96 Fever

Infectious Diseases of the Dog and Cat, 3rd Edition

CHAPTER 96 Fever

Katharine F. Lunn

Fever is a common clinical finding in patients with infectious, parasitic, inflammatory, immune-mediated, or neoplastic disease. In many of these patients, fever is accompanied by other more specific or localizing clinical signs, and the cause of the fever is determined with simple diagnostic tests. In some cases, the cause of the fever is not readily apparent, but it resolves spontaneously or in response to empirical therapy, often with antibiotics. In a small subset of patients, the cause of fever is not easily determined and not therapeutically responsive, and the problem becomes persistent or recurrent. Such cases of fever of unknown origin (FUO) present a particular diagnostic challenge in both human and veterinary medicine.60,32 This chapter outlines the pathophysiology of fever and presents an approach to the small animal patient with FUO.

PATHOPHYSIOLOGY OF FEVER

Body temperature is determined by the set-point of the hypothalamic thermoregulatory center. Thermoregulation depends on sensory information from external and internal thermoreceptors and on physiologic and behavioral effector mechanisms that control heat production and heat loss. Body heat is lost through the skin and the respiratory tract and can be gained by transfer from the environment or generated by muscle activity or body fat catabolism. Body temperature is decreased by panting, cutaneous vasodilation, seeking shelter, and remaining inactive (Fig. 96-1, A). In a cold environment, body temperature is maintained by shivering, postural changes, piloerection, and cutaneous vasoconstriction (see Fig. 96-1, B). In a normal animal, these mechanisms balance heat loss and heat gain and keep the body temperature as close as possible to the normal hypothalamic set-point (Fig. 96-2, A).

Hyperthermia refers to any increase in body temperature above normal. In true fever, the hypothalamic set-point is elevated, and body temperature is increased by enhanced heat production and conservation. Heat gain and heat loss mechanisms now act to maintain body temperature at the new set-point (see Fig. 96-2, B). In nonfebrile hyperthermic conditions, the hypothalamic set-point is not altered, and elevated body temperature is the result of increased and unregulated heat gain or heat production or impaired heat loss (see Fig. 96-2, C). Examples of nonfebrile causes of hyperthermia include heat stroke, exercise-induced hyperthermia, malignant hyperthermia, seizure activity, and hypermetabolic disorders. Hyperthermia of this type can progress to multiorgan-dysfunction syndrome caused by an interplay among circulatory disturbances, hypoxia, increased metabolic demand, cytotoxicity of high temperature, and activation of inflammatory and coagulation cascades.7

Fever is mediated by the action of pyrogens. Exogenous pyrogens (infectious agents and their products, tumors, drugs, and toxins) stimulate inflammatory cells to release endogenous pyrogens (cytokines such as interferons, interleukin [IL]-1 and -6, and tumor necrosis factor [TNF]-) that use the cell-signaling apparatus gp130. Exposure to these cytokines leads to induction of cyclooxygenase 2 activation of the arachidonic acid cascade, with enhanced synthesis of prostaglandin E2(PGE2). PGE2is synthesized by hypothalamic vascular endothelial cells and acts on thermoregulatory neurons to raise the hypothalamic set-point. The thermoregulatory set-point is located in a rich vascular network called the organum vasculosum laminae terminalis in the preoptic-rostral hypothalamus that possesses little if any blood-brain barrier. Endothelial cells within this area are thought to release arachidonic metabolites themselves, and then metabolites of cyclooxygenase such as PGE2 are thought to diffuse the short distance to the hypothalamic neurons and induce fever. PGE2, which itself is not neurally active, may induce production of cyclic adenosine monophosphate (cAMP) or other neurotransmitters, which, in turn,

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CHAPTER 96 Fever Page 1 of 20

Infectious Diseases of the Dog and Cat, 3rd Editionraises the temperature set-point of the body. Additional evidence suggests that the thermoregulatory center may also be stimulated via vagal fibers that respond to release of cytokines locally released in tissues.58 The pathogenesis of fever is summarized in Figure 96-3.

FEVER OF UNKNOWN ORIGIN

FUO in both human and veterinary medicine can be most usefully defined as fever that does not resolve spontaneously in the period expected for self-limited infection and the cause of which cannot be ascertained despite considerable diagnostic effort.2 In veterinary medicine, this diagnostic effort typically includes a complete history and physical examination, complete blood (cell) count (CBC), chemistry, urinalysis (UA), and radiography. Also common is for veterinary patients to receive antibiotic therapy to address possible bacterial infection before it is determined that the origin of the fever is unknown.16

Etiology of Fever of Unknown Origin

Although fever is frequently associated with infectious diseases, the same response can be elicited by many inflammatory, immune, or neoplastic disorders. Because the list of differential diagnoses for FUO is extensive, grouping these causes into broad categories based on the underlying disease process is useful. Table 96-1 shows the causes of FUO divided into infectious and parasitic diseases, Table 96-2 summarizes inflammatory and immune-mediated causes of FUO, and neoplastic and miscellaneous causes are listed in Table 96-3. In the human medical literature, the causes of FUO are typically distributed as follows: 30% to 40% are infectious, 20% to 30% are neoplastic, 10% to 20% are rheumatologic, 15% to 20% are miscellaneous, and 5% to 15% are undiagnosed. Broadly similar distributions have been reported in veterinary patients, but variation can be found among reported case series.46 This variation may be cause by both the particular clinical interests of the authors and their geographic locations. Published case series are also exclusively or predominantly canine.46,23 Infection, immune-mediated disease, and neoplasia are the most common causes of FUO in the dog, whereas FUO in cats appears most likely to be infectious in origin.41

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Fig 96-1 Behavioral mechanisms of decreasing body temperature (A) and increasing body temperature (B) (Courtesy University of Georgia, Athens, Ga.)



Fig 96-2 A, Temperature regulation in the normal animal showing a thermal set-point of 38.31/4 C (1011/4 F) with balanced heat gain and heat loss mechanisms. B, Mechanism of fever involves a rise in set-point to 401/4 C (1041/4 F), which increases endogenous heat production and conservation while maintaining a balance between heat gain and heat loss. C, Mechanism of hyperthermia, in contrast to that of fever, involves an increase in heat load on a normal set-point. Increased heat gain can be from exogenous (environmental) or endogenous (muscle activity) sources. (Courtesy University of Georgia, Athens, Ga.)



Fig 96-3 Pathogenesis of fever.(AMP, Adenosine monophosphate.)



Table 96-1 Infectious and Parasitic Diseases Associated with Fever of Unknown Origin

TYPE OF INFECTION EXAMPLESSystemic bacterial Infective endocarditis (D), bacteremia from inapparent focus (B)Localized bacterial Infective endocarditis (D), pyelonephritis (B), prostatitis (D), stump pyometra (B),

pyothorax and lung infections (B), pancreatitis (D), hepatic abscess or cholangiohepatitis (B), peritonitis (B), septic meningitis (B), septic arthritis (B), osteomyelitis (B), diskospondylitis (B), tooth root abscess (B), other abscesses or cellulitis (B)

Specific bacterial Leptospirosis (D), Lyme disease (D), brucellosis (D), mycobacterial infection (B), bartonellosis (B), plague (C), L-form infections (B)

Viral Feline leukemia virus infection (C), feline immunodeficiency virus infection (C), feline infectious peritonitis (C), feline calicivirus infection (C), canine distemper virus infection (D)

Rickettsial and mycoplasmal Ehrlichiosis (B), anaplasmosis (D), hemotrophic mycoplasmosis (B), mycoplasmal infections (B)

Fungal Blastomycosis (B), cryptococcosis (B), coccidioidomycosis (B), histoplasmosis (B)Protozoal Toxoplasmosis (B), neosporosis (D), hepatozoonosis (B), babesiosis (B), leishmaniasis

(B)D, Predominantly dog; C, Predominantly cat; B, both dog and cat.

Table 96-2 Inflammatory and Immune-Mediated Diseases Associated with Fever of Unknown Origin

TYPE OF DISEASE EXAMPLESImmune-Mediated Systemic lupus erythematosus (D, rare in C), idiopathic

immune-mediated polyarthritis (B), rheumatoid arthritis (D), polymyositis (B), steroid-responsive meningitis-arteritis (beagles, boxers,Akitas, Bernese Mountain dogs, German shorthaired pointers), vasculitis (B)

Inflammatory Nodular panniculitis (B), lymphadenitis (B), steatitis (D), pancreatitis (C), inflammatory bowel disease (B), granulomatous diseases (B), hypereosinophilic syndromes (B)

D, Predominantly dog; C, predominantly cat; B, both dog and cat.

Table 96-3 Neoplastic and Miscellaneous Diseases Associated with Fever of Unknown Origin

TYPE OF DISEASE EXAMPLESSolid tumors Several, including hepatic tumors, gastric tumors, lung

tumors, bone tumors, metastatic disease, and any necrotic tumor (B)

Hematopoietic tumors Lymphoma (B), leukemia (B), myeloma (B), malignant histiocytosis (B)

Miscellaneous Metaphyseal osteopathy (D), panosteitis (D), portosystemic shunt (B), pansteatitis (C), drug reaction (B), Shar-pei fever (D)

D, Predominantly dog; C, predominantly cat; B, both dog and cat.

Fever is rarely an isolated finding in these cases, given that the cytokines induce a large number of complex immunopathologic events. These events include increases in total or relative numbers of circulating immature


Infectious Diseases of the Dog and Cat, 3rd Editionneutrophils and an increase in synthesis of a wide variety of acute-phase proteins from the liver. Other synthesized proteins are antiproteases, complement components, fibrinogen, ceruloplasmin, ferritin, and haptoglobin. In addition, even larger amounts of C-reactive protein and serum amyloid A protein are produced.19 This production occurs despite a dramatic reduction in the synthesis of albumin, lipoprotein lipase, and cytochrome P450 by the liver. The presence of fever and concomitant changes in these serum proteins is referred to as an acute-phase response to infection. The ability of cytokines to suppress or alter gene expression for synthesis or suppression of commonly produced protein molecules accounts for the altered lipid, protein, and drug metabolism observed in patients with chronic infectious or inflammatory disease states. It may also result in the deposition of amyloid proteins in the syndrome known as reactive AA amyloidosis.

IL-1 and TNF also have dramatic effects on endothelial cells, causing the synthesis of prostaglandin I2 (PGI2, prostacyclin) and PGE2. These arachidonate metabolites caused increased blood flow. IL-1 and TNF also stimulate the plasma membrane of endothelial cells by increasing the expression of intercellular adhesion molecule 1 so that they become more adherent and attract neutrophils, monocytes, and lymphocytes. IL-1 and TNF increase procoagulant activity on the endothelial cell surface at the same time that they induce plasminogen activator inhibitor. These effects lead to activation of factor VIII and thrombin and platelet aggregation in the initiation of coagulation. These events are similar and involve the same pathways as those in the body's response to endotoxin (see Chapter 38).

Development of a Diagnostic Plan for Fever of Unknown Origin

Although some patients with FUO may have uncommon infectious, inflammatory, or neoplastic diseases, many patients are ultimately found to have an unusual or early manifestation of a common disorder.2 Therefore the clinician must approach these cases in a systematic fashion that allows for the detection of any potential cause of fever while avoiding unnecessary testing and minimizing patient discomfort. A diagnostic plan for FUO may be based on consideration of the disease process, as outlined in Tables 96-1, 96-2, and 96-3. A complementary approach is summarized in Table 96-4 in which the causes of FUO are grouped according to anatomic or body system location. This approach is helpful in selecting diagnostic tests, particularly when localizing clinical signs are absent or subtle. By combining a disease process and anatomic approach, the clinician can develop a comprehensive diagnostic plan for any FUO patient.

In addition to appropriate diagnostic tests, the diagnostic plan should follow a sequence that is both logical and flexible. The typical diagnostic plan will begin with tests that are safe, simple, inexpensive, and easy to interpret. A staged approach can be used to guide the selection of diagnostic tests, and examples are outlined in Table 96-5.

The results of stage 1 tests in the FUO patient will then determine the tests to be performed at the next stage. If the fever has not been localized, more specialized procedures can also be introduced.

Stage 2 test results again require the repetition of earlier tests and introduce the need for advanced imaging and more invasive procedures. Ideally, the selection of these tests will be based on abnormalities detected in stages 1 and 2.

An important aspect of stage 3 test results in the FUO patient is the need to repeat the early, less invasive, and inexpensive tests frequently enough to detect new changes. The key is not to rigidly follow a predetermined and fixed diagnostic plan but rather to review and modify the plan as new results become available. For

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Infectious Diseases of the Dog and Cat, 3rd Editionexample, if repeated CBCs demonstrate developing pancytopenia, a bone marrow aspirate and biopsy should be performed early in the diagnostic plan and not reserved for stage 3.

Client Communication

The management of the FUO patient demands flexibility, dedication, and patience from both the clinician and the client. By definition, patients with FUO will already have undergone several basic diagnostic tests, and some may have received one or more courses of antibiotic therapy. Clients may be frustrated by the failure to reach a diagnosis or the continuation of the patient's clinical signs. Good client communication is vital to the successful resolution of the FUO case. The clinician should explain that many diagnostic tests, including repeated tests, may be necessary to reach a diagnosis and that the process may be time consuming and expensive. However, clients should also be reassured that a diagnosis is reached in most cases, that many causes of FUO may be treatable or even curable, and that the fever itself is rarely harmful to the patient.

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Table 96-4 Causes of Fevers of Unknown Origin Grouped by Body System or Region

BODY SYSTEM OR REGION APPROPRIATE DIAGNOSTIC TESTS EXAMPLESBlood and hematopoietic CBC, blood film evaluation, bone

marrow aspirate, urinalysis, ophthalmic fundic exam, bone marrow biopsy, serum protein electrophoresis, FeLV and FIV tests, other serology, blood culture

Leukemia, myeloma, bacteremia, drugs, ehrlichiosis, granulocytopathy, hypereosinophilic syndromes, hemotrophic mycoplasmosis, metastatic neoplasia, walled-off hematomas

Lymphoid Lymph node palpation, lymph node cytology and culture, lymph node biopsy, lymphangiography

Lymphoma, lymphadenitis, lymphangitis

Cardiovascular Auscultation, radiography, angiography, electrocardiography, echocardiography, vascular biopsy, pericardiocentesis, blood culture

Endocarditis, pericarditis, vasculitis

Respiratory Radiography, transtracheal or endotracheal wash, fine-needle aspiration, biopsy, ultrasonography, bronchoscopy, bronchoalveolar lavage, CT, thoracoscopy

Bronchial foreign body, fungal or bacterial pneumonia, neoplasia, pulmonary embolism

Nervous system Fundic and neurological examination, radiography, myelography, CT, MRI, nerve or muscle biopsy, CSF analysis

Toxoplasmosis, fungal infection, steroid-responsive meningitis-arteritis, FIP

Musculoskeletal Radiography, arthroscopy, blood culture, arthrocentesis, synovial membrane biopsy, bone biopsy, RF, ANA

Immune-mediated polyarthritis, myositis, panosteitis, diskospondylitis

Gastrointestinal Radiography, barium contrast studies, ultrasonography, rectal examination, fecal cytology, rectal cytology, fecal culture, oral and dental radiographs, lipase and amylase activities trypsin-like immunoreactivity, endoscopy, laparoscopy, exploratory surgery, biopsy

Neoplasia or abscess anywhere in GI tract, pancreatitis, inflammatory bowel disease, fungal disease, portosystemic shunt, hepatobiliary, gastric, or splenic inflammation

Urogenital Urinalysis, urine culture, prostatic wash and ejaculate cytology and culture, radiography, ultrasonography, IV pyelography, cystography, cystoscopy, vaginoscopy, cytology, biopsy

Prostatitis, stump pyometra, pyelonephritis, orchitis

Endocrine Biochemical profile, thyroid hormone HyperthyroidismPleural or peritoneal cavity Radiography, ultrasonography, fluid

analysis, cytology, microbial culture, biopsy

Pyothorax, FIP, peritonitis, neoplasia

Skin Physical examination, cytology, biopsy, microbial culture, fistulography

Abscess, fungal infection, nodular panniculitis, vasculitis, actinomycosis, nocardiosis, mycobacteriosis

ANA, Antinuclear antibody; CT, computed tomography; MRI, magnetic resonance imaging; RF, rheumatoid factor; CBC, complete blood cell count; FeLV, feline leukemia virus; FIV, feline immunodeficiency virus; IV, intravenous; CSF, cerebrospinal fluid; FIP, feline infectious pertonitis; GI, gastrointestinal.

History

The patient history should include details of geographic location and environment, travel history, lifestyle (e.g., indoor versus outdoor, history of hunting), and exposure to ticks or other vectors. All of these factors

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Infectious Diseases of the Dog and Cat, 3rd Editionwill influence exposure to specific microorganisms. The medical history should cover diet, vaccination, heartworm and other parasite treatment and prevention, the administration of any other medications, and previous medical or surgical problems. The response to past therapies used for the fever problem should be noted. Clients should be questioned about the patient's urination and defecation habits and the presence of clinical signs such as lameness; neck, back, or abdominal pain; skin lesions; masses or swellings; weakness; exercise intolerance; coughing; nasal discharge; and dyspnea.

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Table 96-5 Diagnostic Plan for Fever of Unknown Origina

1. History

a. Detailed

b. Additional questions for other medical problems

2. Physical examination

a. System by system complete exam

b. Fundic examination

c. Neurologic examination

3. Laboratory testing

a. CBC, blood smear

b. Biochemical profile

c. Additional biochemistry: bile acids, lipase, amylase, CK, T4

d. Complete urinalysis including sediment

4. Radiologic imaging

a. Thoracic and abdominal radiography

b. Abdominal ultrasonography, if other results negative

c. Echocardiography, if murmur

d. Spinal survey series

e. Long bone or joint survey

f. Dental radiography

g. Contrast radiography as indicated by system

h. Computerized axial tomography

i. Magnetic resonance imaging

j. Nuclear scintigraphy scans

5. Cytologic evaluation

a. Evaluation of any enlarged lymph nodes or masses

b. Synoviocentesis, especially with hyperesthesia

c. Bone marrow evaluation



d. Bronchoscopy with bronchoalveolar lavage

e. CSF analysis, especially with hyperesthesia

6. Serologic testing

a. For persistent pathogens

i. Dogs Ehrlichia, Brucella, Bartonella, Neospora

ii. Cats FeLV, FIV, FCoV, Toxoplasma

iii. Other persistent infections as indicated

b. Immunopathologic diseases

i. ANA, RH, and LE tests

ii. Anti-platelet, anti-erythrocyte, anti-leukocyte tests

7. Bacteriologic testing

a. Urine, blood, or joint-fluid cultures

b. Fecal cultures

8. Tissue biopsy

a. Bronchoscopy or thoracoscopy with biopsy

b. Exploratory laparotomy with biopsy buffet

9. Therapeutic trial

a. Selected antibacterial drugs

b. Antifungal drugsCBC, Complete blood (cell) count; CK, creatinine kinase; T4, thyroxine; CSF, cerebrospinal fluid; FeLV, feline leukemia virus, FIV, feline immunodeficiency virus, FCoV, feline coronavirus; ANA, antinuclear antibody; RF, rheumatoid factor; LE, lupus erythematosus

a Fever is not harmful. Many diagnostic tests are needed and may have to be repeated or this list recycled. Tests listed lower under each section generally have higher cost or risk, or less immediate indication and should be considered with successive work-ups. With persistence, a diagnosis is often made and there is a favorable response to treatment.

Physical Examination

All body systems should be examined in detail, and a complete physical examination should be repeated at each hospital visit for outpatients. Inpatients should be examined twice daily. The physical examination should include careful cardiac auscultation and regular examination of the oral cavity and rectum, bones and joints, lymph nodes, and skin. Repeated ocular examinations should not be overlooked because they may provide evidence of infectious, inflammatory, or neoplastic disease. Given that fever can often wax and wane in FUO, the pattern of fever in an individual patient should be determined by serial measurement

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Infectious Diseases of the Dog and Cat, 3rd Editionof body temperature. This measure is not of any value in elucidating the underlying cause, but it is important in monitoring the response to any subsequent therapy.

Complete Blood Count and Serum Chemistry Profile

The problem of fever is often accompanied by neutrophilia or a stress leukogram, and serum chemistry tests are frequently nonlocalizing in FUO patients. However, any abnormalities detected on these tests should be used to direct further testing. The CBC should always be accompanied by examination of a blood smear so as to determine blood cell morphology and look for microorganisms. Automated CBCs should be verified by manual counts.

Urinalysis and Urine Culture

Because FUO may be associated with focal urogenital infections (e.g., prostatitis, pyelonephritis), UA and urine culture are mandatory in the evaluation of fever patients. Urine samples should be obtained by cystocentesis and submitted for bacterial culture and susceptibility testing, regardless of the appearance of the urine sediment.

Radiography

Thoracic and abdominal radiographs should be obtained during the first stage of evaluation of the FUO patient. These radiographs are simple to obtain and may provide early evidence of neoplastic disease or suggest infectious disease such as bacterial or fungal pneumonia. In the second or third stages of diagnosis, long bone, joint, vertebral, and dental radiographs should be considered. Contrast radiographs (e.g., intravenous [IV] pyelography, barium series, cystography, myelography, fistulography) may be indicated in some cases.

Ultrasonography

Abdominal ultrasonography can be used to look for potential sources of fever in organs such as the liver, spleen, pancreas, gastrointestinal (GI) tract, urinary tract, prostate, uterus, lymph nodes, and adrenal glands. Other regions that can be investigated by ultrasonography include the thorax (particularly in the presence of effusions or masses), the retrobulbar area, and any other peripheral mass lesion or swelling. Ultrasonography is particularly useful in facilitating the minimally invasive acquisition of fine-needle aspirates or biopsies.

Echocardiography

Ultrasonographic examination of the pericardium, myocardium, endocardium, heart valves, and great vessels is essential in the evaluation of the patient with FUO and a heart murmur, particularly if the murmur is of recent onset. These findings are suggestive of infective endocarditis, particularly if a source of infection (e.g., gingivitis, prostatitis, an IV catheter) is also present. Although echocardiography is not 100% specific or sensitive for the diagnosis of infective endocarditis, the finding of vegetative aortic valve lesions is considered to be pathognomonic.73 Mitral valve lesions can suggest a diagnosis of infective endocarditis if present together with other supportive findings. Therefore the results of echocardiography should be interpreted in light of the patient's signalment, clinical signs, and blood culture results. Infective endocarditis is much more common in dogs than it is in cats, and middle-age dogs of medium to large

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Infectious Diseases of the Dog and Cat, 3rd Editionbreeds (e.g., German shepherd dogs, boxers, golden and Labrador retrievers) appear to be over-represented.73

Computed Tomography and Magnetic Resonance Imaging

These advanced imaging modalities are now available to many clinicians in referral hospitals. These assessments should be regarded as third stage tests in the evaluation of the FUO patient and used when clinical signs have been localized to a particular body system. For example, computed tomography is useful for detecting certain pulmonary lesions and for examining the nasal cavity, tympanic bullae, and pharynx. Magnetic resonance imaging is often used in evaluation of the central nervous system (CNS).

Aspirates and Biopsies

Fine-needle aspirates are usually simple and safe to obtain, and touch preparations or impression smears can also be made from ulcerated lesions or discharge material. Cytologic examination of these samples is relatively inexpensive and, depending on the skill of the clinician, can sometimes be performed in-house. For example, if blastomycosis is suspected, repeated aspirates from lymph nodes or skin nodules can be examined for Blastomyces organisms because they are relatively easy to identify. Aspirates can also be obtained from lymph nodes, abnormal fluid accumulations, and from masses or abnormal organs detected with imaging such as ultrasound or radiography. Examples include aspiration of consolidated lung lesions, splenic aspirates if unexplained splenomegaly is detected, and aspiration and analysis of exudates and effusions. Aspirates of fluids such as pleural, pericardial, or peritoneal effusions; cerebrospinal fluid (CSF); synovial fluid; or bile should also be submitted for bacterial and other cultures. Aspiration of peripheral lymph nodes, even if palpably normal, is recommended in the second stage of diagnostic testing if the source of the fever has not been localized.

Specialized techniques such as CSF sampling, bronchoalveolar lavage, transtracheal or endotracheal lavage, prostatic wash and ejaculation, bone marrow aspiration, and arthrocentesis are used to obtain cytology and culture samples from specific locations. The use of bone marrow aspiration and arthrocentesis are discussed later in this chapter.

Tissue biopsies are often obtained in the second or third stages of the diagnostic evaluation, when the source of the fever has been localized to a specific organ or tissue. However, in some cases, specific localizing signs may be absent. When biopsies are obtained with an invasive procedure, for example exploratory laparotomy, obtaining tissue from multiple sites and in sufficient quantities is important to allow histopathology, special stains for infectious agents, and culture for organisms such as aerobic and anaerobic bacteria, mycobacteria, and fungi. If necessary, the diagnostic laboratory should be contacted in advance to discuss optimal tissue handling, preservation, and transport. Biopsies may also be obtained with techniques such as thoracoscopy, laparoscopy, endoscopy, or arthroscopy, or they can be obtained percutaneously, sometimes with guidance from ultrasound or radiography.

Bone Marrow Cytology and Histology

Bone marrow disease is a relatively common cause of FUO. Reported examples include myelodysplasia, lymphoid leukemia, myeloma, and disseminated adenocarcinoma.32,23 Bone marrow aspiration is indicated in the early stages of diagnostic testing if CBCs show unexplained cytopenias. Pancytopenia requires the evaluation of both cytology of a bone marrow aspirate and histopathology of a core biopsy. In cats, bone

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Infectious Diseases of the Dog and Cat, 3rd Editionmarrow cytology slides should also be reserved for feline leukemia virus fluorescent antibody testing. Bone marrow aspiration is indicated in the third stage of the diagnostic plan if the FUO has not yet been localized.

Arthrocentesis

Immune-mediated polyarthritis is a common cause of FUO in published canine case series.46,23 The condition may be idiopathic (nondeforming and nonerosive), or it may be caused by rheumatoid arthritis or associated with other immune-mediated disorders such as systemic lupus erythematosus or steroid-responsive meningitis-arteritis. Occasionally, nonerosive immune-mediated polyarthritis can be secondary to chronic infectious disease, GI disease, or neoplasia.61 Immune-mediated polyarthritis is also seen in cats and occurs as both a chronic periosteal-proliferative form and a less common erosive form.61

Lameness, joint swelling, and periarticular pain may wax and wane or be apparently absent in patients with immune-mediated polyarthritis. Therefore arthrocentesis should be performed in the second stage of evaluation of canine patients with FUO. Samples should be obtained from both carpi, both tarsi, and both stifles. The fluid should be examined for color, clarity, and viscosity and submitted for cytology. Bacterial and mycoplasma culture should also be performed if sample size is large enough.

Dogs with FUO and evidence of spinal pain may have concurrent immune-mediated polyarthritis and steroid-responsive meningitis-arteritis.76 Therefore arthrocentesis is also recommended in all dogs in which this form of meningitis is suspected.

Blood Culture

Blood cultures are indicated in all patients with unexplained fever and are particularly indicated in the presence of a cardiac murmur; back, bone, or joint pain; or neutropenia. Peracute bacteremia associated with sepsis is usually caused by gram-negative organisms such as Escherichia coli. Subacute or chronic bacteremia is usually associated with a persis-tent focus of infection such as infective endocarditis or diskospondylitis.11 More than one half of all canine infective endocarditis cases are caused by infection with coagulase-positive staphylococci and streptococci. Organisms impli-cated in diskospondylitis include Staphylococcus intermedius, Streptococcus canis, Brucella canis, and E. coli. In some cases, these organisms may be seeded from other locations such as the skin or urogenital tract.

Few prospective studies have been done of blood culture techniques in veterinary patients, although this subject has been extensively reviewed in the human study literature.56 In human medicine, the likelihood of obtaining a positive culture result is directly correlated with the volume of blood drawn, regardless of whether the blood is obtained as a single blood culture set or divided into several sets over a 24-hour period. In one study, the yield from a 30-ml blood sample was found to be 62% more than that from a 10-ml sample. However, the sensitivity of blood cultures is also improved by obtaining more than one set. For example, in a study of bacteremic people, 91.5% of bacteremic episodes were detected by the first blood culture set, and 99.3% were detected by the first two sets. Increasing the number of blood culture sets will also increase the specificity of the test because contaminants are unlikely to be present in all sets.

In dogs and cats, blood culture techniques should focus on the collection of adequately large volumes of blood, with less emphasis on the timing or periodicity of the collections. The total volume of blood that can safely be obtained will depend on patient size. If size allows, more than one blood culture set should be obtained to increase the sensitivity and specificity of the test. Samples for blood culture should be obtained

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Infectious Diseases of the Dog and Cat, 3rd Editionby venipuncture, not from intravascular catheters, and the operator should prepare the site using aseptic techniques and should wear sterile gloves for the venipuncture. The blood sample should be immediately and aseptically inoculated into both aerobic and anaerobic blood culture bottles. Bottles of different sizes are available and should be selected to give the optimum ratio of blood-to-culture medium (see Diagnosis under Cardiovascular Infections, Chapter 87). Blood culture bottles containing resins may be used for patients receiving antibiotic therapy.46

Serology

Serologic tests available for the diagnosis of infectious disease include assays for specific antibodies or antigens, as well as molecular tools such as Western blotting and polymerase chain reaction. Consideration of the signalment, clinical signs, geographic location, and possible vector exposure of the patient should direct selection of the most appropriate tests. Vaccination history, timing of the samples, local disease prevalence, sensitivity, specificity, and positive and negative predictive value must be considered when interpreting the results of any serodiagnostic test.

Serologic tests are also available for the diagnosis of certain immune-mediated diseases. For example, the Coombs test detects antibodies against erythrocytes and is used in the diagnosis of immune-mediated hemolytic anemia. However, patients with this disorder are likely to have concurrent localizing clinical signs and are unlikely to present with FUO. Antinuclear antibody (ANA) can be detected in patients with systemic lupus erythematosus. However, diagnosis of this uncommon multisystem disorder requires the demonstration of multiple clinical and immunologic abnormalities and should never be based on elevated ANA alone.14,13 In addition, ANA can be elevated in some normal dogs and in association with other medical conditions. Rheumatoid factor has been found to be of poor sensitivity and specificity in the diagnosis of canine rheumatoid arthritis.61 This disorder is more appropriately diagnosed by a combination of radiographic changes indicating an erosive polyarthritis together with joint fluid analysis and possibly synovial membrane biopsy.

In summary, extensive arrays of wide-ranging serodiagnostic tests are not recommended in the investigation of FUO, and the use of immune panels is particularly discouraged. Ideally, serologic tests should be used to investigate a diagnosis that is suspected based on other findings.

Nuclear Medicine

Nuclear medicine has provided several techniques that can be used to visualize infection or inflammation in human patients.65 Scintigraphic imaging can demonstrate many of the steps involved in the inflammatory process and can therefore potentially localize some causes of FUO. For example, leukocyte infiltration of tissues can be visualized with indium-111 or technetium 99mlabeled neutrophils. The latter approach has been used experimentally to localize abscesses in dogs21 but has not been applied to clinical cases. Other techniques in nuclear medicine include the use of radiolabeled human immunoglobulin, or gallium-67, which binds to transferrin in the blood, to nonspecifically demonstrate areas of increased fluid extravasation associated with enhanced vascular permeability in inflammation. Radiolabeled interleukins have also been used to localize inflammatory cells, and bacterial infection can be detected with labeled antibiotics such as technetium 99m-ciprofloxacin. A recent development in human medicine is the use of positron emission tomography with fluorine-18 fluorodeoxyglucose. This substance accumulates in areas of increased glucose metabolism such as tumors and inflammatory lesions.

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Tissue Biopsy

Specimens can be obtained percutaneously, with or without imaging, or by direct surgical collection. Generally, the organs biopsied are indicated by the suspicions of the clinician; however, in undiagnosed fevers, multiple organ biopsies are often taken via exploratory laparotomy. Samples are placed in fixatives for routine histopathology; however, samples should also be submitted or saved fresh frozen for cultivation of organisms or nucleic acid testing based on the results of the histologic examination. Special stains for fungal or rickettsial agents must be used in some cases in which these agents are suspected based on initial findings.

THERAPY OF FEVER

Trial Therapy

In many cases, the investigation of the FUO patient will achieve a definitive diagnosis, and treatment of the underlying cause will lead to resolution of the fever and other clinical signs. However, in some cases of true FUO, a diagnosis is not reached, and in other cases, diagnostic testing is discontinued because of client or patient factors. In these cases, therapeutic trials are undertaken in the absence of a definitive diagnosis. Antibiotic, antifungal, or corticosteroid therapy are often used in therapeutic trials.

The goals of a therapeutic trial should be to confirm a presumptive diagnosis indirectly, control or cure the underlying disease, and resolve the patient's clinical signs, without inducing intolerable side effects or exacerbating an undiagnosed disease.

A therapeutic trial should be planned and monitored as rigorously as the diagnostic plan. It is important to begin with a tentative diagnosis, select safe and appropriate therapies, and implement a careful monitoring program, using predetermined criteria for success or failure of the therapeutic trial. Medication should be used at appropriate doses, and the duration of therapy should be sufficient to detect both the presence and absence of a response, particularly because fever can wax and wane independent of therapy.

Good client communication is essential in developing and monitoring a therapeutic trial, and clients should understand the risks of such an approach. Such risks include the continued progression of an undiagnosed disease if an ineffective therapy is used, development of medication side effects or toxicities, and the possibility of exacerbating an underlying infectious disease if immunosuppressive therapy is used. Clients should also understand that some medications, such as antifungals, can be expensive. A therapeutic trial is unlikely to be helpful if the client abandons the plan because of expense, side effects, or lack of immediate response to treatment.

Many causes of FUO are inflammatory or immune mediated; therefore glucocorticoids are commonly used in patients with FUO in the absence of a specific diagnosis. This approach can be dangerous if infectious disease has not been ruled out first. If glucocorticoid therapy is used in this way, the patient should be monitored closely for exacerbation or development of new clinical signs. The indiscriminate use of glucocorticoids may also interfere with future diagnostic testing or future more specific therapies. This practice is a particular concern for patients with neoplasia such as lymphoma. Glucocorticoids can also have nonspecific antiinflammatory effects and may improve the patient's clinical signs without addressing the primary cause of the fever. This characteristic is also true of some antibiotics, such as metronidazole or doxycycline.

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Empirical antibiotic therapy is commonly used in small animal patients with fever, often with a successful outcome. Ideally, such therapy should be based on culture and susceptibility testing, although this is not always feasible. In trial therapy for FUO patients, antibiotics should be chosen based on a tentative but specific diagnosis, with consideration of spectrum of activity, and an understanding of pharmacokinetics. A significant risk of indiscriminate antibiotic therapy is that it contributes to antibiotic resistance in bacterial populations,35 which may also be true for other antimicrobial agents.

When a systemic mycosis is suspected, often based on typical radiographic or ocular lesions, but cannot be confirmed, trial therapy with antifungal agents may be attempted. Fever may resolve within days, but fungal lesions may respond slowly to therapy; hence trial therapy with antifungals can take several weeks.

Antipyretic Therapy

If elevated body temperature is the result of nonfebrile factors such as heat stroke or prolonged seizure activity, physical methods of cooling should be employed. Examples include the use of fans and cool water baths and administration of cooled fluids via IV or by colonic or gastric irrigation. These methods are seldom needed for the true FUO patient because body temperature rarely exceeds 41.1oC (106oF) in these cases. Also important to remember is that fever is a regulated elevation in body temperature; therefore any attempts to physically cool the patient will be working against the body's own thermoregulatory mechanisms. Fever is also a protective adaptive response to the effects of infection and can have beneficial effects. External cooling is the treatment of choice for hyperthermia in which core temperature exceeds the thermoregulatory set-point. Thus when external cooling is used to treat hyperthermia, no opposition of regulatory process takes place in an attempt to increase heat gain, as is the case with fever.

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Table 96-6 Doses of Antipyretic Agents Used in Dogs and Cats

DRUG SPECIES DOSE (mg/kg)a ROUTE INTERVAL (HOURS)

ADVERSE EFFECTS AND PRECAUTIONS

Acetaminophen (Paracetamol)

D 1020 PO 1224 Hepatotoxicity if overdosed.Do not use in cats.

Aspirin B D: 10

C: 10

PO D: 824

C: 4872

May cause GI irritation or bleeding; avoid if GI ulcer present.

Reduces platelet aggregation.

Caution with severe liver or renal disease.

Dose carefully in cats due to prolonged half-life.

Carprofen B 2 PO, IV, SC, IM 12 Mild GI irritation.Avoid if bleeding disorder.Idiosyncratic hepatotoxicity reported in dogs.Limit to 2-day duration in cats as safety unknown.

Ketoprofen B 1 PO 24 May cause GI irritation or bleeding; avoid if GI ulcer present.Reduces platelet aggregation.Potentially hepatotoxic or nephrotoxic.Injectible available. Limit to 5-day duration in cats.

Meloxicam B 0.1 PO 24 As above. Not currently approved for veterinary use in the USA.

D, Dog; C, cat; B, dog and cat; GI, gastrointestinal; USA, United States of America: PO, by mouth; IV, intravenously; IM, intramuscularly; SC, subcutaneously.

a Dose per administration at specified interval.

Body temperatures above 41.1oC (106oF) can lead to CNS damage, disseminated intravascular coagulation, metabolic derangements, and even death. Fevers of 39.5oto 40.8oC (103o to 105.5oF) are more typically seen in FUO patients and may be associated with nonspecific signs such as anorexia, lethargy, arthralgia, and dehydration. Dehydration is caused by reduced water intake and increased sensible and insensible losses in the fever patient. IV fluid therapy can correct these conditions in the debilitated patient. In some conditions, attempts to lower the body temperature by cooling and antipyretic drugs might be considered. In patients with


Infectious Diseases of the Dog and Cat, 3rd Editionconcomitant reduced cardiac output, systemic vascular hypertension, or extreme obesity may benefit. If quality of life is significantly affected by the fever, or if body temperatures are in excess of 41.1oC (106oF), antipyretic medications should be considered in patients with FUO. Table 96-6 lists the dosages and potential adverse effects of acetaminophen and several nonsteroidal antiinflammatory drugs that may be effective in reducing fever. These medications inhibit cyclooxygenase and therefore act centrally to reduce the hypothalamic set-point.

Many antipyretic drugs can potentially cause GI irritation, ulceration, or bleeding, and they should not be used concurrently with glucocorticoids. Hepatotoxicities and exacerbation of bleeding tendencies are also possible side effects. The risk of nephrotoxicity is increased if these medications are used in patients with preexisting renal disease, hypotension, hypovolemia, or concurrent administration of nephrotoxic medications. Nonsteroidal antiinflammatory drugs should be used cautiously in elderly or debilitated patients. However, if used carefully, these medications can relieve discomfort while allowing continued diagnostic testing of the patient with FUO.

Suggested Readings*

* See the CD-ROM for a complete list of references.

23. Dunn, KJ, Dunn, JK: Diagnostic investigations in 101 dogs with pyrexia of unknown origin. J Small Anim Pract. 39, 1998, 574580.

60. vreb Bohnhorst, J, Hanssen, I, Moen, T: Immune-mediated fever in the dog. Occurrence of antinuclear antibodies, rheumatoid factor, tumor necrosis factor and interleukin-6 in serum. Acta Vet Scand. 43, 2002, 165171.

76. Webb, AA, Taylor, SM, Muir, GD: Steroid-responsive meningitis-arteritis in dogs with non-infectious, nonerosive, idiopathic, immune-mediated polyarthritis. J Vet Intern Med. 16, 2002, 269273.

Uncited references

9. Breitschwerdt, EB, Abrams-Ogg, ACG, Lappin, MR, et al.: Molecular evidence supporting Ehrlichia canis-like infection in cats. J Vet Intern Med. 16, 2002, 642649.

27. German, AJ, Foster, AP, Holden, D, et al.: Sterile nodular panniculitis and pansteatitis in three weimaraners. J Small Anim Pract. 44, 2003, 449455.

55. McCarthy, PL: Fever without apparent source on clinical examination. Curr Opin Pediatr. 16, 2004, 94106.

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