Introduction and Pathophysiology
Normal body temperature is regulated within a fairly narrow range and is a balance between heat producing and heat dissipating mechanisms of the body. Fever is an elevation of body temperature above the circadian variation as the result of a change in the thermoregulatory center located in the hypothalamus. Substances that cause fever are called pyrogens and may be either exogenous or endogenous. The majority of exogenous pyrogens are microorganisms, their products, or toxins. Endotoxin (lipopolysaccharide, LPS) is the best characterized exogenous pyrogen derived from the cell wall of gram negative and gram-positive bacteria. Exogenous pyrogens can act directly on the brain to cause fever, but they act primarily by inducing the formation of endogenous products that in turn stimulate endogenous pyrogens derived from the host's monocytes and macrophages. These endogenous pyrogen-producing substances include antigen-antibody complexes with complement, complement cleavage products, steroid hormone metabolites, bile acids, and some cytokines.
The term “cytokine” is used to describe the endogenous pyrogens that consist of several interleukins, cell-derived inflammatory polypeptides and growth promoting peptides. The major pyrogenic cytokines include IL-1ß, IL-1alpha, TNF-alpha, TNF-ß, interferon alpha- and IL-6. These cytokines circulate to the anterior hypothalamus where prostaglandin E2 and other arachidonic acid metabolites are produced. These in turn, induce the formation of secondary messengers such as cyclic AMP that cause the rise in the thermoregulating set point leading to increased heat conservation, heat production and fever.
Definition and Etiologies
The classic definition of “fever of undetermined origin” (FUO) provided for humans by Beeson and Petersdorf involves an illness of at least three weeks' duration, fever (continuous or fluctuating of > 40o C), and no established diagnosis after at least one week of hospital investigation. There is no accepted definition of this term in veterinary medicine, except that the term FUO is used to define any febrile animal patient for which there is no obvious cause after “routine” diagnostic tests have been done. What constitutes “routine” will vary amongst different authors. The main diagnostic categories for FUO include infections (local, systemic), neoplasms, and collagen-vascular (immune-mediated) diseases. Other less common causes include granulomatous diseases; noninfectious inflammatory diseases such as pancreatitis, steatitis, tissue necrosis (ischemic insults); and drugs (Table 1). It is only after a thorough search for the above causes that we are left with the diagnosis of FUO. Generally, the etiology of FUO is not a rare disease but is rather a common disease presenting in an atypical fashion.
Infections should always be considered first in the search for the etiology of FUO because of their frequency and potential response to treatment. It is helpful to categorize infections as either localized or systemic in order to allow for an eventual well-focused approach to the patient's problem. In the cat, viral agents such as parvovirus, herpesvirus, or calicivirus usually cause fairly classical clinical signs and rarely persist long enough to fit the definition of true FUO. Feline infectious peritonitis coronavirus infection is a common cause of FUO because it produces insidious, chronic illness and frequently defies easy diagnosis. Fever is often associated with retroviral infections (FeLV, FIV) as a direct result of the virus infection but more often due to an opportunistic infection occurring secondary to the immunosuppressive effects of the viral disease.
Most bacterial infections in the cat are superficial and are easy to recognize and treat. Localized bacterial infections in an occult location (e.g., metritis, low grade pleuritis, osteomyelitis, tooth root abscess) or those caused by fastidious organisms that are not sensitive to treatment with commonly prescribed antimicrobial agents (e.g., Mycobacterium, Nocardia, Mycoplasma, L-form bacteria) are the most likely to cause persistent fever. Systemic mycotic diseases (e.g., histoplasmosis, blastomycosis, coccidioidomycosis) cause antibiotic unresponsive fever and should be included in the differential list for patients residing in or having traveled through regions endemic for these agents. Cryptococcus neoformans rarely produces a febrile response unless infection is generalized or involves the central nervous system. Parasitic infections with Haemobartonella felis, Toxoplasma gondii, aberrant helminth migration, and pulmonary embolization by Dirofilaria immitis may also cause fever.
The urinary and pulmonary systems must be thoroughly assessed in any patient with a fever that cannot be localized on the physical examination. All too often, these are the sites of origin for disseminated infection. Other disorders such as infective endocarditis and localized abdominal abscesses might be difficult to diagnose without the aid provided by imaging techniques such as ultrasound, CT scan and MRI. Only after the site of the infection is localized can a definitive therapeutic plan be devised.
Unfortunately, neoplasia is not a rare cause of fever in the cat. FeLV related cancers (e.g., lymphoma, myeloproliferative disease) are the most common cause of fever in this particular disease class. The fever may be a paraneoplastic syndrome associated with the tumor itself or it can be due to secondary complications from the cancer such as infections occurring as a result of myelophthisic disease. Solid tumors such as pulmonary adenocarcinoma can also cause fever as the result of the host's immune response to the tumor, damage to adjacent tissue from the expanding tumor mass, or because of avascular tumor necrosis.
Immune-mediated diseases are rare and are the most poorly defined causes of fever in the cat. Some immunologic diseases can be readily identified such as immune-mediated hemolytic anemia, the pemphigus family of dermatoses, and systemic lupus erythematosis. Others such as the polyarthropathies and polymyositis are still rather poorly defined.
The other etiologies of fevers should always be considered before settling with a diagnosis of FUO. Some of these in the cat include noninfectious inflammatory diseases such as cholangiohepatitis, inflammatory bowel disease, pancreatitis, and pansteatitis. Drug-associated fever is most common with tetracycline but has also been reported with sulfonamides, penicillins, quinidine, novobiocin, nitrofurantoin, amphotericin B, barbiturates, iodine, propylthiouracil, atropine, cimetidine, salicylates, prednisone, antihistamines, and procainamide. Metabolic and endocrine diseases including hyperthyroidism, pheochromocytoma, hyperlipemia, hypernatremia, and primary neurologic diseases causing CNS inflammation or impinging on the hypothalamic thermoregulatory center may occasionally cause fever.
Approach to the Patient
In most instances, the cause of fever is evident after taking a thorough history and doing a complete physical examination. The history should include vaccination prophylaxis, environment, diet, exposure to other animals, the recent administration of any drugs, and past and recent geographical exposures.
The physical examination should include a critical observation of the patient's posture, ambulation, and a complete review of all systems including fundoscopy and neurological evaluation. All palpable body areas should be thoroughly assessed in order to detect subtle amounts of swelling or discomfort, which can be of great localizing value. All too often, the early signs of bite wound cellulitis might be limited to the presence of tiny bite wounds or scabs covered by a clump of saliva-laden fur that might easily be missed on cursory examination. The examination might subsequently be followed by a general workup that usually includes: CBC, serum chemistries, urinalysis (collected by cystocentesis), FeLV antigen and FIV antibody tests, thoracic and abdominal radiographs, and ultrasonography. Although coronavirus serology is included by some clinicians in the initial evaluation as a screening test for FIP, its diagnostic usefulness is controversial. Additional diagnostic tests might include: urine culture, blood culture, transtracheal wash or bronchoalveolar lavage, echocardiography, bone marrow aspiration cytology, and fine needle aspiration of selected areas of pathology for cytology and culture. Depending on the aforementioned test results, the workup might be extended to include other organ specific diagnostic or functional studies, ultrasound guided biopsies, endoscopic biopsies, additional viral, fungal, or protozoal serology, immune tests, and perhaps even a laparotomy.
Leukocytosis can accompany any of the inflammatory diseases or processes mentioned earlier; however, a marked left shift along with toxic vacuoles and Doehle bodies tends to suggest bacterial infection some but not all of the time. Severe bacterial disease can also cause a leukopenia in the presence of endotoxemia or when there is neutrophil migration and sequestration at the site of infection as seen in conditions such as suppurative pleuritis. Leukocytosis is also present in sterile inflammatory disease conditions, including neoplasia. Therefore, it is important to maintain a full scope of diagnostic objectivity when deciphering the significance of any elevated white blood cell count.
The Undiagnosed FUO Patient
What is the next step in the occasional patient for whom no diagnosis is evident after a diligent search? By this time, the pet owners have spent a substantial amount of money and all you can offer is an “I don't know.” Under such circumstances, the option for empirical treatment will be entertained and antimicrobials, antipyretics, or glucocorticoid drugs will be selected either singly or in combination. A therapeutic trial with a broad-spectrum combination of antibiotics such as a penicillin or cephalosporin with an aminoglycoside or quinolone is a reasonable choice for initial empirical treatment. Corticosteroid preparations should be used judiciously and should ideally be reserved for patients in whom the presence of infectious disease has been thoroughly ruled out. Antipyretics may be beneficial in patients with life-threatening hyperthermia when topical cooling methods fail to adequately reduce the body temperature. However, antipyretics can reduce the body temperature to subnormal levels, will mask the effects of other therapy, and will make it difficult to assess the patient's true status. Aspirin at 10 mg/kg PO q48h or ketoprofen 2 mg/kg PO or IM q24h (not to exceed three days) can be used. Empirical therapy should always be accompanied by thorough communication with the client and your close scrutiny of the patient. With time, most disorders initially characterized as FUO will become more obvious. Repeating the thorough physical examination at frequent intervals is critically important because minor changes that are detected can lead to a diagnosis. It is therefore important for the clinician to have patience, compassion, and objectivity when dealing with this problem.
Causes of Fever of Undetermined Origin
1. Infective endocarditis
3. Miscellaneous, e.g., viral, rickettsial, protozoan, fungal, bacterial infections
2. Lung and pleura
b. Lung abscess
c. Suppurative pleuritis
8. Soft tissue abscess and cellulitis
A. Solid localized tumors (lung, liver)
B. Diffuse (lymphoma, myeloproliferative)
III. Collagen-Vascular and Immune-Mediated
A. Systemic lupus erythematosus
1. Autoimmune hemolytic anemia
2. Immune polyarthropathy
3. Aseptic meningitis
4. Nodular panniculitis
5. Hypersensitivity pneumonitis
IV. Sterile Inflammatory
A. Feline pansteatitis
C. Pulmonary thromboembolism
V. Drug Induced—oral tetracycline
A. Brain tumors
E. Tetany (hypocalcemia)