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Compendium January 2009 (Vol 31, No 1)

Web Supplement: Fever of Unknown Origin in Cats

by Julie Flood

    Identifying the cause of a fever of unknown origin (FUO) in cats is a considerable diagnostic challenge. As in dogs, the diagnostic workup can be frustrating, but most causes of FUO can eventually be determined. Below is some updated information on FUO in cats and up-and-coming techniques in veterinary medicine that may be valuable in diagnosing cats with FUO in the future.

    Differential Diagnosis

    The top diagnostic differentials in feline FUO are infectious disease, neoplasia, immune-mediated disease, and noninfectious inflammatory disease. The following examples are known to cause fever in cats:

    Infectious diseases1,2

    • Localized bacterial infections (e.g., pleuritis, osteomyelitis, periodontal abscess, metritis)
    • Pyelonephritis (the kidneys are a common source of occult infection)
    • Infections with organisms that are not typically sensitive to common antibiotics (e.g., Mycobacterium spp, Mycoplasma spp, L-form bacteria)

    Viral infections1,3

    • Feline infectious peritonitis (FIP)
    • FIV
    • FeLV
    • Feline calicivirus

    Systemic mycotic diseases1

    • Histoplasmosis
    • Blastomycosis
    • Coccidiomycosis

    Protozoal and rickettsial diseases1

    Parasitic infections1

    • Haemobartonella felis
    • Toxoplasma gondii
    • Aberrant parasite migration
    • Pulmonary embolism by Dirofilaria immitis

    Tumors1

    • Lymphoma
    • Myeloproliferative diseases
    • Pulmonary adenocarcinoma

    Noninfectious inflammatory diseases1

    • Cholangiohepatitis
    • Inflammatory bowel disease
    • Pancreatitis
    • Pansteatitis

    Drugs

    • Tetracycline
    • Sulfonamides
    • Penicillins
    • Levamisole

    Immune-mediated diseases rarely cause FUO in cats; however, these diseases are not well described in cats, and their true incidence is unknown.1

    Repeated fundic examination should be performed in cats with FUO because numerous infectious diseases cause ocular changes in cats (e.g., FIP, FIV, FeLV, feline rhinotracheitis, feline bartonellosis, tularemia, toxoplasmosis, systemic mycoses).4 Absence of ocular changes does not rule out infection with these diseases.4

    Clinical Approach

    FeLV and FIV Testing

    FeLV antigen and FIV antibody tests should be conducted on every febrile cat. The FeLV ELISA and the FeLV immunochromatographic assay are rapid, reliable screening tests and can be conducted using serum or plasma from cats of any age.5 A positive FeLV test result usually correlates with viremia, but technical and user errors can lead to false-positive results; therefore, cats should be retested immediately (with the same test) to confirm a positive result.5 To distinguish between transient and persistent viremia, cats should be retested in about 10 weeks.5 A second positive result usually indicates persistent viremia.5 Direct fluorescent antibody testing can also be used on monolayer fresh blood or bone marrow smears for prognostic purposes or to confirm positive results.5

    Cats with positive FIV ELISA antibody test results should be retested by Western blot to confirm the diagnosis.6 Positive results of the FIV ELISA antibody test confirm infection in an unvaccinated cat older than 5 months (maternal antibodies can be present in kittens up to 16 weeks of age) but do not necessarily correlate to disease induced by the virus.6 Diagnostic testing for other opportunistic infections is advisable with both positive FeLV and FIV test results.6 Unfortunately, the Western blot test cannot discriminate between infection and vaccination. New PCR tests that may be helpful are becoming available.6

    Cytology

    Cats with cytauxzoonosis occasionally present with fever, anorexia, and lethargy before they become anemic and icteric, so blood smears are extremely important.7 Anemic cats should be evaluated for mycoplasmosis using fresh, thin blood smears and a PCR assay.8 However, 50% of negative blood smear results for mycoplasmosis are false negatives.8 Cats with submandibular lymphadenopathy and fever or signs of pneumonia should undergo fine-needle aspiration of the affected lymph node, with samples evaluated for characteristic bipolar rods in areas endemic for Yersinia pestis.8

    Serologic Testing

    Serum samples should be submitted for testing for FIP virus only if this disease is suspected because the test cannot distinguish FIP virus from feline coronavirus (FCoV).9 Lymphopenia, neutrophilia (with or without a left shift), polyclonal hypergammaglobulinemia, and an albumin:globulin ratio of <0.4 in effusion or serum can be suggestive of FIP infection.9 Measuring α1-acid glycoprotein (AGP; an acute-phase protein) in plasma or effusions can be helpful; this protein is moderately elevated in FIP patients (AGP >1500 µg/mL) but is a nonspecific marker for infectious disease.9 AGP can help differentiate FIP from other noninflammatory diseases such as cardiomyopathy and neoplasia.9

    Currently, there is no single diagnostic test for FIP, and histopathology and antigen detection in tissue or effusion samples is still the gold standard.9 Positive antigen staining of FCoV-infected macrophages is diagnostic for FIP, but a negative result does not rule out FIP.9 The mRNA reverse transcriptase polymerase chain reaction (RT-PCR) assay has been investigated for use in the diagnosis of FIP. In one study,10 93% (75 of 81) of cats diagnosed with FIP on histopathology had positive mRNA RT-PCR results, and 17 cats without FIP had negative results. However, another recent study9 showed that mRNA RT-PCR may detect FCoV in blood samples from healthy cats as well as FIP virus in cats with clinical signs of FIP.11 RT-PCR testing may be valuable in the future.

    Samples may be submitted for blood culture, PCR assay, or serologic testing for cats with suspected bartonellosis (e.g., a febrile cat with uveitis, lethargy, lymphadenopathy, gingivitis, or neurologic disease).8 If the results of these tests are positive, bartonellosis should remain on the list of differentials, but other causes should still be investigated.8 A positive PCR assay result for Bartonella, hemoplasma, Rickettsia, Ehrlichia, or Anaplasma infection does not equate to a diagnosis of clinical illness from these agents.8

    Arthrocentesis

    Immune-mediated polyarthritis is classified into erosive (periosteal proliferative form and rheumatoid arthritis) and nonerosive (systemic lupus erythematosus and idiopathic polyarthritis) forms.12,13 These conditions are not well documented or described in cats. A recent study12 showed that 12 cats were diagnosed with rheumatoid arthritis over a 3-year period, which suggests that this disease may not be as rare as previously thought. Siamese cats were overrepresented in this study. Periosteal proliferative polyarthritides are apparently more common in cats, particularly young, male, neutered cats.12 Rheumatoid factor testing is not definitive; cats with polyarthritis are not always rheumatoid factor positive, and other disease states may cause positive results.12,13

    Advanced Imaging

    Computed tomography (CT) and magnetic resonance imaging can be used to help delineate conditions found via the use of other techniques or when the diagnosis remains uncertain.14 In humans with FUO, nuclear scintigraphy with gallium 67, technetium (Tc) 99m, or indium-labeled leukocytes is commonly used for detecting inflammatory conditions and neoplastic lesions that are frequently missed by CT.14 Nuclear scintigraphy is being used more frequently in veterinary medicine, and there are reports of its use in dogs and cats for evaluation of thyroid diseases, mammary lymphoscintigraphy, gastric emptying, glomerular filtration rate, portosystemic shunts, reverse patent ductus arteriosus, and pancreatitis.15-24 It may also be a valuable tool in investigating FUO through the use of radiolabeled leukocytes or antibiotics to detect sources of occult inflammation or infection (abscesses).25

    One of the newest imaging modalities being used in investigating human FUO is called image fusion or coregistration. It combines positron emission tomography (PET; a type of nuclear imaging) and CT,14 allowing one continuous body scan that simultaneously captures PET images of tiny changes in the body's metabolism caused by abnormal cells (infection or neoplasia) and CT images of abnormal tissue.26 One nonspecific tracer of increased glucose metabolism that is commonly used with PET is called 18F-fluorodeoxyglucose (FDG), which accumulates in neoplastic and activated inflammatory cells.27 The increased glycolytic activity of these cells causes increased 18F-FDG uptake at the site of inflammation and infection.28 Essentially, coregistration detects small lesions or tumors with PET and precisely locates them with CT.26 The human medical literature states that PET has a high negative predictive value in ruling out inflammatory causes of fever.14 Absence of areas of increased uptake with PET/CT may rule out infection.28

    Three case reports on the use of PET/CT in dogs29-31 and one report on the use of this technology in cats32 demonstrate that this imaging modality could play an important role in diagnostic imaging in veterinary medicine. The report on the use of PET/CT in cats describes normal uptake of a radiotracer in the head.32 One of the problems with interpreting some of the more advanced imaging techniques is obtaining proof that the documented abnormality is the cause of the fever.33 PET/CT seems promising as a noninvasive diagnostic technique, but because of its limited availability in humans and, therefore, small animals, it is too early to tell.14

    Brief Tips for Handling Fractious Febrile Cats

    Mild sedation may be necessary for the handling of fractious cats to enable physical examination as well as perform minor diagnostic procedures. The choice of sedative agent will depend on the patient's clinical status as well as the procedure to be performed.34 Butorphanol, a κ-agonist and µ-antagonist (dosed at 0.2 mg/kg IV, IM, or SC), or buprenorphine, a partial µ-agonist (dosed at 0.01 mg/kg IV, IM, or SC), are good choices because they cause less respiratory depression and can be reversed with naloxone, if needed.34 The dose of naloxone used to reverse the effects of butorphanol is 0.01 to 0.02 mg/kg IV, IM, or SC. To reverse the effects of buprenorphine, a dose 10 times greater may be required (i.e., 0.1 to 0.2 mg/kg).34 If deemed necessary, a small amount of acepromazine can be added (0.005 to 0.02 mg/kg IV or 0.01 to 0.05 mg/kg IM) if the cat is normovolemic and has stable cardiovascular function.34

    This document supplements the article "The Diagnostic Approach to Fever of Unknown Origin in Cats," which appeared in the January 2009 issue of Compendium.

    Downloadable PDF

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

    2. Wolfe AM. Fever of undetermined origin in the cat. Proc ACVIM 1991:125.

    3. Hurley KE, Pesavento PA, Pedersen NC, et al. An outbreak of virulent systemic feline calicivirus disease. JAVMA 2004;224(2):241-249.

    4. Greene CE, Mayo C. Disease rule-outs for medical problems. Appendix 7. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:1174-1185.

    5. 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.

    6. 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.

    7. Meinkoth J, Kocan AA, Whitworth L. Cats surviving natural infection with Cytauxzoon felis: 18 cases (1997-1998). J Vet Intern Med 2000;14(5):521-525.

    8. Lappin MR. Infectious causes of fever in cats [supplemental handout]. Proc ACVIM 2008.

    9. Addie DD, Jarrett O. Feline coronavirus infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:88-102.

    10. Simons FA, Vennema H, Rofina JE, et al. A mRNA PCR for the diagnosis of feline infectious peritonitis. J Virol Methods 2005;124(1-2):111-116.

    11. Can-Sahna K, Soydal Ataseven V, Pinar D, et al. The detection of feline coronaviruses in blood samples from cats by mRNA RT-PCR. J Feline Med Surg 2007;9(5):369-372.

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

    13. 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.

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

    15. Daniel GB, Sharp DS, Nieckarz JA, Adams W. Quantitative thyroid scintigraphy as a predictor of serum thyroxin concentration in normal and hyperthyroid cats. Vet Radiol Ultrasound 2002;43(4):374-382.

    16. Pereira CT, Marques FLN, Williams J, et al. 99mTc-labeled dextran for mammary lymphoscintigraphy in dogs. Vet Radiol Ultrasound 2008;49(5):487-491.

    17. Goggin JM, Hoskinson JJ, Kirk CA, et al. Comparison of gastric emptying times in healthy cats simultaneously evaluated with radiopaque markers and nuclear scintigraphy. Vet Radiol Ultrasound 1999;40(1):89-95.

    18. Lester NV, Roberts GD, Newell SM, et al. Assessment of barium impregnated polyethylene spheres (BIPS) as a measure of solid-phase gastric emptying in normal dogs—comparison to scintigraphy. Vet Radiol Ultrasound 1999;40(5):465-471.

    19. Kampa N, Lord P, Maripuu E, et al. Effects of measurement of plasma activity input on normalization of glomerular filtration rate to plasma volume in dogs. Vet Radiol Ultrasound 2007;48(6):585-593.

    20. Halling KB, Graham JP, Newell SP, et al. Sonographic and scintigraphic evaluation of acute renal allograft rejection in cats. Vet Radiol Ultrasound 2003;44(6):707-713.

    21. Morandi F, Cole RC, Echandi RL, et al. Transsplenic portal scintigraphy using 99m Tc-mebrofenin in normal dogs. Vet Radiol Ultrasound 2007;48(3):286-291.

    22. McEvoy FJ, Forster-van Hufte MA, White RN. Detection of portal blood flow using per-rectal 99mTc-pertechnetate scintigraphy in normal cats. Vet Radiol Ultrasound 1998;39(3):234-237.

    23. Morandi F, Daniel GB, Gompf RE, et al. Diagnosis of congenital cardiac right-to-left shunts with 99mTc-macroaggregated albumin. Vet Radiol Ultrasound 2004;45(2):97-102.

    24. Head LL, Daniel GB, Becker TJ, et al. Use of computed tomography and radiolabeled leukocytes in a cat with pancreatitis. Vet Radiol Ultrasound 2005;46(3):263-266.

    25. Moon ML, Hinkle GN, Krakowka GS. Scintigraphic imaging of technetium 99m-labeled neutrophils in the dog. Am J Vet Res 1988;49(6):950-955.

    26. Radiological Society of North America, Inc., American College of Radiology. PET/CT Basics. Positron emission tomography (PET) scanning. Accessed September 2008 at radiologyinfo.org.

    27. Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al. A prospective multicenter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine 2007;86(1):26-38.

    28. Dumarey N, Egrise D, Blocklet D, et al. Imaging infection with 18F-FDG-labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006;47(4):625-632.

    29. Peremans K, DeWinter F, Janssens L, et al. An infected hip prosthesis in a dog diagnosed with a 99mTC-ciprofloxacin (infection) scan. Vet Radiol Ultrasound 2002;43(2):178-182.

    30. Berry CR, DeGrado TR, Nutter F, et al. Imaging of pheochromocytoma in 2 dogs using p-[18F] fluorobenzylguanidine. Vet Radiol Ultrasound 2002;43(2):183-186.

    31. Ballegeer EA, Forrest LJ, Jeraj R, et al. PET/CT following intensity-modulated radiation therapy for primary lung tumor in a dog. Vet Radiol Ultrasound 2006;47(2):228-233.

    32. Barthez PY, Schaafsma IA, Pollak YWEA. Multimodality image fusion to facilitate anatomic localization of 99mTc-pertechnetate uptake in the feline head. Vet Radiol Ultrasound 2006;47(5):503-506.

    33. Knockaert DC, Dujardin KS, Bobbaers HJ. Long-term follow-up of patients with undiagnosed fever of unknown origin. Arch Intern Med 1996;156:618-620.

    34. Perkowski SZ. Sedation of the critically ill patient. In: Silverstein DC, Hopper K, eds. Small Animal Critical Care Medicine. St. Louis: Elsevier Saunders; 2009:700-704.

    References »

    NEXT: Web Supplement: Fever of Unknown Origin in Dogs

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