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Home , Feline foamy virus, Fever of unknown origin

3 CE CREDITS CE Article 2

The Diagnostic Approach to of Unknown Origin in *

❯❯ Julie Flood, DVM, DACVIM Abstract: Identifying the cause of fever of unknown origin (FUO) in cats is a diagnostic challenge, Antech Diagnostics just as it is in dogs. is the most common cause of FUO in cats. As in dogs, the diagnostic Irvine, California workup can be frustrating, but most FUO causes can eventually be determined. This article address- es the potential diagnostic tests for, and the differential diagnosis and treatment of, FUO in cats.

rue fever (pyrexia) is defined as an during the initial workup or responds to increase in body temperature due to antibiotic treatment; therefore, most cats T an elevation of the thermal set point do not have a true FUO.4 in the anterior hypothalamus secondary to the release of pyrogens.1 With hyperther- Differential Diagnosis mic conditions other than true fever, the Information regarding FUO in cats is hypothalamic set point is not adjusted.1 extremely limited, and there are no retro- At a Glance Nonfebrile occurs when heat spective studies. are common in cats, gain exceeds heat loss, such as with inade- and most diseases associated with FUO Differential Diagnosis quate heat dissipation, exercise, and patho- in cats are infectious.5 Neoplasia is a less Page 26 logic or pharmacologic causes.1 common cause of FUO in cats, and FUO Clinical Approach Cats with true fever typically have body due to immune-mediated disease is rare in Page 26 temperatures between 103°F and 106°F cats.6 FUO causes are often separated into Potential Causes of Fever (39.5°C to 41.1°C).2 Cats are less likely than groups based on the underlying disease of Unknown Origin in Cats dogs to succumb to the dangerous effects mechanism.2,3,7 Most FUOs are caused by a Page 27 of body temperatures greater than 106°F, common disease presenting in an obscure 8 Staged Diagnostic which are usually seen with nonfebrile fashion. Box 1 lists some causes of FUO in 3 Approach to Fever of causes of hyperthermia. Temperatures cats. It is thought that about 10% to 15% of Unknown Origin in Cats less than 106°F are unlikely to be harm- FUOs in cats remain undiagnosed despite 4 Page 28 ful in cats and may be somewhat benefi- thorough diagnostic evaluation. cial because they constitute a protective T r e a t m e n t 1,4 a Page 30 response to inflammation. Clinical Approach The term fever of unknown origin (FUO) As in dogs, the diagnostic approach to FUO is used liberally in veterinary medicine. It in cats must be targeted to each patient. It should be used to identify a fever that does should be guided by history and physi- not resolve spontaneously, that does not cal examination findings, laboratory test respond to treatment with antibiotics, and results, and the potential causes common for which the diagnosis remains uncertain to the geographic location.9,10 A three- after an initial diagnostic workup.4 Along stage approach, such as the one presented with a thorough history and physical in Box 2, is commonly used.2–4 The goal of examination, initial diagnostics include investigating an FUO is to promptly estab- WEB a complete blood count (CBC), an FeLV lish a definitive diagnosis while minimiz- EXCLUSIVE antigen test, an FIV antibody test, a serum ing patient discomfort, client expense, biochemistry profile, and urinalysis with antimicrobial culture. The cause of fever aFor more information on the clinical ap- Supplemental material to this in most cats is infection that either is found proach to cats with FUO, please refer to the article is available at clinical approach section in the article starting CompendiumVet.com. *A companion article about fever of unknown on page 14. Many of the same tests used in origin in dogs begins on page 14. dogs can also be used in cats.

26 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com FREE The Diagnostic Approach to FUO in Cats CE and invasive diagnostic tests.2 Communication History and Physical Examination with the owner is of utmost importance to Obtaining a thorough history is the first step ensure understanding of the time and finan- to a successful diagnostic approach. The vac- cial commitment that may be required in order cination history should be ascertained because to obtain a definitive diagnosis. vaccines can cause immune-mediated fevers If possible, all medications should be dis- in cats during the immediate postvaccination continued early in the evaluation to help rule period, and modified live vaccines can out a drug-induced fever. If the fever persists induce local lymphoid replication of the atten- beyond 72 hours after cessation of the medi- uated agent.5,12 Determining indoor/outdoor cation, a drug reaction can be ruled out.11 status, travel history, flea and control and Drugs that are known to induce fever in cats potential exposure to diseases transmitted by include tetracycline, sulfonamides, penicillins, parasites (e.g., hemotrophic mycoplasmosis, and levamisole. , , cytauxzoonosis), and contact with other cats is also impor- Box 1 tant as many FUO causes are transmissable.5 Potential Causes of Fever Knowledge of ingestion of prey species may 2,4 be helpful because songbirds can carry sal- of Unknown Origin in Cats monellosis, rabbits can carry , and rodents can carry plague or .5 B acterial infection (focal or systemic): Bac- Cats are frequently affected by stress hyper- teremia, infective , septic arthritis, thermia, which must be ruled out before an , diskospondylitis, septic menin- extensive diagnostic evaluation is pursued. As gitis, pyothorax, , prostatitis, in dogs, FUO diagnostic clues in cats are gen- stump pyometra, peritonitis, Bacterial diseases: Bartonellosis, borrelio- erally not readily apparent on physical exami- sis(?), mycoplasmosis (hemotrophic and non- nation, so repeated detailed examinations are 9 hemotrophic), and other myco- essential. The whole body should be carefully bacterial diseases, diseases caused by L-form palpated to detect subtle swelling or discom- bacteria (e.g., cellulitis or synovitis secondary fort, which may help localize the fever source. to bite wounds or surgical incisions) The thorax should be gently compressed Viral: FeLV, FIV, feline infectious peritonitis, to evaluate for a cranial mediastinal mass. feline calicivirusa Repeated fundic examination should be per- Rickettsial: Feline ehrlichiosis, , formed because numerous infectious diseases QuickNotes Rocky Mountain spotted fever (e.g., FIP, FIV, FeLV) cause ocular changes. Fungal: , , cryp­ Absence of ocular changes does not rule out Infectious diseases tococcosis, infection with these diseases. Repeated neu- are the most com- Protozoal : Toxoplasmosis, cytaux- rologic and orthopedic examinations should mon causes of zoonosis, neosporosis(?), (?), try- be performed, although they can be difficult fever and fever of panosomiasis(?) to interpret in an uncooperative . unknown origin in Immune-mediated diseases: Polyarthritis, cats. systemic erythematosus, rheumatoid Feline and Feline arthritis, , meningitis, steroid-re- Immunodeficiency Virus sponsive and fever FeLV antigen and FIV antibody blood tests Neoplastic: , leukemia, multiple should be conducted on every febrile cat. myeloma, necrotic solid tumors Noninfectious inflammatory diseases: These tests are rapid and reliable, but it is Lympha­denitis, panniculitis, pansteatitis, important to understand how to interpret posi- 13,14 , granulomatosis tive results. Miscellaneous: Portosystemic shunt, drug reaction, toxin, , idiopathic Fecal Examinations causes Fecal samples should be obtained from cats with FUO. If diarrhea is discovered, rectal aHurley KE, Pesavento PA, Pedersen NC, et al. An cytology should also be conducted. Other outbreak of virulent systemic dis- diagnostic tests to consider include fecal flota- ease. JAVMA 2004;224(2):241-249. tion with centrifugation, direct fecal examina-

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Box 2 tion, and fecal cultures. Cats can be bacteremic Staged Diagnostic Approach to Fever from Salmonella (and possibly Campylobacter) 2,3 of Unknown Origin in Cats infection without diarrhea, so fecal cultures should be submitted, especially if Stage 1 are evident on rectal cytology.15-17 If clostridial Take a thorough history. spores are seen on cytology, samples should Stop all medications to rule out drug-induced fever. be submitted for Clostridium perfringens Perform a meticulous physical examination, including enterotoxin testing.5 fundic and neurologic examinations. Conduct FeLV and FIV testing. CBC and Serum Biochemistry Profile Obtain samples for CBC, blood smear, and serum chemistry profile. Typically, the changes seen on the CBC and Save serum for serology or other testing. serum chemistry profile in cats with FUO are Conduct a complete urinalysis and urine culture. nonspecific but can help suggest the next diag- Submit a sample for urine protein:creatinine ratio if nostic steps. A blood smear should always be proteinuria and inactive sediment are present. evaluated along with the CBC to help identify Conduct fecal centrifugation and fecal cytology, if indicated. morphologic changes, infectious organisms, or Consider obtaining thoracic and abdominal radiographs. changes consistent with neoplasia. Serum should Consider trial antibiotics if bacterial infection is suspected be saved at this point for future testing, if needed. (e.g., doxycycline if ehrlichiosis is suspected). Recently, a cat with nonspecific signs and a fever If necessary, proceed to stage 2. was diagnosed with a portosystemic shunt, so a serum bile acids assay should be considered.18 Stage 2 Repeat stage 1 tests as indicated. Urinalysis with Culture Obtain thoracic and abdominal radiographs if not obtained A urine sample collected by cystocentesis (unless in stage 1. contraindicated) should be submitted for urinaly- Conduct abdominal and other ultrasonography as indicated. sis with antimicrobial culture and sensitivity for Conduct echocardiography if a is present. every cat with FUO, regardless of the appear- Perform fine-needle aspiration with cytology of masses, ance of the urine. If the cat has a history of lower lymph nodes, and fluids (cyst, pleural, peritoneal). urinary tract disease, urine should be submitted Conduct . for urinalysis and culture and sensitivity on mul- Perform arthrocentesis. Conduct fecal cultures, if indicated. tiple occasions because a negative urine culture Conduct bone marrow aspiration if warranted by CBC results. does not rule out infection. A sample should be Conduct serology for infectious diseases. submitted for urine protein:creatinine ratio if pro- Obtain long bone and joint radiographs. teinuria is present with inactive sediment. Conduct an immune panel, if indicated. If necessary, proceed to stage 3. Cytology Fine-needle aspiration should be conducted on any Stage 3 suspicious masses, lymph nodes, fluid accumula- Repeat stage 1 and 2 tests as indicated. tions, or abnormal organs, and samples should Conduct echocardiography even if no murmur is present. be submitted for cytology (Figure 1). Im­pression Conduct transesophageal echocardiography. cytology (nasal planum, skin lesion, feces, rectal Perform bone marrow aspiration even if CBC results mucosa) can also be conducted, if indicated. are normal. Perform biopsy as indicated. Serology Perform bronchoscopy and bronchoalveolar lavage Serum samples should be submitted for infec- as indicated. tious disease testing (e.g., feline infectious Conduct cerebrospinal fluid analysis. peritonitis, bartonellosis, hemoplasmosis, rick- Perform dental radiography. ettsiosis, anaplasmosis) if a disease is clinically Consider computed tomography, magnetic resonance im- suspected and if patient history suggests pos- aging, nuclear imaging, or positron emission tomography. sible exposure. Toxoplasmosis serology (IgG Perform laparoscopy or thoracoscopy as indicated. Consider exploratory celiotomy. and IgM) should be submitted for all cats Administer trial antibiotic or antifungal (if indicated) therapy. with FUO. Natural clinical infections in cats with neosporosis have not been documented,

28 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com FREE The Diagnostic Approach to FUO in Cats CE so testing for this disease may not be war- FIGURE 1 ranted.19 Serology for feline foamy virus (pre- viously 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 , 21,22

pyrexia, and shifting leg lameness. McSherry Ty of Dr. Courtesy Vegetative endocarditis is uncommon in cats, Histoplasma organisms found in a pulmo- but these animals typically have heart mur- nary fine-needle aspirate from a cat.The organisms murs.21,22 Underlying predisposing causes for are located predominately in the macrophages. which patients should be evaluated include pyothorax, septic peritonitis, gastrointestinal are all associated with polyarthritis in cats.24–27 tract disease, pneumonia, endocarditis, pyelo- Other infective arthritides include fungal, rick- nephritis, osteomyelitis, pyometra, and bite ettsial, and protozoal diseases.28 wounds.21 In a recent study,23 bacteremia was diagnosed in 66 cats over a 9-year period. Immunodiagnostic Screening Panels Immune panels (antinuclear antibody, rheuma- Radiography toid factor [RF], Coombs) are thought to be unre- Two-view abdominal and three-view thoracic warding in cats with FUO, but in a recent study, QuickNotes radiographs should be obtained if the mini- 10 of 12 cats definitively diagnosed with rheu- Urine culture should mum database does not reveal the cause of matoid arthritis were strongly seropositive for the FUO. Cats with lower respiratory disease RF.2,8,29,30 Therefore, although RF is not specific be conducted for are frequently asymptomatic, so care must be for , it may be an important every cat with fever taken to rule out primary or secondary respi- diagnostic test in cats. The study also stated that of unknown origin ratory problems. four cats diagnosed with periosteal proliferative regardless of the polyarthritis were negative for RF.30 Antiplatelet appearance of the Ultrasonography antibody tests and serum protein electrophore- urine sediment. Abdominal ultrasonography can be valuable sis can be conducted if thrombocytopenia or in detecting lesions not seen on radiographs. hyperglobulinemia, respectively, is present. It can also assist with fine-needle aspiration or biopsy if needed. Thoracic ultrasonogra- Other Diagnostic Testing phy is not rewarding unless there are radio- Other diagnostic tests, such as cerebrospinal graphic changes. fluid analysis and bronchoscopy with broncho- alveolar lavage or transtracheal wash, should Bone Marrow Evaluation Bone marrow aspiration should be performed FIGURE 2 early in the evaluation of cats with FUO if CBC abnormalities consistent with bone mar- row 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 dis- Allison Robin of Dr. Courtesy ease. Calicivirus, mycoplasmosis, L-form bacte- Histoplasma organisms in a bone marrow rial infection, and FeLV with feline foamy virus aspirate from a cat.

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FIGURE 3 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 , dehydration, and anorexia; therefore, clinicians must decide in each case whether NSAIDs could be benefi- cial.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 sus- pected fungal infections that cannot be proven.

Courtesy of Dr. Robin Allison Robin of Dr. Courtesy Trial corticosteroids can be considered in cats Toxoplasma organisms in a bronchoal- with FUO for which the cause cannot be iden- veolar lavage cytology sample from a cat. tified, making sure to discuss potential compli- cations with the owner before use. be considered if clinical abnormalities suggest QuickNotes neurologic or respiratory disorders, respectively. Conclusion Samples should be submitted for cytologic eval- Fevers are common in cats, and infectious Repeated fundic uation and aerobic and anaerobic bacterial cul- disease is the most common cause of fever examinations ture and sensitivity testing if quantity permits in cats. Using a logical diagnostic approach are essential in (Figure 3). Bronchoalveolar lavage samples to a cat with an FUO will usually result in a cats with fever of should also be submitted for mycoplasma and definitive diagnosis. Sometimes, being patient unknown origin. slow-growing fungal cultures. Advanced and allowing new diagnostic clues to emerge imaging techniques and biopsy may be helpful by revamping historical information (via in some cases, as in dogs. reassessing current information and possibly obtaining a more detailed history) and repeat- Treatmentb ing physical examinations and simple labora- Specific treatment is based on the definitive tory tests is more desirable than proceeding diagnosis, if found. A fan directed toward the with more invasive and expensive tests if the cat’s cage or administration of intravenous flu- cat is stable. Communication with the client is ids may be all that is necessary to lower the of utmost importance. A broad knowledge of body temperature to a safer level. Antipyretics the possible causative diseases and the ability (e.g., ketoprofen, flunixin meglumine, dipy- to interpret specific diagnostic test results in rone) are not typically advocated because the the context of FUO in cats is essential to cor- fever can be beneficial, and many argue that rectly diagnose the source of an FUO. to learn more antipyretic therapy can have a negative impact For more information on on immune responses by causing Acknowledgments special tests that can be The author thanks Robin W. Allison, DVM, and impairing host immune defenses.3,4,31 used in diagnosing the PhD, DACVP, of the Department of Veterinary cause of FUO in cats, b Pathobiology at Oklahoma State University and Leo please visit the Web For more information on the treatment of cats with “Ty” McSherry, DVM, DACVP, clinical pathologist Exclusives section of FUO, please refer to the treatment section in the at Antech Diagnostics in Irvine, California, for the CompendiumVet.com. article starting on page 14. Many of the treatments used in dogs can also be used in cats. cytology images.

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10. Mourad O, Palda V, Detsky AS. A comprehensive evidence- 20. Greene CE. Feline foamy (syncytium-forming) virus infection. based approach to fever of unknown origin. Arch Intern Med In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. 2003;163:545-551. St. Louis: Elsevier Saunders; 2006:154-155. 11. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 21. Calvert CA, Wall M. Cardiovascular infections. In: Greene CE, 1996;10:85-91. ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: El- 12. Greene CE, Schultz RD. Immunoprophylaxis. In: Greene CE, ed. sevier Saunders; 2006:841-865. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier 22. Malik R, Barrs VR, Church DB, et al. Vegetative endocarditis in Saunders; 2006:1069-1119. six cats. J Feline Med Surg 1999;1(3):171-180. 13. Hartmann K. infection. In: Greene CE, ed. 23. Greiner M, Wolf G, Hartmann K. Bacteraemia in 66 cats and an- Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier timicrobial susceptibility of the isolates (1995–2004). J Feline Med Saunders; 2006:105-131. Surg 2007;9(5):404-410. 14. Sellon RK, Hartmann K. Feline immunodeficiency virus infec- 24. Dawson S, Bennett D, Carter SD, et al. Acute arthritis of cats associ- tion. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ated with feline calicivirus infection. Res Vet Sci 1994;56(2):133-143. ed. St. Louis: Elsevier Saunders; 2006:131-143. 25. Liehmann L, Degasperi B, Spergser J, et al. Mycoplasma felis 15. Dow SW, Jones RL, Henik RA, et al. Clinical features of salmonello- arthritis in two cats. J Small Anim Pract 2006;47(8):476-479. sis in cats: six cases (1981–1986). JAVMA 1989;194(10):1464-1466. 26. Carro T, Pedersen NC, Beaman BL, et al. Subcutaneous ab- 16. Rossi M, Hanninen ML, Revez J, et al. Occurrence and species scesses and arthritis caused by a probable bacterial L-form in cats. level diagnostics of Campylobacter spp., enteric Helicobacter spp. JAVMA 1989;194(11):1583-1588. and Anaerobiospirillum spp. in healthy and diarrheic dogs and cats. 27. Pedersen NC, Pool RR, O’Brien T. Feline chronic progressive Vet Microbiol 2008;129(3-4):304-314. polyarthritis. Am J Vet Res 1980;41(4):522-535. 17. Fox JG. Enteric bacterial infections. In: Greene CE, ed. Infec- 28. Bennett D. Immune-mediated and infective arthritis. In: Ettinger tious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saun- SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol ders; 2006:339-369. 2. 6th ed. St. Louis: Elsevier Saunders; 2005:1958-1965. 18. Wess G, Unterer S, Haller M, et al. Recurrent fever as the only 29. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of or predominant clinical sign in four dogs and one cat with con- fever in dogs: laboratory testing, diagnoses and influence prior to genital portosystemic vascular anomalies. Schweiz Arch Tierheilkd treatment. J Small Anim Pract 2006;47:370-376. 2003;145(8):363-368. 30. Hanna FY. Disease modifying treatment for feline rheumatoid 19. Dubey JP, Lappin MR. Toxoplasmosis and neosporosis. In: arthritis. Vet Comp Orthop Traumatol 2005;18(2):94-99. Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. 31. Klein NC, Cunha BA. Treatment of fever. Infect Dis Clin North Louis: Elsevier Saunders; 2006:754-775. Am 1996;10(1)211-216.

3 CE CREDITS CE Test 2 This article qualifies for 3 contact hours of continuing education credit from the Auburn University College of Veterinary Medicine. Subscribers may take individual CE tests online and get real-time scores at CompendiumVet.com. Those who wish to apply this credit to fulfill state relicensure requirements should consult their respective state authorities regarding the applicability of this program.

1. An example of a true fever would be an 5. The underlying predisposing causes of 9. Which statement regarding fever in cats elevated body temperature bacteremia in cats include is true? a. secondary to heatstroke. a. pneumonia. a. Cats with true fevers typically have body b. associated with a drug reaction. b. pyelonephritis. temperatures between 103°F and 106°F. c. secondary to a prolonged seizure. c. gastrointestinal tract disease. b. Cats are not affected by stress hyper- d. secondary to malignant d. all of the above thermia; therefore, a thorough diagnos- hyperthermia. tic evaluation should immediately be 6. The most common cause of FUO in cats is conducted on every febrile cat. 2. Stage 1 diagnostic testing for cats with a. neoplasia. c. A subtle subcutaneous swelling on FUO should include b. infectious disease. the limb of a febrile cat can be ignored a. urinalysis. c. immune-mediated disease. because it is an unlikely cause of fever. b. ultrasonography. d. none of the above d. About 50% of FUOs in cats remain undi- c. arthrocentesis. agnosed despite thorough diagnostic d. biopsy. 7. ______has been reported to cause evaluation. FUO in cats. 3. ______examination should be con- a. A portosystemic shunt c. Lymphadenitis 10. Which statement regarding testing in ducted repeatedly in cats with an FUO. b. Polyarthritis d. all of the above cats with FUO is true? a. Physical c. Neurologic a. FeLV and FIV tests do not need to be b. Fundic d. all of the above 8. Thoracic radiography should be conducted conducted in cats previously tested for a. in all cats with FUO. these diseases. 4. Which is not known to be associated b. if ultrasonography results indicate b. A serum bile acids assay is never indi- with polyarthritis in cats? respiratory disease. cated in a cat with FUO. a. feline infectious peritonitis c. if the minimum database does not c. A blood smear should be evaluated along b. mycoplasma reveal the cause of the FUO. with the CBC for every cat with an FUO. c. calicivirus d. only in cats with clinical signs of respi- d. Bone marrow aspiration is indicated d. L-form bacterial infection ratory disease. only when the CBC is abnormal.

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