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Compendium January 2009 (Vol 31, No 1)

The Diagnostic Approach to Fever of Unknown Origin in Cats

by Julie Flood

    CETEST This course is approved for 3.0 CE credits

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    Abstract

    Identifying the cause of fever of unknown origin (FUO) in cats is a diagnostic challenge, just as it is in dogs. Infection is the most common cause of FUO in cats. As in dogs, the diagnostic workup can be frustrating, but most FUO causes can eventually be determined. This article addresses the potential diagnostic tests for, and the differential diagnosis and treatment of, FUO in cats.

    True fever (pyrexia) is defined as an increase in body temperature due to an elevation of the thermal set point in the anterior hypothalamus secondary to the release of pyrogens.1 With hyperthermic conditions other than true fever, the hypothalamic set point is not adjusted.1 Nonfebrile hyperthermia occurs when heat gain exceeds heat loss, such as with inadequate heat dissipation, exercise, and pathologic or pharmacologic causes.1

    Cats with true fever typically have body temperatures between 103°F and 106°F (39.5°C to 41.1°C).2 Cats are less likely than dogs to succumb to the dangerous effects of body temperatures greater than 106°F, which are usually seen with nonfebrile causes of hyperthermia.3 Temperatures less than 106°F are unlikely to be harmful in cats and may be somewhat beneficial because they constitute a protective response to inflammation.1,4

    The term fever of unknown origin (FUO) is used liberally in veterinary medicine. It should be used to identify a fever that does not resolve spontaneously, that does not respond to treatment with antibiotics, and for which the diagnosis remains uncertain after an initial diagnostic workup.4 Along with a thorough history and physical examination, initial diagnostics include a complete blood count (CBC), an FeLV antigen test, an FIV antibody test, a serum biochemistry profile, and urinalysis with antimicrobial culture. The cause of fever in most cats is infection that either is found during the initial workup or responds to antibiotic treatment; therefore, most cats do not have a true FUO.4

    Differential Diagnosis

    Information regarding FUO in cats is extremely limited, and there are no retrospective studies. Fevers are common in cats, and most diseases associated with FUO in cats are infectious.5 Neoplasia is a less common cause of FUO in cats, and FUO due to immune-mediated disease is rare in cats.6 FUO causes are often separated into groups based on the underlying disease mechanism.2,3,7 Most FUOs are caused by a common disease presenting in an obscure fashion.8 Box 1 lists some causes of FUO in cats. It is thought that about 10% to 15% of FUOs in cats remain undiagnosed despite thorough diagnostic evaluation.4

    Clinical Approach

    As in dogs, the diagnostic approach to FUO in cats must be targeted to each patient. It should be guided by history and physical examination findings, laboratory test results, and the potential causes common to the geographic location.9,10 A three-stage approach, such as the one presented in Box 2 , is commonly used.2-4 The goal of investigating an FUO is to promptly establish a definitive diagnosis while minimizing patient discomfort, client expense, and invasive diagnostic tests.2 Communication with the owner is of utmost importance to ensure understanding of the time and financial commitment that may be required in order to obtain a definitive diagnosis.

    If possible, all medications should be discontinued early in the evaluation to help rule out a drug-induced fever. If the fever persists beyond 72 hours after cessation of the medication, a drug reaction can be ruled out.11 Drugs that are known to induce fever in cats include tetracycline, sulfonamides, penicillins, and levamisole.

    History and Physical Examination

    Obtaining a thorough history is the first step to a successful diagnostic approach. The vaccination history should be ascertained because vaccines can cause immune-mediated fevers in cats during the immediate postvaccination period, and modified live virus vaccines can induce local lymphoid replication of the attenuated agent.5,12 Determining indoor/outdoor status, travel history, flea and tick control and potential exposure to diseases transmitted by parasites (e.g., hemotrophic mycoplasmosis, ehrlichiosis, bartonellosis, cytauxzoonosis), and contact with other cats is also important as many FUO causes are transmissable.5 Knowledge of ingestion of prey species may be helpful because songbirds can carry salmonellosis, rabbits can carry tularemia, and rodents can carry plague or toxoplasmosis.5

    Cats are frequently affected by stress hyperthermia, which must be ruled out before an extensive diagnostic evaluation is pursued. As in dogs, FUO diagnostic clues in cats are generally not readily apparent on physical examination, so repeated detailed examinations are essential.9 The whole body should be carefully palpated to detect subtle swelling or discomfort, which may help localize the fever source. The thorax should be gently compressed to evaluate for a cranial mediastinal mass. Repeated fundic examination should be performed because numerous infectious diseases (e.g., FIP, FIV, FeLV) cause ocular changes. Absence of ocular changes does not rule out infection with these diseases. Repeated neurologic and orthopedic examinations should be performed, although they can be difficult to interpret in an uncooperative cat.

    Feline Leukemia and Feline Immunodeficiency Virus

    FeLV antigen and FIV antibody blood tests should be conducted on every febrile cat. These tests are rapid and reliable, but it is important to understand how to interpret positive results.13,14

    Fecal Examinations

    Fecal samples should be obtained from cats with FUO. If diarrhea is discovered, rectal cytology should also be conducted. Other diagnostic tests to consider include fecal flotation with centrifugation, direct fecal examination, and fecal cultures. Cats can be bacteremic from Salmonella (and possibly Campylobacter) infection without diarrhea, so fecal cultures should be submitted, especially if neutrophils are evident on rectal cytology.15-17 If clostridial spores are seen on cytology, samples should be submitted for Clostridium perfringens enterotoxin testing.5

    CBC and Serum Biochemistry Profile

    Typically, the changes seen on the CBC and serum chemistry profile in cats with FUO are nonspecific but can help suggest the next diagnostic steps. A blood smear should always be evaluated along with the CBC to help identify morphologic changes, infectious organisms, or changes consistent with neoplasia. Serum should be saved at this point for future testing, if needed. Recently, a cat with nonspecific signs and a fever was diagnosed with a portosystemic shunt, so a serum bile acids assay should be considered.18

    Urinalysis with Culture

    A urine sample collected by cystocentesis (unless contraindicated) should be submitted for urinalysis with antimicrobial culture and sensitivity for every cat with FUO, regardless of the appearance of the urine. If the cat has a history of lower urinary tract disease, urine should be submitted for urinalysis and culture and sensitivity on multiple occasions because a negative urine culture does not rule out infection. A sample should be submitted for urine protein:creatinine ratio if proteinuria is present with inactive sediment.

    Cytology

    Fine-needle aspiration should be conducted on any suspicious masses, lymph nodes, fluid accumulations, or abnormal organs, and samples should be submitted for cytology (Figure 1). Impression cytology (nasal planum, skin lesion, feces, rectal mucosa) can also be conducted, if indicated.

    Serology

    Serum samples should be submitted for infectious disease testing (e.g., feline infectious peritonitis, bartonellosis, hemoplasmosis, rickettsiosis, anaplasmosis) if a disease is clinically suspected and if patient history suggests possible exposure. Toxoplasmosis serology (IgG and IgM) should be submitted for all cats with FUO. Natural clinical infections in cats with neosporosis have not been documented, so testing for this disease may not be warranted.19 Serology for feline foamy virus (previously known as feline syncytium-forming virus) can be conducted for cats with FUO and suspected joint disease.20

    Blood Cultures

    Blood culture should be conducted for cats with FUO and suspected bacteremia. Typical signs of bacteremia in cats include anorexia, pyrexia, and shifting leg lameness.21,22 Vegetative endocarditis is uncommon in cats, but these animals typically have heart murmurs.21,22 Underlying predisposing causes for which patients should be evaluated include pyothorax, septic peritonitis, gastrointestinal tract disease, pneumonia, endocarditis, pyelonephritis, osteomyelitis, pyometra, and bite wounds.21 In a recent study,23 bacteremia was diagnosed in 66 cats over a 9-year period.

    Radiography

    Two-view abdominal and three-view thoracic radiographs should be obtained if the minimum database does not reveal the cause of the FUO. Cats with lower respiratory disease are frequently asymptomatic, so care must be taken to rule out primary or secondary respiratory problems.

    Ultrasonography

    Abdominal ultrasonography can be valuable in detecting lesions not seen on radiographs. It can also assist with fine-needle aspiration or biopsy if needed. Thoracic ultrasonography is not rewarding unless there are radiographic changes.

    Bone Marrow Evaluation

    Bone marrow aspiration should be performed early in the evaluation of cats with FUO if CBC abnormalities consistent with bone marrow disease are present (Figure 2). It should be considered later if no definitive diagnosis has been made, even if the CBC is normal, because neoplasia and infectious disease can cause FUO in cats.2

    Arthrocentesis

    Arthrocentesis should be conducted on cats even if there is no obvious evidence of joint disease. Calicivirus, mycoplasmosis, L-form bacterial infection, and FeLV with feline foamy virus are all associated with polyarthritis in cats.24-27 Other infective arthritides include fungal, rickettsial, and protozoal diseases.28

    Immunodiagnostic Screening Panels

    Immune panels (antinuclear antibody, rheumatoid factor [RF], Coombs) are thought to be unrewarding in cats with FUO, but in a recent study, 10 of 12 cats definitively diagnosed with rheumatoid arthritis were strongly seropositive for RF.2,8,29,30 Therefore, although RF is not specific for rheumatoid arthritis, it may be an important diagnostic test in cats. The study also stated that four cats diagnosed with periosteal proliferative polyarthritis were negative for RF.30 Antiplatelet antibody tests and serum protein electrophoresis can be conducted if thrombocytopenia or hyperglobulinemia, respectively, is present.

    Other Diagnostic Testing

    Other diagnostic tests, such as cerebrospinal fluid analysis and bronchoscopy with bronchoalveolar lavage or transtracheal wash, should be considered if clinical abnormalities suggest neurologic or respiratory disorders, respectively. Samples should be submitted for cytologic evaluation and aerobic and anaerobic bacterial culture and sensitivity testing if quantity permits (Figure 3). Bronchoalveolar lavage samples should also be submitted for mycoplasma and slow-growing fungal cultures. Advanced imaging techniques and biopsy may be helpful in some cases, as in dogs.a

    Treatment

    Specific treatment is based on the definitive diagnosis, if found. A fan directed toward the cat's cage or administration of intravenous fluids may be all that is necessary to lower the body temperature to a safer level. Antipyretics (e.g., ketoprofen, flunixin meglumine, dipyrone) are not typically advocated because the fever can be beneficial, and many argue that antipyretic therapy can have a negative impact on immune responses by causing hypothermia and impairing host immune defenses.3,4,31 Fevers may increase the bactericidal effect of antibiotics and serum and can also decrease the pathogenicity of some pathogens.3,31 Fever can result in considerable malaise, dehydration, and anorexia; therefore, clinicians must decide in each case whether NSAIDs could be beneficial.3 If an antipyretic is considered necessary, aspirin dosed at 10 mg/kg q48-72h PO can be used.2,4 Empirical antibiotic therapy should be based on the organ system involved or the infectious agent suspected.5 Trial antifungal therapy should be considered for cats with suspected fungal infections that cannot be proven. Trial corticosteroids can be considered in cats with FUO for which the cause cannot be identified, making sure to discuss potential complications with the owner before use.b

    Conclusion

    Fevers are common in cats, and infectious disease is the most common cause of fever in cats. Using a logical diagnostic approach to a cat with an FUO will usually result in a definitive diagnosis. Sometimes, being patient and allowing new diagnostic clues to emerge by revamping historical information (via reassessing current information and possibly obtaining a more detailed history) and repeating physical examinations and simple laboratory tests is more desirable than proceeding with more invasive and expensive tests if the cat is stable. Communication with the client is of utmost importance. A broad knowledge of the possible causative diseases and the ability to interpret specific diagnostic test results in the context of FUO in cats is essential to correctly diagnose the source of an FUO.

    *Read the companion article about fever of unknown origin in dogs.

    aFor more information on the clinical approach to cats with FUO, please refer to the clinical approach section in the companion article. Many of the same tests used in dogs can also be used in cats.

    bFor more information on the treatment of cats with FUO, please refer to the treatment section in the companion article. Many of the treatments used in dogs can also be used in cats.

    Acknowledgments

    The author thanks Robin W. Allison, DVM, PhD, DACVP, of the Department of Veterinary Pathobiology at Oklahoma State University and Leo "Ty" McSherry, DVM, DACVP, clinical pathologist at Antech Diagnostics in Irvine, California, for the cytology images.

    Downloadable PDF

    1. Miller JB. Hyperthermia and fever of unknown origin. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 1. 6th ed. St. Louis: Elsevier Saunders; 2005:9-13.

    2. Lunn KF. Fever of unknown origin: a systematic approach to diagnosis. Compend Contin Educ Pract Vet 2001;23(11):976-992.

    3. Johannes DM, Cohn LA. A clinical approach to patients with fever of unknown origin. Vet Med 2000;95(8):633-642.

    4. Couto CG. Fever of undetermined origin. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; 2009:1274-1277.

    5. Lappin MR. Fever of unknown origin I and II. Proc Western Vet Conf 2003.

    6. Wolfe AM. Fever of undetermined origin in the cat. Proc Atl Coast Vet Conf 2002.

    7. Feldman BF. Fever of undetermined origin. Compend Contin Educ Pract Vet 1980;2(12):970-977.

    8. Dunn JK, Gorman NT. Fever of unknown origin in dogs and cats. J Small Anim Pract 1987;28:167-181.

    9. Roth AR, Basello GM. Approach to the adult patient with fever of unknown origin. Am Fam Phys 2003;68:2223-2228.

    10. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med 2003;163:545-551.

    11. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85-91.

    12. Greene CE, Schultz RD. Immunoprophylaxis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:1069-1119.

    13. Hartmann K. Feline leukemia virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:105-131.

    14. Sellon RK, Hartmann K. Feline immunodeficiency virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:131-143.

    15. Dow SW, Jones RL, Henik RA, et al. Clinical features of salmonellosis in cats: six cases (1981-1986). JAVMA 1989;194(10):1464-1466.

    16. Rossi M, Hanninen ML, Revez J, et al. Occurrence and species level diagnostics of Campylobacter spp., enteric Helicobacter spp. and Anaerobiospirillum spp. in healthy and diarrheic dogs and cats. Vet Microbiol 2008;129(3-4):304-314.

    17. Fox JG. Enteric bacterial infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:339-369.

    18. Wess G, Unterer S, Haller M, et al. Recurrent fever as the only or predominant clinical sign in four dogs and one cat with congenital portosystemic vascular anomalies. Schweiz Arch Tierheilkd 2003;145(8):363-368.

    19. Dubey JP, Lappin MR. Toxoplasmosis and neosporosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:754-775.

    20. Greene CE. Feline foamy (syncytium-forming) virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:154-155.

    21. Calvert CA, Wall M. Cardiovascular infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:841-865.

    22. Malik R, Barrs VR, Church DB, et al. Vegetative endocarditis in six cats. J Feline Med Surg 1999;1(3):171-180.

    23. Greiner M, Wolf G, Hartmann K. Bacteraemia in 66 cats and antimicrobial susceptibility of the isolates (1995-2004). J Feline Med Surg 2007;9(5):404-410.

    24. Dawson S, Bennett D, Carter SD, et al. Acute arthritis of cats associated with feline calicivirus infection. Res Vet Sci 1994;56(2):133-143.

    25. Liehmann L, Degasperi B, Spergser J, et al. Mycoplasma felis arthritis in two cats. J Small Anim Pract 2006;47(8):476-479.

    26. Carro T, Pedersen NC, Beaman BL, et al. Subcutaneous abscesses and arthritis caused by a probable bacterial L-form in cats. JAVMA 1989;194(11):1583-1588.

    27. Pedersen NC, Pool RR, O'Brien T. Feline chronic progressive polyarthritis. Am J Vet Res 1980;41(4):522-535.

    28. Bennett D. Immune-mediated and infective arthritis. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 2. 6th ed. St. Louis: Elsevier Saunders; 2005:1958-1965.

    29. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of fever in dogs: laboratory testing, diagnoses and influence prior to treatment. J Small Anim Pract 2006;47:370-376.

    30. Hanna FY. Disease modifying treatment for feline rheumatoid arthritis. Vet Comp Orthop Traumatol 2005;18(2):94-99.

    31. Klein NC, Cunha BA. Treatment of fever. Infect Dis Clin North Am 1996;10(1)211-216.

    References »

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    CETEST This course is approved for 3.0 CE credits

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