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Compendium January 2009 (Vol 31, No 1)

Web Supplement: Fever of Unknown Origin in Dogs

by Julie Flood

    Identifying the cause of a fever of unknown origin (FUO) in dogs is a considerable diagnostic challenge. The diagnostic workup can be frustrating for veterinarians and clients, especially when it fails to reach a final diagnosis after extensive testing. Fortunately, most causes of FUO can be found or treated successfully.1 Below is some of the most recent information about up-and-coming diagnostic techniques that may be valuable in diagnosing FUO in dogs in the future.

    Fever-Inducing Drugs and Toxins

    Although any medication has the potential to cause fever in dogs, the following medications are known to do so1:

    • Albuterol2
    • Amphotericin
    • Antihistamines
    • Atropine
    • Barbiturates
    • Bleomycin
    • Cimetidine
    • Colchicine
    • Heavy metals
    • Nitrofurantoin
    • Penicillins
    • Procainamide
    • Salicylates (high dosages)
    • Sulfa drugs
    • Tetracyclines

    Diagnostic Tests

    Frequently, diagnostic clues are not readily apparent on physical examination, so repeated detailed physical examinations are essential (by multiple clinicians if possible).3

    Blood Cultures

    Development of a new DNA isolation kit that can eliminate background human DNA known to cause cross-reactions and inhibit polymerase chain reaction (PCR) has enabled the use of new PCR technology in human medicine for the rapid detection and identification of bacteria and fungi (Candida spp). In one study,4 all of the positive blood cultures that were later judged to be contaminated had negative results on PCR. Out of 83 negative blood culture samples, six showed a positive PCR result.4 This technique, when available for dogs, may be a supplemental tool to blood culture in dogs with FUO, especially those that are seriously ill or are infected with slow-growing pathogens.

    Synovial Cultures

    A recently developed PCR-based test for rapid detection and classification of bacteria from human septic arthritis patients is also available.5 This test is reliable for the diagnosis of septic arthritis in humans and has improved speed and accuracy compared with other PCR-based tests.5 The results are promising, and such tests could be very valuable in canine FUO patients if they become available.

    C-Reactive Protein and Erythrocyte Sedimentation Rate

    C-reactive protein (CRP) is an acute-phase protein that is commonly measured in human patients and is becoming more commonly measured in dogs. Serum CRP is a nonspecific inflammatory marker that may aid in the diagnosis of FUO or other infectious/inflammatory conditions by indicating the presence and extent (local versus generalized, neurologic versus arthritic) of inflammation.6 In one study,6 the CRP concentration did not increase in dogs with intervertebral disk protrusion, leading the authors to conclude that it might be useful in differentiating arthritis from spinal or brain diseases in dogs with lameness. In the same study, CRP was found to be markedly elevated in many diseases with inflammation and tissue damage, especially neoplastic and immune-mediated diseases.

    In human medicine, the erythrocyte sedimentation rate (ESR) is often monitored along with CRP. The amount of fibrinogen in the blood directly correlates with the ESR.7 The ESR is helpful in the specific diagnosis and monitoring of a few conditions in humans, such as temporal arteritis, polymyalgia rheumatica, and rheumatoid arthritis.7 It may also help predict relapse in human patients with Hodgkin's disease.7 According to one report,7 infection is the leading cause of a markedly elevated ESR, followed by collagen vascular disease and metastatic malignant tumors.

    CRP measurement in dogs is becoming more important and is known to provide diagnostic information about the presence of inflammatory lesions and infectious and immune-mediated diseases as well as response to treatment.8 Fibrinogen levels were reported to be markedly elevated in canine patients with immune-mediated conditions in the 1998 retrospective study by Dunn and Dunn.9 Unfortunately, CRP was not measured. The role of these acute-phase proteins (fibrinogen and CRP) is still being investigated, but they may help in diagnosing and localizing lesions in dogs with FUO.

    Advanced Imaging

    Computed tomography (CT) and magnetic resonance imaging (MRI) should be used to help delineate conditions found via other techniques or when the diagnosis remains uncertain.3 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 underdiagnosed by CT scans.3 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, lymphatic vasculature, gastric emptying, glomerular filtration rate, portosystemic shunts, reverse patent ductus arteriosus, and pancreatitis.10-18 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).19

    One of the newest imaging modalities being used in investigation of human FUO is called image fusion or coregistration. It combines positron emission tomography (PET; a type of nuclear imaging) and CT,3 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.20 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.21 The increased glycolytic activity of these cells causes increased 18F-FDG uptake at the site of inflammation and infection.22 Essentially, coregistration detects small lesions or tumors with PET and precisely locates them with CT.20 The human medical literature states that PET has a high negative predictive value in ruling out inflammatory causes of fever.3 One study21 showed that it was especially helpful when the CRP and ESR were both elevated. Absence of areas of increased uptake with PET/CT may rule out infection in humans.22

    Three case reports on the use of PET/CT in dogs demonstrate that this imaging technique could play an important role in diagnostic imaging in veterinary medicine.23-25 Also, a recent report attempts to establish baseline normal levels for thoracic and abdominal organ uptake of a radiotracer in healthy dogs.26 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. 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.3,27

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

    Downloadable PDF

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

    2. McCown JL, Lechner ES, Cooke KL. Suspected albuterol toxicosis in a dog. JAVMA 2008;232(8):1168-1171.

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

    4. Gebert S, Siegel D, Wellinghausen N. Rapid detection of pathogens in blood culture bottles by real-time PCR in conjunction with the pre-analytic tool MolYsis. J Infect 2008;57:307-316.

    5. Yang S, Ramachandran P, Hardick A, et al. Rapid PCR-based diagnosis of septic arthritis by early gram-type classification and pathogen identification. J Clin Microbiol 2008;46(4):1386-1390.

    6. Nakamura M, Takahashi M, Ohno K, et al. C-reactive protein concentration in dogs with various diseases. J Vet Med Sci 2008;70(2):127-131.

    7. Brigden ML. Clinical utility of the erythrocyte sedimentation rate. Am Fam Phys 1999;60:1443-1450.

    8. Parra MD, Tecles F, Martinez-Subiela S, et al. C-reactive protein measurement in canine saliva. J Vet Diagn Invest 2005;17:139-144.

    9. Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of unknown origin. J Small Anim Pract 1998;39:574-580.

    10. Feeney DA, Anderson KL. Nuclear imaging and radiation therapy in canine and feline thyroid disease. Vet Clin North Am Small Anim Pract 2007;37(4):799-821.

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

    12. 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.

    13. 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.

    14. Hecht S, Daniel GB, Mitchell SK. Diuretic renal scintigraphy in normal dogs. Vet Radiol Ultrasound 2006;47(6):602-608.

    15. 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.

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

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

    18. 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.

    19. 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.

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

    21. 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 (Baltimore) 2007;86(1):26-38.

    22. 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.

    23. 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.

    24. 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.

    25. 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.

    26. LeBanc AK, Jakoby B, Townsend DW, et al. Thoracic and abdominal organ uptake of 2-deoxy-2-[18F] fluoro-D-glucose (18FDG) with positron emission tomography in the normal dog. Vet Radiol Ultrasound 2008;49(2):182-188.

    27. 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.

    References »

    NEXT: Analgesia, Sedation, and Anesthesia: Making the Switch from Medetomidine to Dexmedetomidine (January 2009)

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