, meningitis, IMHA, ITP, steroid-responsive fever, polymyositis

Neoplasia

• Leukemia, lymphoma, malignant histiocytosis, multiple myeloma, necrotic solid tumors, carcinomatosis

Miscellaneous

• PTE, drugs (e.g. antibiotics), metabolic bone diseases, tissue necrosis, hepatic failure

Clinical Approach

The key to diagnosis of FUO is to develop and follow a systematic plan that allows for the detection of both common and uncommon causes of fever. However, it is important to remember that uncommon presentations of common disorders are much more likely than common presentations of rare diseases. The diagnostic evaluation should not be a "shotgun" approach in which dozens of tests are ordered indiscriminately. Rather, a logical, step-wise evaluation should be guided by repeated history-taking and physical examinations. In most cases, the history and physical examination reveal a potential cause of the fever, or help narrow the number of differentials. A tiered approach to diagnosis can assist in choosing appropriate tests.

First Tier: The first tier should include history, thorough physical examination, a complete blood count, blood chemistries, urinalysis, urine culture and fine needle aspiration of any masses or effusions.

History: The history should emphasize the vaccination, travel and presence of localized signs that may help in defining an anatomic diagnosis.

• Vaccination status, parasite control, heartworm prevention

• Exposure to vectors

• Lifestyle

• Indoors x outdoors

• Hunter

• Access to wooded areas

• Travel history

• Travel to endemic areas for particular diseases

• Camping

• Hunting

• Previous medical and surgical conditions

• Medications

• Response of the fever to previous therapies

• Systemic signs

• Weight loss, decreased appetite and activity, presence of skin lesions

Localized signs

• Cough, abdominal pain, urinary signs, localized (osteomyelitis or tumors) or multifocal (panosteitis) bone pain, lameness, neck pain, masses

Complete Physical Examination is one of the most important tools in the approach of a dog with FUO. Presence of cough usually places the origin of the fever in the respiratory tract, whereas fever and diarrhea is more likely a result of a gastrointestinal disease. Generalized lymphadenopathy may be secondary to lymphoma, systemic infectious disease and occasionally, immune-mediated disease. A localized lyphadenopathy is more likely due to a local infection or a tumor. Bacterial endocarditis can be very difficult to diagnose. However, a diastolic murmur best heard over the aorta valve is very suggestive of bacterial endocarditis. Ophthalmologic examination is important to look for ocular findings be associated with infectious disease (e.g.; uveitis, fundic lesions).

Laboratory Examination: the hematologic and chemistry changes in FUO are often nonspecific, but may suggest further diagnostic tests. Urine culture should always be performed regardless of the appearance of the urine sediment, because circulating bacteria are many times isolated in the urine.

Second Tier: The results obtained in the first tier should guide a second tier diagnostic testing. The second tier can be viewed as a targeted inflammation (mostly due to infection) and tumor search.

Image Techniques: Thoracic and abdominal radiographs are useful screening tools for the early localization of fever. Other places may be radiographed if indicated in the first tier (e.g. skeletal radiographs in patients with bone pain). Abdominal ultrasound may reveal a source of fever in the abdomen, such as neoplasia, peritonitis, pancreatitis, or abscesses. Echocardiography is useful in patients with diastolic aortic murmurs.

Immune testing: ANA should be obtained in patients that have clinical and laboratory findings compatible with systemic lupus. Protein electrophoresis may be helpful in patients with hyperglobulinemia.

Infectious disease search: Selected serologies and PCR's are indicated based on the results of previous tests and physical examination. Blood culture should be performed in patients in which sepsis or bacterial endocarditis is a consideration.

Other tests: Bone marrow biopsy is important in dogs with unexplained CBC abnormalities; whereas CSF analysis should be considered if neurologic signs are present. All effusions should be citologically examined. Arthrocentesis should be considered even in the absence of specific signs, because polyarthritis is a common cause of FUO in dogs. Biopsies for histopathology, special stains and appropriate cultures can be useful after clinical signs or initial diagnostic tests have localized the fever.

Third Tier: The third tear includes specialized testing following results obtained in the second tier and therapeutic trials. If a diagnosis is obtained, specific therapy should be instituted. Unfortunately, in some patients all test results are negative or normal, and the treatment decision is not straight-forward. Therapeutic trials with antibiotics, antifungal or immunosuppressive drugs can be considered, especially in a seriously ill or rapidly deteriorating patient. In general, empiric treatment without a definite diagnosis is not recommended. The goals of a therapeutic trial are to indirectly confirm a diagnosis, control or cure the patient's condition. Owners should be made aware of the risks of failure or, in case of immunosuppressive drugs, worsening the dog's clinical condition if the FUO results from an infectious disease. Realistic and measurable goals for evaluation therapy efficacy should be established ahead of time.

Antibiotics: in human medicine, empiric antibiotic therapy is only used in FUO patients with culture negative bacterial endocarditis. In dogs, however, empiric antibiotic therapy is common, many times with success. Antibiotics should always be selected considering the most likely diagnosis. The risk of inducing bacterial resistance should always be weighed before starting an empiric antibiotic therapy. Doxycycline is frequently used in patients with a high risk for tick-borne diseases. It should be remembered that in most cases, clinical improvement is expected within 48 hours.

Antifungals: empiric antifungal therapy can be attempted patients in which fungal disease cannot be confirmed, but radiographic signs and ophthalmologic examination are suggestive of a systemic mycosis. Fever and general condition usually get better within 5 days, but other signs may take longer to improve.

Immunosuppressive drugs: Many cases of FUO are secondary to non-infectious inflammation and may improve with immunosuppressive medications, usually glucocorticoids. The main concern is the possibility of exacerbating an undiagnosed infectious disease. Patients should be carefully monitored, ideally in the hospital, and therapy stopped immediately if there is deterioration of the general clinical condition. Most patients with steroid-responsive FUO will improve within 48 hours.

Treating Fever: Fever evolved as a host defense mechanism, but not all fevers are beneficial. Fever, like most nonspecific host defense responses, is highly stereoptypical. Infection with any number of different organisms will produce similar acute-phase responses characterized by loss of food appetite, lethargy, increased sleep, fever, and synthesis of a wide array of acute phase proteins. It is likely that fever itself has some beneficial effects, particularly in infectious diseases. However, fever can lead to anorexia, lethargy, and dehydration. Thus, FUO patients may benefit from IV fluid therapy or from the use of antipyretic medications. There are concerns in human medicine that the use of antipyretic/anti-inflammatory/ analgesic drugs, when they lead to the suppression of fever, results in the increased morbidity and mortality during most infections. Nevertheless, antipyretics (e,g, aspirin, meloxicam) can be attempted in patients in which the fever is interfering substantially with quality of life or with body temperatures > 106°F.

References available upon request