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Compendium CompendiumVet.com | Peer Reviewed | Listed in MEDLINE Vol 31(1) January 2009 9 CE Contact Hours CONTI N U I NG EDUCATION FOR VETERI NARIANS ® FREE CE Fever of Unknown Origin Diagnostic Approaches NEW Focus on Nutrition W I Improving Adherence i Ad to Recommendations Understanding Behavior: Patient Assessment IT n! N m IO lu Co 22 R O ion ge T Pa NU S trit CU Nu Se N FO New e

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January 2009 Vol 31(1) CompendiumVet.com | Peer Reviewed | Listed in MEDLINE EDITORIAL BOARD Anesthesia Internal Medicine Nora S. Matthews, DVM, DACVA Dana G. Allen, DVM, MSc, DACVIM AMERICAN Texas A&M University Ontario Veterinary College BOARD OF Cardiology Internal Medicine and Emergency/ VETERINARY Bruce Keene, DVM, MSc, DACVIM Critical Care PRACTITIONERS North Carolina State University Alison R. Gaynor, DVM, DACVIM (ABVP) REVIEW (Internal Medicine), DACVECC Clinical Chemistry, Hematology, North Grafton, Massachusetts BOARD and Urinalysis Betsy Welles, DVM, PhD, DACVP Nephrology Eric Chafetz, DVM, DABVP Auburn University Catherine E. Langston, DVM, ACVIM (Canine/Feline) Animal Medical Center Dentistry Vienna Animal Hospital New York, New York Gary B. Beard, DVM, DAVDC Vienna, Virginia Auburn University Neurology Canine and Feline Medicine EDITOR IN CHIEF R. Michael Peak, DVM, DAVDC Curtis W. Dewey, DVM, MS, DACVIM (Neurology), DACVS Henry E. Childers, DVM, Douglass K. Macintire, The Pet Dentist—Tampa Bay Veterinary Cornell University Hospital for Animals Dentistry DABVP (Canine/Feline) DVM, MS, DACVIM, DACVECC Largo, Florida Oncology Cranston Animal Hospital Department of Clinical Sciences Ann E. Hohenhaus, DVM, DACVIM Cranston, Rhode Island College of Veterinary Medicine Emergency/Critical Care and (Oncology and Internal Medicine) Canine and Feline Medicine Auburn University, AL 36849 Respiratory Medicine Animal Medical Center Lesley King, MVB, MRCVS, DACVECC, New York, New York DACVIM David E. Harling, DVM, University of Pennsylvania Gregory K. Ogilvie, DVM, DACVIM DABVP (Canine/Feline), (Internal Medicine and Oncology) DACVO Endocrinology and Metabolic Disorders CVS Angel Care Cancer Center and Special Reidsville Veterinary Hospital Marie E. Kerl, DVM, ACVIM, ACVECC Care Foundation for Companion Animals Reidsville, North Carolina University of Missouri-Columbia San Marcos, California Canine and Feline Medicine, EXECUTIVE Epidemiology Ophthalmology Ophthalmology ADVISORY Philip H. Kass, DVM, MPVM, MS, PhD, David A. Wilkie, DVM, MS, DACVO BOARD DACVPM The Ohio State University Jeffrey Katuna, DVM, DABVP University of California, Davis MEMBERS Parasitology Wellesley-Natick Veterinary Exotics Byron L. Blagburn, MS, PhD Hospital Avian Behavior Auburn University Natick, Massachusetts Thomas N. Tully, Jr, DVM, MS, DABVP Sharon L. Crowell-Davis, (Avian), ECAMS David S. Lindsay, PhD Canine and Feline Medicine DVM, PhD, DACVB Louisiana State University Virginia Polytechnic Institute The University of Georgia and State University Robert J. Neunzig, DVM, Reptiles DABVP (Canine/Feline) Douglas R. Mader, MS, DVM, DABVP (DC) Pharmacology Dermatology Marathon Veterinary Hospital Katrina L. Mealey, DVM, PhD, DACVIM, The Pet Hospital Craig E. Grifﬁn, DVM, Marathon, Florida DACVCP Bessemer City, North Carolina Washington State University Canine and Feline Medicine DACVD Small Mammals Animal Dermatology Clinic Karen Rosenthal, DVM, MS, DABVP Rehabilitation and Physical Therapy San Diego, California (Avian) Darryl Millis, MS, DVM, DACVS University of Pennsylvania University of Tennessee Wayne S. Rosenkrantz, Feline Medicine Surgery Compendium is a DVM, DACVD Michael R. Lappin, DVM, PhD, Philipp Mayhew, BVM&S, MRCVS, refereed journal. Articles Animal Dermatology Clinic DACVIM (Internal Medicine) DACVS Colorado State University Columbia River Veterinary Specialists published herein have Tustin, California been reviewed by at least Vancouver, Washington Margie Scherk, DVM, DAVBP (Feline Medicine) C. Thomas Nelson, DVM two academic experts on Nutrition the respective topic and Cats Only Veterinary Clinic Animal Medical Center Kathryn E. Michel, DVM, Vancouver, British Columbia Anniston, Alabama by an ABVP practitioner. MS, DACVN Gastroenterology Surgery and Orthopedics University of Pennsylvania Debra L. Zoran, DVM, MS, PhD, Ron Montgomery, DVM, MS, DACVS DACVIM (Internal Medicine) Auburn University Surgery Texas A&M University Any statements, claims, or product Toxicology Elizabeth M. Hardie, endorsements made in Compendium Infectious Disease Tina Wismer, DVM, DABVT, DABT DVM, PhD, DACVS are solely the opinions of our authors Derek P. Burney, PhD, DVM ASPCA National Animal Poison Control and advertisers and do not necessarily North Carolina State Gulf Coast Veterinary Specialists Center reﬂect the views of the Publisher or University Houston, Texas Urbana, Illinois Editorial Board. 2 CompendiumVet.com

Service... SevoFlo® (sevoflurane) anesthesia—with expert service, support and training—is smart, efficient and profitable for your practice. Only SevoFlo— You’re probably familiar with SevoFlo. But, do you realize how Abbott Animal available through Health’s exceptional service and product support helps you, your patients and all major distributors your practice? —provides four unique benefits: SevoFlo and Abbott Animal Health can help your surgical suite run efficiently 1. A minimum of and profitably. Our team of local representatives provides support and advice. 300 ppm water In addition, our technical support department and panel of anesthesiologists 2. Shatter-resistant are standing by to discuss techniques and equipment. Abbott Animal Health PEN bottles also helps educate you and your staff by providing “lunch-and-learns,” in-clinic 3. Local Abbott training materials and CE sponsorships—we’re committed to the veterinary representatives community. and expert advice 4. Commitment To learn more about SevoFlo, our other anesthetics and our commitment to training to serving you, contact Abbott Animal Health Customer Service at and education 888-299-7416 or visit www.abbottanimalhealth.com. Important Information: How Supplied: SevoFlo is packaged in amber colored bottles containing 250 mL sevoflurane. Indications: SevoFlo is indicated for induction and maintenance of general anesthesia in dogs. Warnings, Precautions, and Contraindications: Like other inhalation anesthetics, sevoflurane is a profound respiratory depressant. Respiration must be monitored closely in the dog and supported when necessary with supplemental oxygen and/or assisted ventilation. Due to sevoflurane’s low solubility in blood, increasing concentration may result in rapid hemodynamic changes compared to other volatile anesthetics. SevoFlo is contraindicated in dogs with a known sensitivity to sevoflurane or other halogenated agents. Adverse Reactions: The most frequently reported adverse reactions during maintenance anesthesia were hypotension, followed by tachypnea, muscle tenseness, excitation, apnea, muscle fasciculations and emesis. See package insert for full prescribing information. See Page 4 for Product Information Summary SEVO-186 June 2008 ©2008 Abbott Laboratories

PRECAUTIONS: Halogenated volatile anesthetics can react with desiccated decreased at hourly intervals, from 500 mL/min (36 and 18 ppm Compound A) to 250 SevoFlo® 5458 carbon dioxide (CO2) absorbents to produce carbon monoxide (CO) that may mL/min (43 and 31 ppm) to 50 mL/min (61 and 48 ppm).8 (sevoflurane) result in elevated carboxyhemoglobin levels in some patients. To prevent this Fluoride ion metabolite: Sevoflurane is metabolized to hexafluoroisopropanol (HFIP) reaction, sevoflurane should not be passed through desiccated soda lime or with release of inorganic fluoride and CO2. Fluoride ion concentrations are influenced by Inhalation Anesthetic For Use in Dogs barium hydroxide lime. the duration of anesthesia and the concentration of sevoflurane. Once formed, HFIP is Caution: Federal law restricts this drug to use by or on the order of a Replacement of Desiccated CO2 Absorbents: When a clinician suspects rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other licensed veterinarian. that the CO2 absorbent may be desiccated, it should be replaced before metabolic pathways for sevoflurane have been identified. In humans, the fluoride ion DESCRIPTION: SevoFlo (sevoflurane), a volatile liquid, is a halogenated administration of sevoflurane. The exothermic reaction that occurs with half-life was prolonged in patients with renal impairment, but human clinical trials general inhalation anesthetic drug. Its chemical name is fluoromethyl 2,2,2- sevoflurane and CO2 absorbents is increased when the CO2 absorbent contained no reports of toxicity associated with elevated fluoride ion levels. In a study in trifluoro-l- (trifluoromethyl) ethyl ether, and its structural formula is: becomes desiccated, such as after an extended period of dry gas flow through which 4 dogs were exposed to 4% sevoflurane for 3 hours, maximum serum fluoride the CO2 absorbent canisters. Extremely rare cases of spontaneous fire in the concentrations of 17.0-27.0 mcmole/L were observed after 3 hours of anesthesia. respiratory circuit of the anesthesia machine have been reported during Serum fluoride fell quickly after anesthesia ended, and had returned to baseline by 24 sevoflurane use in conjunction with the use of a desiccated CO2 absorbent, hours post-anesthesia. In a safety study, eight healthy dogs were exposed to specifically those containing potassium hydroxide (e.g. BARALYME). sevoflurane for 3 hours/day, 5 days/week for 2 weeks (total 30 hours exposure) at a Potassium hydroxide containing CO2 absorbents are not recommended for use flow rate of 500 mL/min in a semi-closed, rebreathing system with soda lime. Renal Sevoflurane Physical Constants are: with sevoflurane. An unusually delayed rise in the inspired gas concentration toxicity was not observed in the study evaluation of clinical signs, hematology, serum Molecular weight 200.05 (decreased delivery) of sevoflurane compared with the vaporizer setting may chemistry, urinalysis, or gross or microscopic pathology. Boiling point at 760 mm Hg 58.6°C indicate excessive heating of the CO2 absorbent canister and chemical DRUG INTERACTIONS: In the clinical trial, sevoflurane was used safely in dogs that Specific gravity at 20°C 1.520-1.525 g/mL breakdown of sevoflurane. The color indicator of most CO2 absorbent may not received frequently used veterinary products including steroids and heartworm and flea Vapor pressure in mm Hg at 20°C 157 change upon desiccation. Therefore, the lack of significant color change preventative products. at 25°C 197 should not be taken as an assurance of adequate hydration. CO2 absorbents Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, at 36°C 317 should be replaced routinely regardless of the state of the color indicator. propofol and other commonly used intravenous anesthetics. Benzodiazepines and Distribution Partition Coefficients at 37°C: Opioids: Benzodiazepines and opioids would be expected to decrease the MAC of The use of some anesthetic regimens that include sevoflurane may result in Blood/Gas 0.63-0.69 sevoflurane in the same manner as other inhalational anesthetics. Sevoflurane is bradycardia that is reversible with anticholinergics. Studies using sevoflurane Water/Gas 0.36 compatible with benzodiazepines and opioids as commonly used in surgical practice. anesthetic regimens that included atropine or glycopyrrolate as premedicants Olive Oil/Gas 47-54 Phenothiazines and Alpha2-Agonists: Sevoflurane is compatible with phenothiazines showed these anticholinergics to be compatible with sevoflurane in dogs. Brain/Gas 1.15 and alpha2- agonists as commonly used in surgical practice. During the induction and maintenance of anesthesia, increasing the Mean Component/Gas Partition Coefficients at 25°C for Polymers Used In a laboratory study, the use of the acepromazine/oxymorphone/ thiopental/sevoflurane concentration of sevoflurane produces dose dependent decreases in blood Commonly in Medical Applications: anesthetic regimen resulted in prolonged recoveries in eight (of 8) dogs compared to pressure and respiratory rate. Due to sevoflurane’s low solubility in blood, Conductive rubber 14.0 recoveries from sevoflurane alone. these changes may occur more rapidly than with other volatile anesthetics. Butyl rubber 7.7 CLINICAL EFFECTIVENESS: Excessive decreases in blood pressure or respiratory depression may be Polyvinyl chloride 17.4 The effectiveness of sevoflurane was investigated in a clinical study involving 196 dogs. related to depth of anesthesia and may be corrected by decreasing the Polyethylene 1.3 Thirty dogs were mask-induced with sevoflurane using anesthetic regimens that inspired concentration of sevoflurane. RESPIRATION MUST BE MONITORED included various premedicants. During the clinical study, one hundred sixty-six dogs CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITH Sevoflurane is nonflammable and nonexplosive as defined by the requirements of received sevoflurane maintenance anesthesia as part of several anesthetic regimens SUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION. The low International Electrotechnical Commission 601-2-13. Sevoflurane is a clear, that used injectable induction agents and various premedicants. The duration of solubility of sevoflurane also facilitates rapid elimination by the lungs. colorless, stable liquid containing no additives or chemical stabilizers. anesthesia and the choice of anesthetic regimens were dependent upon the procedures The use of sevoflurane in humans increases both the intensity and duration of Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and that were performed. Duration of anesthesia ranged from 16 to 424 minutes among the neuromuscular blockade induced by nondepolarizing muscle relaxants. The petroleum benzene, and it is slightly soluble in water. Sevoflurane is stable when individual dogs. Sevoflurane vaporizer concentrations during the first 30 minutes of use of sevoflurane with nondepolarizing muscle relaxants has not been stored under normal room lighting condition according to instructions. maintenance anesthesia were similar among the various anesthetic regimens. The evaluated in dogs. INDICATIONS: SevoFlo is indicated for induction and maintenance of general quality of maintenance anesthesia was considered good or excellent in 169 out of 196 Compromised or debilitated dogs: Doses may need adjustment for geriatric or anesthesia in dogs. dogs. The table shows the average vaporizer concentrations and oxygen flow rates debilitated dogs. Because clinical experience in administering sevoflurane to DOSAGE AND ADMINISTRATION: Inspired Concentration: The delivered during the first 30 minutes for all sevoflurane maintenance anesthesia regimens: dogs with renal, hepatic and cardiovascular insufficiency is limited, its safety in concentration of SevoFlo should be known. Since the depth of anesthesia may these dogs has not been established. be altered easily and rapidly, only vaporizers producing predictable percentage Average Average Average Average Breeding dogs: The safety of sevoflurane in dogs used for breeding purposes, Vaporizer Vaporizer Oxygen Oxygen concentrations of sevoflurane should be used. Sevoflurane should be vaporized during pregnancy, or in lactating bitches, has not been evaluated. Concentrations Concentrations Flow Flow using a precision vaporizer specifically calibrated for sevoflurane. Sevoflurane Neonates: The safety of sevoflurane in young dogs (less than 12 weeks of among among Rates Rates contains no stabilizer. Nothing in the drug product alters calibration or operation age) has not been evaluated. Anesthetic Individual among among of these vaporizers. The administration of general anesthesia must be HUMAN SAFETY: Not for human use. Keep out of reach of children. Regimens Dogs Anesthetic Individual individualized based on the patient’s response. WHEN USING SEVOFLURANE, Regimens Dogs Operating rooms and animal recovery areas should be provided with 3.31 - 3.63% 1.6 - 5.1% 0.97 - 1.31 0.5 - 3.0 PATIENTS SHOULD BE CONTINUOUSLY MONITORED AND FACILITIES adequate ventilation to prevent the accumulation of anesthetic vapors. L/minute L/minute FOR MAINTENANCE OF PATENT AIRWAY, ARTIFICIAL VENTILATION, AND There is no specific work exposure limit established for sevoflurane. However, OXYGEN SUPPLEMENTATION MUST BE IMMEDIATELY AVAILABLE. the National Institute for Occupational Safety and Health has recommended an During the clinical trial, when a barbiturate was used for induction, the times to Replacement of Desiccated CO2 Absorbents: When a clinician suspects that 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents extubation, sternal recumbency and standing recovery were longer for dogs that the CO2 absorbent may be desiccated, it should be replaced. An exothermic in general. Direct exposure to eyes may result in mild irritation. If eye exposure received anesthetic regimens containing two preanesthetics compared to regimens reaction occurs when sevoflurane is exposed to CO2 absorbents. This reaction is containing one preanesthetic. Recovery times were shorter when anesthetic regimens occurs, flush with plenty of water for 15 minutes. Seek medical attention if increased when the CO2 absorbent becomes desiccated (see PRECAUTIONS). irritation persists. Symptoms of human overexposure (inhalation) to used sevoflurane or propofol for induction. The quality of recovery was considered good Premedication: No specific premedication is either indicated or contraindicated sevoflurane vapors include respiratory depression, hypotension, bradycardia, or excellent in 184 out of 196 dogs. Anesthetic regimen drug dosages, physiological with sevoflurane. The necessity for and choice of premedication is left to the shivering, nausea and headache. If these symptoms occur, remove the responses, and the quality of induction, maintenance and recovery were comparable discretion of the veterinarian. Preanesthetic doses for premedicants may be between 10 sighthounds and other breeds evaluated in the study. During the clinical individual from the source of exposure and seek medical attention. The lower than the label directions for their use as a single medication.1 material safety data sheet (MSDS) contains more detailed occupational safety study there was no indication of prolonged recovery times in the sighthounds. Induction: For mask induction using sevoflurane alone, inspired concentrations information. For customer service, adverse effects reporting, and/or a HOW SUPPLIED: SevoFlo (sevoflurane) is packaged in amber colored bottles up to 7% sevoflurane with oxygen are employed to induce surgical anesthesia in copy of the MSDS, call (888) 299-7416. containing 250 mL sevoflurane, List 5458. the healthy dog. These concentrations can be expected to produce surgical STORAGE CONDITIONS: Store at controlled room temperature 15°-30°C (59°-86°F). CLINICAL PHARMACOLOGY: Sevoflurane is an inhalational anesthetic anesthesia in 3 to 14 minutes. Due to the rapid and dose dependent changes agent for induction and maintenance of general anesthesia. The Minimum REFERENCES: in anesthetic depth, care should be taken to prevent overdosing. Alveolar Concentration (MAC) of sevoflurane as determined in 18 dogs is 1. Plumb, D.C. ed., Veterinary Drug Handbook, Second Edition, University of Iowa Respiration must be monitored closely in the dog and supported when 2.36%.2 MAC is defined as that alveolar concentration at which 50% of healthy Press, Ames, IA: p. 424 (1995). necessary with supplemental oxygen and/or assisted ventilation. patients fail to respond to noxious stimuli. Multiples of MAC are used as a 2. Kazama, T. and Ikeda, K., Comparison of MAC and the rate of rise of alveolar Maintenance: SevoFlo may be used for maintenance anesthesia following mask guide for surgical levels of anesthesia, which are typically 1.3 to 1.5 times the concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology. induction using sevoflurane or following injectable induction agents. The MAC value. Because of the low solubility of sevoflurane in blood (blood/gas 68: 435-437 (1988). concentration of vapor necessary to maintain anesthesia is much less than that partition coefficient at 37°C = 0.63-0.69), a minimal amount of sevoflurane is 3. Scheller, M.S., Nakakimura, K., Fleischer, J.E. and Zornow, M.H., Cerebral effects of required to induce it. Surgical levels of anesthesia in the healthy dog may be required to be dissolved in the blood before the alveolar partial pressure is in sevoflurane in the dog: Comparison with isoflurane and enflurane. Brit. J. Anesthesia maintained with inhaled concentrations of 3.7-4.0% sevoflurane in oxygen in the equilibrium with the arterial partial pressure. During sevoflurane induction, 65: 388-392 (1990). absence of premedication and 3.3-3.6% in the presence of premedication. The there is a rapid increase in alveolar concentration toward the inspired 4. Frink, E.J., Morgan, S.E., Coetzee, A., Conzen, P.F. and Brown, B.R., Effects of use of injectable induction agents without premedication has little effect on the concentration. Sevoflurane produces only modest increases in cerebral blood sevoflurane, halothane, enflurane and isoflurane on hepatic blood flow and oxygenation concentrations of sevoflurane required for maintenance. Anesthetic regimens that flow and metabolic rate, and has little or no ability to potentiate seizures.3 in chronically instrumented greyhound dogs. Anesthesiology 76: 85-90 (1992). include opioid, alpha2-agonist, benzodiazepine or phenothiazine premedication Sevoflurane has a variable effect on heart rate, producing increases or 5. Kazama, T. and Ikeda, K., The comparative cardiovascular effects of sevoflurane will allow the use of lower sevoflurane maintenance concentrations. decreases depending on experimental conditions.4,5 Sevoflurane produces with halothane and isoflurane. J. Anesthesiology 2: 63-8 (1988). CONTRAINDICATIONS: SevoFlo is contraindicated in dogs with a known dose-dependent decreases in mean arterial pressure, cardiac output and 6. Bernard, J. M., Wouters, P.F., Doursout, M.F., Florence, B., Chelly, J.E. and Merin, sensitivity to sevoflurane or other halogenated agents. myocardial contraction.6 Among inhalation anesthetics, sevoflurane has low R.G., Effects of sevoflurane on cardiac and coronary dynamics in chronically WARNINGS: Sevoflurane is a profound respiratory depressant. DUE TO THE arrhythmogenic potential.7 Sevoflurane is chemically stable. No discernible instrumented dogs. Anesthesiology 72: 659-662 (1990). RAPID AND DOSE DEPENDENT CHANGES IN ANESTHETIC DEPTH, degradation occurs in the presence of strong acids or heat. Sevoflurane reacts 7. Hayaski, Y., Sumikawa, K., Tashiro, C., Yamatodani, A. and Yoshiya, I., RESPIRATION MUST BE MONITORED CLOSELY IN THE DOG AND through direct contact with CO2 absorbents (soda lime and barium hydroxide Arrhythmogenic threshold of epinephrine during sevoflurane, enflurane and isoflurane SUPPORTED WHEN NECESSARY WITH SUPPLEMENTAL OXYGEN lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F6O), anesthesia in dogs. Anesthesiology 69: 145-147 (1988). AND/OR ASSISTED VENTILATION. also known as Compound A, and trace amounts of pentafluoromethoxy 8. Muir, W.W. and Gadawski, J., Cardiorespiratory effects of low-flow and closed circuit In cases of severe cardiopulmonary depression, discontinue drug administration, isopropyl fluoromethyl ether (PMFE, C5H6F6O), also known as Compound B. inhalation anesthesia, using sevoflurane delivered with an in-circuit vaporizer and ensure the existence of a patent airway and initiate assisted or controlled Compound A: The production of degradants in the anesthesia circuit results concentrations of compound A. Amer. J. Vet. Res. 59 (5): 603-608 (1998). ventilation with pure oxygen. Cardiovascular depression should be treated with from the extraction of the acidic proton in the presence of a strong base plasma expanders, pressor agents, antiarrhythmic agents or other techniques as (potassium hydroxide and/or NaOH) forming an alkene (Compound A) from NADA 141-103, Approved by FDA appropriate for the observed abnormality. Due to sevoflurane’s low solubility in SevoFlo® is a registered trademark of Abbott Laboratories. sevoflurane. blood, increasing the concentration may result in rapid changes in anesthetic Compound A is produced when sevoflurane interacts with soda lime or barium Manufactured by Abbott Laboratories, North Chicago, IL depth and hemodynamic changes (dose dependent decreases in respiratory rate hydroxide lime. Reaction with barium hydroxide lime results in a greater 60064, USA and blood pressure) compared to other volatile anesthetics. Excessive decreases production of Compound A than does reaction with soda lime. Its concentration Product of Japan in blood pressure or respiratory depression may be corrected by decreasing or in a circle absorber system increases with increasing sevoflurane discontinuing the inspired concentration of sevoflurane. Under license from concentrations and with decreasing fresh gas flow rates. Sevoflurane Maruishi Pharmaceutical Co., LTD Potassium hydroxide containing CO2 absorbents (e.g. BARALYME®) are not degradation in soda lime has been shown to increase with temperature. Since 2-3-5, Fushimi-Machi, Chuo-Ku, recommended for use with sevoflurane. the reaction of carbon dioxide with absorbents is exothermic, this temperature Osaka, Japan ADVERSE REACTIONS: The most frequently reported adverse reactions during increase will be determined by the quantities of CO2 absorbed, which in turn maintenance anesthesia were hypotension, followed by tachypnea, muscle For customer service call (888) 299-7416. will depend on fresh gas flow in the anesthetic circle system, metabolic status tenseness, excitation, apnea, muscle fasciculations and emesis. of the patient and ventilation. Although Compound A is a dose-dependent Infrequent adverse reactions include paddling, retching, salivation, cyanosis, ©Abbott 8/2006 nephrotoxin in rats, the mechanism of this renal toxicity is unknown. Two Taken from Commodity Number 03-5474/R6, SevoFlo, sevoflurane, package insert, January 11, 2007 premature ventricular contractions and excessive cardiopulmonary depression. spontaneously breathing dogs under sevoflurane anesthesia showed Transient elevations in liver function tests and white blood cell count may occur increases in concentrations of Compound A as the oxygen flow rate was with sevoflurane, as with the use of other halogenated anesthetic agents. SEVO-152 January 2007 page 1 of 1 ©2007 Abbott Laboratories

E Each CE article is accredited for 3 contact hours by CE A Auburn University College of Veterinary Medicine. Section Name January 2009 Vol 31(1) Features 8 Understanding Behavior CompendiumVet.com | Peer Reviewed | Listed in MEDLINE Behavior Assessment: The First Appointment ❯❯ Sharon L. Crowell-Davis Once a behavior prob- An In-Depth Look FREE lem has been identified and described, the 14 The Diagnostic Approach to CE circumstances in which it Fever of Unknown Origin in D Dogs occurs must be clarified. ❯❯ Julie Flood This is the second article in this series on behav- FREE ior patient assessment. 26 The Diagnostic Approach to CE Fever of Unknown Origin in C t Cats 22 Focus on Nutrition NEW ❯❯ Julie Flood Using a Diet History to Improve Fever is a common clinical sign in dogs and Adherence to Dietary Recommendations i cats, but its cause is not always apparent. ❯❯ Kathryn E. Michel These articles present a thorough overview of physical examination findings and diag- The first article in this quarterly series explains nostic tests that can help guide diagnosis of how to effectively use diet history forms and the underlying condition. what information is most important. 33 Immunosuppressive Therapy for Canine ine Immune-Mediated Hemolytic Anemia FREE ❯❯ Suliman Al-Ghazlat CE The author describes the range of current treatment options for dogs with this potentially deadly condition. 47 Focus on Nutrition Sample Diet History Form This form is also downloadable from CompendiumVet.com. Departments 6 Editorial: Clinical Snapshot Focus on Nutrition PAGE 11 ❯❯ Kathryn E. Michel 14 7 CompendiumVet.com ©2009 iofoto/Shutterstock.com 11 Clinical Snapshot A Dog with “Bumps” on its Skin On the Cover ❯❯ Karen A. Moriello Starting on page 14, Dr. Julie Flood describes the diagnostic approach to fever 25 Letters of unknown origin in dogs and cats. 32 Product Forum 45 Classified Advertising Supplemental material to both articles 45 Market Showcase 46 Index to Advertisers is available at CompendiumVet.com. CompendiumVet.com 5

Editorial ❯❯ Kathryn E. Michel, DVM, MS, DACVN, University of Pennsylvania Focus on Nutrition The goal of this new quarterly column is to provide veterinary health professionals with state-of-the-art information on best practices for the nutritional management of companion animals. D etermining and implementing the The articles will be written by members appropriate dietary management of of the ACVN, the recognized specialty board companion animals have long been in this area of expertise. The column will recognized by the veterinary profession as also include information about the ACVN, the key components of maintaining wellness and services its diplomates can offer to practicing treating disease. Now, pet owners are increas- veterinarians, and resources for those who ingly aware of the benefits and risks that cer- may be interested in specializing in the field tain dietary habits may entail. In the present of nutrition. “information age,” it is a growing challenge for We all know that diet is a subject of great veterinary practitioners to stay abreast of this concern to many pet owners and one about dynamic field to be able to offer their clients which people often hold strong opinions. It accurate information about companion animal can be a sensitive subject to broach, and it is nutrition and diet choices and their patients often difficult to get clients to adhere to the the latest advances in nutritional management. dietary recommendations we make for their pets. I hope that Focus on Nutrition will help We all know that diet is a subject of great veterinary health professionals become more concern to many pet owners and one about informed on entering into and feel more confident when this subject a dialogue on diet which people often hold strong opinions. and dietary management with their clients to ensure the best possible outcome for their In order to help practitioners meet this patients. challenge, this issue of Compendium is launch- ing the Focus on Nutrition series in collabora- tion with the American College of Veterinary SHARE YOUR COMMENTS Nutrition (ACVN). This new column, which will Have something to say about this appear quarterly, is devoted to current topics in editorial or topic? Let us know: small animal nutrition. The goal is to provide E-MAIL editor@CompendiumVet.com veterinary health professionals with state-of- the-art information on best practices for the FAX 800-556-3288 nutritional management of companion animals, both to maintain wellness and to treat disease. 6 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

January WEB EXCLUSIVES 2009 Vol 31(1) and bird owners, these metals are frequently FEATURES WEB found in the environments of pet and aviary EXCLUSIVE ❯❯ Supplements: The Diagnostic birds, and intoxications are common. Once VIDEO Approach to Fever of Unknown diagnosed, intoxication can be effectively Origin in Dogs and Cats treated by (1) preventing further exposure, (2) administering chelating drugs, and (3) ❯❯ Julie Flood providing symptomatic and supportive care. Diagnosing the cause of fever of unknown origin (FUO) can require a battery of tests. Date: __________ Case Number: __________ __________ __________ __________ DIET HISTO __________ __________ RY Behavior _______ FORM DIET HIS TORY HANDOUTS Owner Information What is__________ your pet’s attitude FORM Name: __________ Greed toward food? __________ Indifference Table foods Email address: __________ Has your or scaps; __________ __________ attitude pet’s Avoidan _______ toward This supplemental material elaborates on __________ ______ ce ______ home-p Phone (home): ________________ food change ______ repared __________ ________________ ______ foods s __________ ______ ______ d? If so, ______ ______ Phone (cell): __________ ______ ______ describe: ______ ______ __________ __________ ______ ______ ______ ______ _____ ______ __________ ______ ______ ______ ______ ______ Best time to ______ __________ ______ ______ ______ ______ ______ ______ call:________________ __________ ______ ____ ______ ______ _____ ____ ______ __ ______ ______ ______ ______ ______ ________________ ______ ______ ______ ______ __________ ______ ___ ______ ____ ______ ______ ____ Pet Information ______ ______ ______ ______ ______ If you have ______ ______ ______ ______ _ ______ ______ ______ ______ ______ ____ Name: __________ other pets, ______ ____ ______ ______ ______ is this pet ______ Dietary ______ ______ _______ __________ Domina domina ______ supplem ______ ____ __________ ____ ______ Species: __________ ____ Age: nt Has your ________Submissive left out or submissive Is food nt ______ ents; food used to ______ ______ _______ __________ pet to for your pet duringthem? ______ give pills ____ Gender: _ Breed: __________ recently ______ some of the diagnostic tools that can be used Male Female ______ lost Does your _________ or gained the day? ______ ______ Neutered/spayed: ______ pet have weight? access to other, Yes______ No ______ Current weight: ______ If ______ ______ ______ __________ Yes No____________ (e.g., treats fed so, please describ unmonitored ______ ______ Body condition ___ Usual ____________ ______ by neighbor, food e: ______ sources food ______ ______ ______ ___ ______ ____ weight: __________ ❯❯ Focus on Nutrition: ______ ______ ______ ______ _______ score (1–9): _____ ______ ______ _______________ Yes No ______ left for outdoor______ ______ cats)? ______ ______ ______ _ ____ Evidence of muscle ______ ______ ____ ______ ______ wasting ______ If yes, please ____________ ______ ______ _______ None ____________ Mild ______ ______describe:____________ ____ ______ ______ ______ ______ __ ____ ______ ______ ______ Reason for Visit Have there Severe ______ __________ ______ ______ ____________________ ________________________________ List anythin ______ _______ ______ __ ____ been any ______ __________ g else given ______ _____________ ______ recent change __________ ______ __________ ______ __________ by mouth ______ _______ __________ ______ __________ s in activity ______ ______ (e.g., medica ______ ___ ____ __________ ______ ____ __________ ______ __ ❯❯ CAPC 2008 Road Show __________ ______ __________ ______ __________ level? ______ __________ ______ __________ ____________ ations): tions): t __________ ______ _________ ______ __________ ____ ______ __ __________ ______ ______ __________ ______ ______ __________ __________ ______ __________ ____________ __________ ____________ __________ ______ __ or may become available for patients with __________ ______ __________ ______ ____________ ______ ______ _____ __________ ________ ______ ____ __________ ______ ______ ____ __________ ______ ______ Have you __________ ______If you have more than ______ __________ ______ __________ ____________ ______ ________ _ observe ______ one pet, do they ____________ ____ __ ______ ________ Household Demograph d any__ food? of the followin ______ ______ have access ______ ______ ______ ________ _ ics Nausea/salivat Yes ______ ______ to each other’s ______ ______ How many adults g: No If____ ______ yes, please describe: ______ ______ _____ ____ ion ______ Sample Diet History are in your household? Difficul __________ ______ ______ ________ _ __________ How many children __________ ty chewin __________ ____________ ______ ______ ______ _____ ____ are in your household, Dyspha g _________ __________ __________ ______ ______ ___ Yes __________ __________ ______ ______ __________ and how old are gia __________ Is your pet’s No __ ______ ______ ______ ____ _ __________ they? __________ __________ current ______ __________ Vomitin Yes __________ __________ a change diet ______ _________ _ ______ __________ __________g __________ No Yes __ from its _____ __________ ____ Presentations __________ __ __________ __________ No typical diet? __________ Yes __________ __________ al __________ Diarrhea __________ __________ __________ If so, please No __ __________ __ __________ __________ describe __________ Yes __________ __________ change the Constip __________ ____________ FUO, the differential diagnosis, and tips on __________ __________ ation No __ and why __________ __________ How do you __________ ______ the diet __________ Have __ store Yes pet’s your ______ __________ ______ t was change Where is your __________ there been food? __________ No ______ __ ______ pet housed? __________ any change ______ d. Indoors __ s ____________________ Yes __________ ______ ______________ ______ ______ ______ ____ ______ Do you have Outdoors in urinatio No ______ ______ ____________ other pets? Diet Both __________n? __________ ______ ______ ____ _ Yes __________ __________ ______ ____ Form and specify if No If so, please Yes __________ ____________ ______ __ ______ ____________ they live indoors For each list species __________ No __________ ______ ______ ______ ____ or outdoors. of the __________ __________ ______ ______ ____ _ __________ __________ cable) and followin __________ ____________ __ ______ __________________ g categor __________ __________ ______ ______ _____ Drs. Byron L. Blagburn and __________ __________ __________ often each amounts of all __________ __________ foods __________ ies, list __________ the brand ______________________ __________ ______ __ ______ ______ ___________ ____________ __________ food __ your pet names (if __________ ______ ______ _____ __________ __________ is fed (e.g., twice Comme eats ____________________Are you daily, as appli- __________ ______ __ ______ ______ _____ ______ ______ __________ __________ rcial foods a day). open __________ to making ______ ______ ____ __________ __ well as __________ change ______ _____ __________ __________ ______ how a __ ______ ______ __________ __________ Activity Yes safe sedation of fractious febrile cats. __________ ______ __ No in your ______ ____ __________ __________ ____________ pet’s diet? ______ How active What are ? __________ __________ __________________ ____________ is your pet? your pet’s __________ ____________ ______ ______ ______ food prefere Feeding Manageme __________________ ____________ Hyperactive __________ Very active ______ ______ ______ nces?_______ ______ ______ ______ ______ _____ nt ______ ______ ______ Average ______ ______ ______ Who typically ______ ______ Not very active ____ ______ ______ ______ _____ ___ ______ ______ Hardly moves Dwight D. Bowman present feeds your pet? ______ ______ How ______ ______ ______ ______ ______ ______ ______ This downloadable form can __________ ________________ __________ ______ often is your pet ______ ____ ______ ______ ______ _____ ____ __________ ______ ________ ______ walked? ______ ______ __________ Comme ______ ______ What foods ______ ______ ______ __________ __________ rcial treats; ______ At least 3 times/day __________ does your ______ _____ ____ __________ __________ dental hygiene ______ 1-2 times/day pet ______ __ ______ ______ When is your __________ ______ __________ ______ __________ products Seldom ______ Never ____ ______Once a day refuse? ______ ______ ______ _ _____ ____ pet fed? __________ ______ ______ ______ ______ ______ __ Do ______ ______ ______ ____ ______ __________ __________ ______ __________ ______ you have access to a ______ ______ ______ ______ __________ _ __________ ______ ____ ______ yard? ______ ______ ______ __________ ______ ______ ______ Is it difficult ______ Yes ______ ______ _______ __________ __________ ______ __________ ____________ to exercise your ______ ______ No ______ ____ ___ __________ ______ ____ pet? Are ______ ______ __________ ______ ______ __ Can exercise______ there foods ______ ______ _______ __________ __________ ______ __________ ____________ ______ be increased? Yes No ______ ____ ___ __________ ______ ____ to which ______ ________ current data and personal __________ ______ Has your____________ If so, your _______ ______ __________ ______ __________ ____________ pet participated in training? which foods? ____ Yes No pet is allergic? ____ ___ ______ ______ ________ Has your____________ pet participated ______ ______Yes ______ Yes ______ ______ No ______ No be given to clients to gather ______ ____ in competition ______ ______ ______ ? ______ ______ ____ ______ ______ Yes ______ ______ ______ ____ ______ No ______ ______ ___ ______ ______ ______ ________ _ ______ ______ ____ ______ ______ __ ______ ______ ______ ______ _________ _ ______ ____ _ ______ ______ _________ _ ____ _ CE ARTICLES experience to demonstrate important information about their pet’s diet diet. h i t’ di t the importance of preventing ❯❯ The Renin–Angiotensin–Aldosterone parasitic infections and re- NEWS BITES lated disease in companion System: Approaches to Cardiac and animals. Renal Therapy ❯❯ What Makes Ticks Tick? ❯❯ Melanie Otte and Alan Spier ❯❯ Laparoscopic Studies of tick salivary glands may reduce OVH and OVE The renin–angiotensin–aldosterone system incidence of Lyme disease. (RAAS) plays a significant role in preserv- ing hemodynamic stability in response to ❯❯ Compendium Board Member Talks to the loss of blood volume, salt, and water. ABC News About Feline Cancer Manipulation of the RAAS is the mainstay of Gregory K. Ogilvie is interviewed about a cancer therapy for cardiac and renal diseases. diagnosis for Socks the cat. ❯❯ Lead and Zinc Intoxication ❯❯ Winn Foundation Announces Grants in Companion Birds for Feline Health Studies ❯❯ Birgit Puschner and Robert H. Poppenga ❯❯ “Workaholic” Dolphins are Spongers Although the toxicity of lead and zinc to ❯❯ AVMA Calls for More Veterinary birds is widely recognized by veterinarians Oversight of Meat Production E-NEWSLETTER ❯❯ COMPENDIUM EXTRA Our monthly e-newsletter service Four videos from Dr. Philipp provides Web Exclusive articles Mayhew demonstrate some and news, as well as a preview of of the techniques described this month’s journal. Sign up at in the August 2008 Surgical CompendiumVet.com. Views article by Dr. Sara Gower and Dr. Mayhew, “Canine Laparoscopic and Laparoscopic-Assisted CONTACT US Ovariohysterectomy and Ovariectomy.” ❯❯ Email your questions, suggestions, corrections, or letters to the editor: editor@CompendiumVet.com CompendiumVet.com 7

Understanding Behavior Behavior Assessment: The First Appointment* About This Column ❯❯ Sharon L. Crowell-Davis, DVM, PhD, DACVB,a The University of Georgia Behavior problems are a signifi- *The first article in this series on patient evaluation, “Behavior Assessment: History Forms cant cause of death (euthanasia) and Interviews,” was published in the December 2008 issue of Compendium and is avail- in companion animals. While most able at CompendiumVet.com. veterinary practices are necessarily geared toward the medical aspect of care, there are many opportuni- ties to bring behavior awareness A s described in the first article in this series, gaining an accurate description of a pet’s undesirable behavior is crucial to correctly diagnosing the cause of the behavior. However, more information is needed than a good into the clinic for the benefit of description. The circumstances in which the behavior occurs must also be the pet, the owner, and ourselves. clarified, along with any treatments the owner has already attempted, either This column acknowledges the alone or with advice from a veterinarian, animal trainer, or other source. The importance of behavior as part of pet’s signalment, environment, and background may all affect its behavior and should be discussed with the owner. Some of this information can be veterinary medicine and speaks gathered in advance through the use of history forms; some may be better practically about using it effectively obtained through interviews and conversation with the owner during the first in daily practice. appointment devoted specifically to the behavior problem. History of the Behavior One of the most important pieces of information to gather is the current frequency and intensity of the undesirable behavior. Without this information as a baseline, it will be impossible to determine if a treatment is helping, harming, or having no effect. The specific circumstances in which the problem behavior is most likely to occur must also be ascertained. In some cases, it may be possible to avoid these situations; in others, the treatment protocol may need to include desensitization and counterconditioning to the specific circumstances. a Dr. Crowell-Davis discloses that she has received financial support from CEVA Animal Health. QuickNotes All behaviors that the owner perceives to be problem behaviors need to be identified. 8 CompendiumVet.com | January 2009

The history of the behavior is also important. How after administering it for just 1 week, the medication long has the animal been exhibiting this behavior? did not have time to take effect. While there are exceptions, it is often the case that problems of long duration will take longer to resolve Other Behavior Problems than problems of short duration. This is especially The animal may have other behavior problems in true of behaviors that have developed as a conse- addition to the chief complaint. Sometimes these quence of operant conditioning, such as persistently problems come up in the discussion of the chief waking the owners during the night, because the complaint, but not always. Before proceeding to undesirable behavior has been reinforced hundreds issues other than the animal’s presenting or even thousands of times, rather than a few dozen behavior, ask if the owner has noticed QuickNotes times. Also, in attempts to treat the problem, the any other behavior problems that have owners may have reinforced the undesirable behav- not been mentioned yet. Occasionally, The duration, fre- ior on a variable-ratio or variable-interval schedule it turns out that the owner considers a quency, intensity, by trying to ignore the behavior for a while but even- problem other than the presenting com- and context of the tually acknowledging it. If this is the case, the behav- plaint to be of more concern but had problem behavior will have become very resistant to extinction. not previously mentioned it because ior need to be he or she believes it to be untreatable. identified. History of Treatment For example, a dog may be aggressive, Another critical piece of the history is how the own- but the owner has brought it in for storm phobia ers have already attempted to correct the behavior. because of a recent news story about treatments There is a tremendous amount of information about for storm phobia. animal behavior on the Internet. Some is excellent. If the animal has multiple behavior problems, Some is mediocre. Some is unclear or confusing, and it may be necessary to prioritize treatments. It is some will actually make behavior problems worse. rare that the treatments for multiple problems are Clients are likely to have tried various treatment pro- mutually exclusive. More typically, there are simply tocols they have found on the Internet or in books. limitations to how much time and effort a client can As with terms describing behaviors, this is a poten- put into treating a pet’s behavior problems. Thus, if tial area of misunderstanding. Just because a client a dog has fear aggression toward men, moderate knows the word desensitization does not mean that storm phobia, mild separation anxiety, and a nui- the Web site or book where he or she read about it sance habit of jumping up on women as a form of described it accurately or that the client understood friendly greeting, and the client can spend approxi- the description correctly. Even if the original resource mately 20 minutes a day conducting specific behav- is accurate, the client may have conducted the pro- ior modification, it will be impossible to address all tocol improperly and attempted a different treatment, these problems at once. It therefore makes sense to such as flooding, instead. Thus, if a client says that prioritize them in the order presented. he or she has already tried “treatment X,” ask for an exact, detailed description of what he or she did. Owner Commitment In some cases, the client has identified the cor- For some owners, the amount of time and effort rect behavior modification treatment and conducted necessary to treat one problem, let alone several, it appropriately, and it is helping, but not enough. In is daunting. Therefore, one of the most important this circumstance, confirm that the treatment should pieces of information to obtain at the first appoint- be continued. However, it will be necessary to build ment, in addition to a complete on the current protocol, perhaps with a new variation description of any problem behav- TO LEARN of the established behavior modification plan or with ior, is a full understanding of how MORE medication. In other cases, the treatment may be a motivated the owner is to treat the reasonable option, and the client may be conducting problem and keep the pet. At one it accurately, but it is having no effect. In these cases, end of the spectrum are owners For more information about an entirely different approach is needed. who intend to keep the pet, regard- clarifying the correct terms If medications prescribed by other veterinar- less of the success of treatment. At in conversations with owners, see the December ians have not been effective, verify the medication, the other end are those who intend 2008 article “Behavior the dose, and how long it was given to determine to euthanize or give away the pet Assessment: History Forms whether it was genuinely not beneficial or was sim- if resolution of the behavior prob- and Interviews” at ply not given at an adequate dose for an adequate lem is not quick and easy. If the CompendiumVet.com. time. For example, if a client discontinued fluoxetine owners are considering giving the CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 9

Understanding Behavior pet away, it is important to in which the pet lives. The apprise them of the difficul- - Previously attempted treat- same information should ties of finding an alternative be gathered for all the home for a pet with a major r ments need to be identi- other pets in the household. behavior problem. This is fied. It is important to Finally, ask for a complete especially the case with description of the pet’s phys- aggressive pets. Sometimes verify that these treatments ical environment, including owners think the police or r the house and yard. How armed forces will want their r were carried out correctly big is the house? Are there aggressive dog as a guard and appropriately. The parts of the house in which dog. However, for guard and the pet is not allowed? Is the attack work, police and mili- - fact that someone knows yard fenced in, and does the tary organizations want only y a word characteristic of fencing adequately contain k dogs that are trained to attack the pet? Is the pet walked on in a specific way at a spe- - the jargon of learning and a leash? If so, how often and cific command. They do not for how long? What is the want dogs that have behavior r behavior modification neighborhood like? Is there problems and are likely to does not mean that he or a problem with encoun- infl ict bites because of such tering other pets while on issues as fear. she knows how to conduct walks? Are pedestrians and Beyond the extremes of f the treatment correctly. cars rare, common, or con- willingness to keep a pet or r stant? Does this vary with intent to give it up, there is the time of day? the question of how much time and effort an owner Certain aspects of the environment may be iden- can and will put into treating a pet. Major behavior tified as contributing to the existence and exacer- problems typically require daily effort by the owner bation of the problem. For example, if the pet is during a period of weeks or months. Even if the nervous and timid, living in the midst of boister- owner is highly motivated to do whatever it takes, ous young children may make improvement difficult it is essential for the owner and the veterinarian to unless a mechanism can be identified to give the pet take a realistic look at the owner’s current schedule time away from the children in a quiet, calm atmo- and lifestyle. If the owner can realistically identify sphere. Aspects of the environment that can be used only three times a week in which he or she can to help the pet, or that need to be changed for the do structured behavior modification for 20 minutes, pet, can also be identified. If a healthy young dog it is important to set up a treatment program that is getting inadequate exercise because no one has assumes only three treatment sessions a week. If the time to take it on long walks or jogs, the addition treatment plan assumes that the owner will conduct of fencing in the backyard may be critical. In some behavior modification every day and this is simply cases, the owners may have already been consider- not possible, then the owner and the pet are on ing a change (e.g., a fence). The news that making track for failure from the beginning. the change is likely to help their pet may be all that is needed to get them to follow through. Environment Owner lifestyle is only one aspect of the context in Signalment which the pet’s behavior problem exists. To prop- Signalment is a basic erly identify and treat the problem, it is important to information set that TO LEARN understand all the aspects of the pet’s environment, veterinarians are MORE both social and physical. The social environment already accustomed includes the people and animals with which the pet to collecting. As with regularly interacts. All the humans who either live many medical con- For more information about in the same household as the pet or visit frequently, ditions, signalment cognitive dysfunction, see the February 2008 article either as guests or employees (e.g., gardener, maid), often gives us infor- “Cognitive Dysfunction in need to be identified. In addition to their names, mation about the Senior Pets” at sexes, and ages, their relationship and interactions relative likelihood CompendiumVet.com. with the pet are critical to understanding the world of a given behav- 10 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

ior problem. In cases of older pets presenting with with treatment. Dogs and cats that were born and behavior problems, it is essential to identify whether raised in puppy or kitten mills where they received the current problem is actually of recent onset. little to no socialization with humans may be exces- Sometimes owners have tolerated a given behavior sively shy around humans and susceptible to devel- problem in a pet for years, but changes in the fam- oping a variety of anxiety disorders as ily circumstances, rather than any substantial changes a consequence of their early experience. QuickNotes in the pet, have made the problem less tolerable. If Extra effort will be required to help them the problem is of recent onset, or if there has been overcome these problems. Likewise, pets Signalment will a significant change in the intensity or frequency of that have spent time as strays, fending for assist in prioritiz- the problem in an older pet, cognitive dysfunction, themselves to survive, may have become ing the differential analogous to Alzheimer disease, should be consid- very aggressive around food, especially diagnosis. ered. However, cognitive dysfunction should not be if their ability to obtain food while stray considered as a possible diagnosis in a young animal. was not very successful and they became under- If the complaint is aggression in a dog, aggressively weight. Owners who find problem behaviors very “herding” people or other animals should be a diag- frustrating are often more tolerant of them if they nostic differential for herding breeds, but it is unlikely understand why their pet behaves in an undesir- in nonherding breeds. able fashion. If possible, find out about the early history of the pet. Sometimes this is not possible because the Conclusion owners adopted the pet at several months to several The third article in this series will complete the years of age. However, if background information discussion of the history that needs to be reviewed is available, it can be useful in helping the owners at the first visit and address direct assessment of understand the problem, even if it does not help the patient. Clinical Snapshot Particularly intriguing or difficult cases Case Presentation #1 ❯❯ Karen A. Moriello, DVM, DACVD, University of Wisconsin-Madison A 7-month-old dog presented with “bumps,” a common clinical presenta- TO LEARN MORE tion of superficial bacterial pyoderma in dogs. Note the “goose bumps” or hive-like lesions on the skin. Clinical Snapshot presents illustrated 1. What is the name of this condition, case histories and challenges you to and what is seen upon close examina- answer the questions posed. This case tion of the skin? is part of the series of Self-Assessment Colour Review books on multiple topics 2. What are the diagnostic differentials, from Manson Publishing Ltd., London, and what diagnostic tests should be available from Blackwell Publishing conducted to confirm the diagnosis? Professional. 3. What is the mechanism of action of fluoroquinolone antibiotics, and why For more information or to obtain any of the would this drug class not be an appro- books in the series, call 800-862-6657 priate antibiotic choice in this dog? or visit BlackwellProfessional.com SEE PAGE 21 FOR ANSWERS AND EXPLANATIONS. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 11

Advertorial COLOSTRUM IN THE DIET FOR CANINE INTESTINAL HEALTH AND IMMUNE SYSTEM SUPPORT Arleigh Reynolds, DVM, PhD, DACVN COLOSTRUM BENEFITS SHOWN Ebenezer Satyaraj, PhD Research shows dietary colostrum may benefit growing While veterinarians have long recognized the connection puppies and adult dogs. Weaned puppies fed a bovine between colostrum and enhanced immunity in newborns, colostrum–supplemented diet for 10 days after arrival at recent research shows dogs of all ages can benefit from pet stores had significantly improved fecal quality compared colostrum’s supportive effects on gastrointestinal (GI) health. to the control group.4 In a 40-week study, bovine colostrum was fed to adult Alaskan sled dogs under exercise stress.5 The findings demonstrate that, while colostral antibodies Compared to controls, colostrum-supplemented dogs had: are not absorbed by older puppies and adult dogs as in 1- or 2-day-old pups, the immunoglobulin-rich substance contains • Increased intestinal microflora diversity,5 which reduces elements that support proper GI tract development, nutrient the risk of bacterial pathogens colonizing the GI tract.6 absorption, growth and healthy intestinal microflora.1 • More stable microbial populations following stress, which GI TRACT KEY TO IMMUNE FUNCTION helps reduce risk of diarrhea and GI upset.5 The GI tract plays a vital role in protecting the body • Increased fecal IgA levels, indicating improved GI mucosal from pathogens. With gut-associated lymphoid tissue immune status.5 (GALT), the intestinal tract is the body’s largest • Greater, persistent antibody levels following canine immune organ.2,3 distemper virus (CDV) vaccination, suggesting enhanced The intestinal mucosa provides a protective barrier and systemic immune status. The immune systems of secretes immunoglobulin A (IgA), which helps neutralize colostrum-supplemented dogs were not hyperactive, based potential pathogens and stabilize intestinal microflora. on normal C-reactive protein levels. 5 Measure of microflora stability 90 * 80 81.50 Percentage 70 60 50 40 46.00 30 Control 20 Colostrum 10 0 * <0.05 During stress, dogs fed a colostrum-supplemented diet had more stable gut microflora. 1. Edwards, Christine. Interactions between nutrition and the intestinal microflora. GI TRACT KEY TO IMMUNE FUNCTION Proc Nutr Soc. 1993;52(2):375–82. 2. Hall EJ. Mucosal immunity—Why it’s important [Internet]. In: The 32nd Congress of the (1) Immunoglobulin (Ig) binds to an immune cell in the GI mucosa. World Small Animal Veterinary Association Proceedings Online; 2007 Aug 19–23; Sydney, (2) Ig binding activates the immune cell. Australia. Available at: http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA 2007&PID=18137&Print=2986&O=Generic. Accessed April 25, 2008. (3) Cytokines are secreted into the circulatory system, enabling 3. Tizard IR. Immunity at body surfaces. In: Tizard IR, ed. Veterinary Immunology: An communication with other immune cells. Introduction. 7th ed. Philadelphia, Pa: Saunders; 2004:234–246. (4a) Activated systemic immune cells release IgG into the 4. Giffard CJ, Seino MM, Markwell PJ, Bektash RM. Bene ts of bovine colostrum on fecal quality in recently weaned puppies. J Nutr. 2004;134:2126S–2127S. circulatory system in response to immune system challenges. 5. Data on le, 2006. Nestlé Purina PetCare Company. (4b) Mucosal immune cells release IgA into the GI tract lumen, 6. Kuehl CJ, Wood HD, Marsh TL, et al. Colonization of the cecal mucosa by Helicobacter hepaticus impacts the diversity of the indigenous microbiota. Infect Immun. leading to increased levels of fecal IgA. 2005;73:6952–6961.

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3 CE CREDITS CE Article 1 The Diagnostic Approach to Fever of Unknown Origin in Dogs* ❯❯ Julie Flood, DVM, DACVIM Abstract: Identifying the cause of a fever of unknown origin (FUO) in dogs presents a consider- Antech Diagnostics able diagnostic challenge. The diagnostic workup can be frustrating for veterinarians and clients, Irvine, California especially when it fails to reach a final diagnosis after extensive testing. Fortunately, most causes of FUO can be found or treated successfully. This article discusses FUO in dogs and provides information about common causes, the diagnostic approach, and potential treatments. T rue fever (pyrexia) is defined as an serum biochemistry profile, and urinaly- increase in body temperature due to sis with antimicrobial culture. The cause an elevation of the thermal set point of fever in most dogs is an infection that in the anterior hypothalamus secondary to either is found during the initial workup or the release of pyrogens.1 With hyperther- responds to antibiotic treatment; therefore, mic conditions other than true fever, the most dogs do not have a true FUO.5 hypothalamic set point is not adjusted.1 At a Glance Nonfebrile hyperthermia occurs when heat Differential Diagnosis Differential Diagnosis gain exceeds heat loss, such as with inade- The differential diagnosis for FUO in dogs Page 14 quate heat dissipation, exercise, and patho- is extensive, and development of an algo- Clinical Approach logic or pharmacologic causes.1 rithm covering all causes is not feasible. Page 14 Dogs with true fever typically have body Some causes of FUO in dogs are listed Potential Causes of Fever temperatures between 103°F and 106°F in BOX 1.2,4,5 Most FUOs are caused by a of Unknown Origin in Dogs (39.5°C to 41.1°C).2 Prolonged body tem- common disease presenting in an obscure Page 15 peratures above 106°F are dangerous and fashion.6 can result in organ failure, disseminated Current information in the veterinary Staged Diagnostic Approach to Fever of intravascular coagulation, systemic inflam- literature regarding FUO in dogs is lim- Unknown Origin in Dogs matory response syndrome, and death.1,3 ited.1,5 Infectious, immune-mediated, and Page 16 Such temperatures are usually seen with neoplastic diseases are all important and nonfebrile causes of hyperthermia rather common causes.2,5,7,8 About 10% to 15% Treatment Page 19 than with true fever.4 Temperatures less of FUOs in dogs remain undiagnosed than 106°F are unlikely to be harmful and despite thorough diagnostic evaluation.5 may be beneficial because they constitute The prognosis for undiagnosed FUO in a protective response to inflammation.1,5 dogs is not known. However, a retrospec- The term fever of unknown origin (FUO) tive study7 revealed that in 13 of 14 dogs is used liberally in veterinary medicine.5 with undiagnosed FUO, the fever either It should be used to identify a fever that resolved spontaneously or responded to does not resolve spontaneously, that does antibiotics, NSAIDs, or corticosteroids. not respond to antibiotic treatment, and for which the diagnosis remains uncer- Clinical Approach WEB tain after an initial diagnostic workup.5 The diagnostic approach must be tailored EXCLUSIVE Along with a thorough history and physi- to the patient. It should be guided by his- cal examination, initial diagnostics should tory and physical examination findings, Supplemental material to this include a complete blood count (CBC), simple laboratory testing, and the poten- article is available at tial causes common to the geographic CompendiumVet.com. *A companion article about fever of unknown location.9,10 A three-stage approach, such as origin in cats begins on page 26. the one presented in BOX 2, is commonly 14 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE The Diagnostic Approach to FUO in Dogs CE used.2,4,5 Communication with the owner is or subtle clinical signs (historical, intermit- of utmost importance to ensure understand- tent, and current) because these may help ing of the time and financial commitment that localize the fever source. A history of stiffness may be required to obtain a definitive diagno- may suggest joint disease, but fevers can pres- sis. Fortunately, a diagnosis can be obtained ent similarly.3 Often, diagnostic clues are not in most circumstances, and many causes are readily apparent on physical examination, so treatable or manageable.8 repeated detailed physical examinations are All medications should be discontinued to essential (by multiple clinicians, if possible).10 help rule out a drug-induced fever. If the fever Careful attention should be paid to the whole persists beyond 72 hours after medication cessa- body—pulses, skin, mucous membranes, oral tion, a drug reaction can be ruled out.11 cavity, lymph nodes, heart, abdomen, bones and joints, and rectum. Repeated fundic and History and Physical Examination neurologic examinations are also important to Obtaining a thorough history is the first step identify subtle changes. As the disease pro- of a successful diagnostic approach. Clients gresses, new clues may emerge to help guide should be questioned carefully about specific the next diagnostic steps. BOX 1 Complete Blood Count and Serum Potential Causes of Fever Biochemistry Profile of Unknown Origin in Dogs2,5 CBC and serum biochemistry profile abnormalities in dogs with FUO are generally non- Bacterial infection (focal or systemic): Bacter- specific, but they may indicate a need for emia, infective endocarditis, septic arthritis, further diagnostic tests. Every CBC should osteomyelitis, diskospondylitis, septic meningi- be accompanied by a blood smear evaluation tis, pyothorax, pyelonephritis, prostatitis, stump to detect morphologic changes and parasites. pyometra, peritonitis, deep pyoderma, abscess Frequently, multiple blood smears and care- Bacterial diseases: Brucellosis, bartonello- ful scanning are necessary to find infectious sis, borreliosis, leptospirosis, mycoplasmo- organisms (FIGURE 1). Sometimes only one sis (hemotrophic and nonhemotrophic), tu- organism will be seen on an entire slide. It berculosis and other mycobacterial diseases, is wise to save serum for serologic testing or QuickNotes diseases caused by L-form bacteria (e.g., cel- other special tests that may be crucial in the lulitis, synovitis) future. A serum bile acids assay may be indi- Urine culture should Viral: Canine distemper, parvovirus cated because fever may be the only predomi- be conducted for all Rickettsial: Ehrlichiosis, anaplasmosis, Rocky dogs with fever of nant clinical sign in dogs with portosystemic Mountain spotted fever, salmon poisoning shunts.12 unknown origin. Fungal: Histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis Protozoal: Toxoplasmosis, neosporosis, Urinalysis with Culture babesiosis, trypanosomiasis, hepatozoonosis, A urine sample obtained via cystocentesis leishmaniasis (unless contraindicated) should be submitted Immune-mediated diseases: Immune- FIGURE 1 mediated hemolytic anemia, polyarthritis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, meningitis, steroid- responsive neutropenia and fever Neoplastic: Lymphoma, leukemia, multiple Courtesy of Dr.Ty McSherry myeloma, malignant histiocytosis, necrotic solid tumors Noninfectious inflammatory diseases: Lym- phadenitis, panniculitis, pansteatitis, panos- teitis, pancreatitis, granulomatosis Miscellaneous: Portosystemic shunt, drug reaction, toxin, shar-pei fever, metabolic bone disorders, idiopathic causes HISTOPLASMA ORGANISMS found on a blood smear from a dog. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 15

FREE CE The Diagnostic Approach to FUO in Dogs BOX 2 for a complete urinalysis with bacterial cul- Staged Diagnostic Approach to Fever ture even if sediment is inactive. These tests of Unknown Origin in Dogs2,4 should be repeated, especially if there is a history of lower urinary tract disease, as a nega- Stage 1 tive urine culture does not rule out infection. Take a thorough history. Further diagnostic testing could include urine Stop all medications to rule out drug-induced fever. protein:creatinine ratio if proteinuria is pres- Perform a meticulous physical examination, including fundic and ent with inactive sediment. neurologic examinations. Obtain samples for CBC, blood smear, and serum chemistry profile. Radiography Save serum for serology or other testing. Two-view abdominal and three-view thoracic Obtain a urine sample for complete urinalysis and urine culture. radiographs should be obtained if the mini- Submit a sample for urine protein:creatinine ratio if proteinuria and inactive sediment are present. mum database does not reveal the cause of the Conduct fecal centrifugation and fecal cytology, if indicated. fever. Total body radiographs can help aid in Consider obtaining thoracic and abdominal radiographs. the diagnosis of masses, pneumonia, pyotho- Consider trial antibiotics if bacterial infection is suspected (e.g., rax, or other infections. Joint radiographs can doxycycline if ehrlichiosis is suspected). aid in the diagnosis of an erosive immune- If necessary, proceed to stage 2. mediated polyarthritis.3 Other anatomic areas to radiograph include long bones (especially in Stage 2 young dogs), the spine, and dental structures Repeat stage 1 tests as indicated. (tooth root abscesses, masses). Special contrast Obtain thoracic and abdominal radiographs if not obtained in stage 1. radiographic studies can focus on other body Conduct abdominal and other ultrasonography as indicated. systems (urogenital, spinal, gastrointestinal). Conduct echocardiography if a heart murmur is present. Conduct heartworm testing, if indicated. Ultrasonography Conduct fine-needle aspiration with cytology of masses, lymph Abdominal ultrasonography allows for evalu- nodes, and fluids (cyst, pleural, peritoneal, prostatic wash), if ation of organ parenchyma and can detect indicated. lesions not apparent on survey radiographs. Conduct blood culture. It can also assist with fine-needle aspiration Conduct arthrocentesis. or biopsy if needed. Thoracic ultrasonogra- Conduct fecal cultures, if indicated. phy can be conducted if abnormalities (e.g., Conduct bone marrow aspiration if warranted by CBC results. pleural effusion, cysts, masses) are detected Conduct serology for infectious diseases. on radiographs. When thoracic disease is Obtain long bone and joint radiographs. not radiographically evident, ultrasonography Conduct protein electrophoresis, if indicated. is not rewarding because the lungs obscure Conduct an immune panel, if indicated. intrathoracic anatomy.13 Ultrasonography can If necessary, proceed to stage 3. also be used to evaluate ocular (including Stage 3 retrobulbar), ventral cervical (thyroid/parathy- Repeat stage 1 and 2 tests as indicated. roid, lymph node, salivary gland), and muscu- Conduct echocardiography even if no murmur is present. loskeletal (skin, subcutaneous, joint, muscle) Conduct transesophageal echocardiography. regions if indicated.14–16 Conduct bone marrow aspiration even if CBC results are normal. Perform biopsy as indicated. Echocardiography Conduct bronchoscopy and bronchoalveolar lavage as indicated. Echocardiography should be conducted in Conduct cerebrospinal fluid analysis. dogs with FUO and a heart murmur, especially Conduct dental radiography. a new or diastolic murmur. Vegetative lesions Consider computed tomography, magnetic resonance imaging, must be differentiated from proliferative myx- nuclear imaging, or positron emission tomography. omatous valve degeneration. Dogs with infec- Conduct laparoscopy or thoracoscopy as indicated. tive endocarditis are usually medium to large Consider exploratory celiotomy. breeds that do not tend to have myxomatous Administer trial antibiotic or antifungal therapy. valve degeneration.17 Echocardiography can CBC = complete blood count also be used to evaluate for a heart base mass if one is clinically suspected. 16 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE The Diagnostic Approach to FUO in Dogs CE Blood Culture FIGURE 2 Blood cultures should be conducted (prefera- bly during a pyrexic episode) for all dogs with FUO, especially those with a heart murmur, bounding pulses, lameness (polyarthritis), Courtesy of Dr.Ty McSherry back pain (diskospondylitis), or urinary tract infection, as the latter three conditions can be sequelae to endocarditis.17 It is common for dogs with positive blood cultures to have isolation of the same organism from other tissue or fluid sites (cardiac, urinary, spinal).18 Aseptic techniques for obtaining samples are described elsewhere.2,19,20 The volume of the blood sam- MORULAE in macrophages in a splenic aspirate from a dog infected with ple is more important than the timing; larger Ehrlichia canis. volumes are associated with an increased diagnostic yield in human medicine.19,21,22 Patient FIGURE 3 size determines the amount of blood to be drawn. As a general guideline, 16 to 20 mL of blood should be obtained from large dogs, and 5 mL of blood should be obtained from Courtesy of Dr.Ty McSherry cats and small dogs.2 The blood should be divided evenly and placed aseptically into aerobic and anaerobic blood culture vials (~70-mL vials for large patients, and ~20-mL vials for small patients).2 If the patient’s size allows, a second blood sample can be obtained immediately from a different site and divided as described above.2 If the dog has recently FINE-NEEDLE ASPIRATE from a spleen in a dog with malignant histiocytosis. received antibiotics, blood culture vials with resins that bind antibiotics should be used.2,19 planum, skin, feces) can also be conducted if Evidence suggests that recovery is improved in indicated. Fluid samples should be submitted samples from blood culture resin vials because for bacterial culture if the sample quantity is the resins may absorb inhibitors other than anti- sufficient. biotics23; therefore, use of these vials for all blood samples may be warranted. Bartonella Bone Marrow Evaluation spp are emerging as an important cause of Bone marrow aspiration should be conducted culture-negative infective endocarditis in dogs; early in the evaluation of dogs with FUO if CBC QuickNotes therefore, submission of samples for Bartonella abnormalities consistent with bone marrow Arthrocentesis can polymerase chain reaction (PCR) testing as disease are present. It should be considered in yield critical diag- well as serology is recommended in suspected later diagnostic stages if no definitive diagno- nostic information cases.24 Blood culture PCR techniques are sis has been made, even if the CBC is normal, being used in human medicine and may be because neoplasia and infectious diseases can for many dogs with valuable for use in dogs for detecting other be common causes of FUO in dogs.2,8 fever of unknown infections in the future.25 origin. Arthrocentesis Cytologic Examination Immune-mediated polyarthritis is a common Fine-needle aspiration with cytology should cause of FUO in dogs even when no signs of be conducted on any suspicious masses or arthritis are present (FIGURE 4).7,8 Arthrocentesis lymph nodes, fluid accumulations, or abnor- should be conducted on several joints and the mal organs. Cytology can be rewarding in samples submitted for cytologic evaluation the diagnosis of many infections as well (EDTA microcontainer) and possibly bacterial as in the identification of abnormal cells culture (aerobic, anaerobic, and mycoplasma). (FIGURES 2 AND 3). Impression cytology (nasal Infectious arthropathy needs to be ruled out CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 17

FREE CE The Diagnostic Approach to FUO in Dogs FIGURE 4 exposure (e.g., fungal disease, most rickettsial diseases) or previous infection (e.g., protozoal disease) and does not necessarily correlate with active disease or current clinical signs.28 Immunodiagnostic Screening Panels Immunodiagnostic panels (antinuclear antibody, rheumatoid factor, Coombs) are typically Courtesy of Dr.Ty McSherry unrewarding in dogs with FUO for several reasons, including the potential for false-positive results.2,7,8 Antiplatelet antibody tests and serum protein electrophoresis can be conducted if thrombocytopenia or hyperglobulinemia, respectively, is present. JOINT FLUID from the tarsus of a dog with immune-mediated polyarthritis. Other Diagnostic Tests Other diagnostic tests, such as prostatic wash, if suppurative inflammation is seen on cytol- cerebrospinal fluid analysis, and bronchos- ogy because samples from septic joints do not copy with bronchoalveolar lavage, should be always contain degenerate neutrophils, and a considered if clinical abnormalities suggest negative joint culture does not rule out infec- prostatic, neurologic, or respiratory disorders, tion.26 If only a small sample can be obtained, respectively. Samples should be submitted for it should be used for direct cytology. Otherwise, cytologic evaluation as well as aerobic and it is recommended to submit synovial fluid sam- anaerobic bacterial culture if quantity permits. ples in blood culture medium to improve the Bronchoalveolar lavage samples should also diagnostic yield.26 Synovial membrane biopsy be submitted for mycoplasma and slow-grow- with culture can also be considered.26 Bacterial ing fungal cultures. endocarditis can cause true infective arthritis or immune-mediated arthritis, and the two Advanced Imaging conditions must be differentiated.27 Immune- Computed tomography (CT) and magnetic res- mediated polyarthritis tends to involve the onance imaging (MRI) should be used to help carpi and tarsi, whereas infective arthritis fre- delineate diagnosed conditions or when the quently involves larger joints (e.g., stifle, elbow, diagnosis remains equivocal.10 Nuclear scintig- shoulder).27 If immune-mediated polyarthritis is raphy is being used more frequently in vet- suspected, serology for rickettsial disease and a erinary medicine to detect infections and may heartworm test may be indicated.27 be a valuable tool in the investigation of FUO in dogs.29 Another promising imaging modal- Serology ity being used in human medicine, called Serum samples should be submitted for fungal image fusion, is the combination of positron and rickettsial disease testing if these diseases emission tomography (PET; a type of nuclear are clinically suspected and if patient history imaging) and CT. A few reports of the use indicates possible exposure. These tests should of image fusion in dogs demonstrate that this not be used as screening procedures in the technique could play an important role in hope that something abnormal will be found. investigating canine FUO.30–33 Because Toxoplasma and Neospora spp are ubiquitous protozoal parasites, paired serum Biopsy TO LEARN MORE antibody titers for IgG and IgM should be sub- If fine-needle aspiration cytology cannot pro- For more information on mitted if a diagnosis continues to be elusive. A vide a definitive diagnosis, a biopsy may be special tests that can be single high IgM indicates active or recent infec- helpful. In one study,7 biopsy samples submit- used in diagnosing the cause of FUO in dogs, tion, and a fourfold IgG rising titer confirms ted for histopathology enabled a diagnosis in please visit the Web infection.28 It is important to remember that a 15 of 17 dogs with FUO. Tissue samples can Exclusives section of negative antibody titer does not rule out infec- be obtained percutaneously (with or without CompendiumVet.com. tion and that a single positive titer implies either imaging assistance); via endoscopy, laparos- 18 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE The Diagnostic Approach to FUO in Dogs CE copy, or thoracoscopy; or surgically during trial antifungal agents may be of use. laparotomy. Submission of tissue samples for If the fever does not respond to antibiotics or histopathology and possibly bacterial or fun- antifungals, options include waiting to see if new gal cultures is recommended. Exploratory diagnostic clues arise and considering an immu- celiotomy with biopsy is indicated only by the nosuppressive trial of corticosteroids. A dramatic results of diagnostic testing.8 The diagnostic improvement should be expected within 24 to yield of exploratory celiotomy in a dog with 48 hours of corticosteroid therapy in dogs with no indication for surgery is unknown. an immune-mediated FUO.2,5 It is important to inform owners about the risks of trial corticos- Treatment teroids, such as allowing a fungal or bacterial Specific treatment is based on the definitive infection to disseminate or further decreasing the diagnosis, if found. Administering intravenous chance to diagnose the problem, as with lym- fluids or placing a fan blowing toward the cage phoma. Ideally, during a corticosteroid trial, the can be used to reduce the temperature in hos- dog should be hospitalized and monitored closely pitalized patients. In dogs for which extensive for adverse effects.5 Initial improvement does not investigation yields no diagnosis, judicious use equal successful treatment. One study7 revealed of antibiotic therapy may be warranted. The that treatment 24 hours before referral was associ- choice of antibiotic depends on the suspected ated with a statistically significant increase in the bacterial agent. If no response is seen after 72 time to diagnosis. Therefore, it is suggested that, hours with appropriate dosing, another antibi- when possible, therapy be withheld or withdrawn otic that covers a different spectrum may be in dogs referred for investigation of FUO. chosen.34 If a bacterial infection is suspected in a severely ill patient, the four-quadrant Conclusion approach—choosing an antibiotic or combi- The most common and important causes of nation of antibiotics that is effective against FUO in dogs are infection, immune-mediated aerobic, anaerobic, gram-positive, and gram- disease, and cancer. Using a logical diagnostic negative organisms—is recommended.34 If anti- approach to FUO in dogs usually results in a biotic therapy is not successful, NSAIDs can be definitive diagnosis. Sometimes, being patient QuickNotes administered, keeping in mind the potential and allowing new diagnostic clues to emerge The most common side effects.5,7 Fever can result in considerable by revamping historical information (via reas- malaise, dehydration, and anorexia; therefore, sessing current information and possibly and important clinicians must decide in each case whether obtaining a more detailed history) and repeat- causes of FUO in NSAIDs could be beneficial.4 Antipyretics (e.g., ing physical examinations and simple labora- dogs are infection, ketoprofen, flunixin meglumine, dipyrone) tory tests is more desirable than proceeding immune-mediated should be used with caution because fever can with more invasive and expensive tests if the disease, and cancer. be beneficial, and many argue that antipyretic dog is stable. Communicating with the client therapy can have a negative impact on the is of utmost importance. A broad knowledge body by causing hypothermia and impairing of the possible causative diseases and the abil- the host’s immune defenses.4,5,35 Fevers may ity to interpret specific diagnostic test results increase the bactericidal effect of antibiotics in the context of FUO in dogs are essential to and serum and can also decrease the pathoge- diagnose the source of an FUO. nicity of some pathogens.4,5,35 If an antipyretic Acknowledgments is considered necessary, aspirin can be admin- The author thanks Leo “Ty” McSherry, DVM, DACVP, istered at a dosage of 10 mg/kg q12h PO.2 If clinical pathologist at Antech Diagnostics in Irvine, there is clinical suspicion of a fungal disease, California, for the cytology images. References 1. Miller JB. Hyperthermia and fever of unknown origin. In: Etting- 4. Johannes DM, Cohn LA. A clinical approach to patients with er SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. fever of unknown origin. Vet Med 2000;95(8):633-642. Vol 1. 6th ed. St. Louis: Elsevier Saunders; 2005:9-13. 5. Couto CG. Fever of undetermined origin. In: Nelson RW, Couto 2. Lunn KF. Fever of unknown origin: a systematic approach to CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; diagnosis. Compend Contin Educ Pract Vet 2001;23(11):976-992. 2009:1274-1277. 3. Bennett D. Diagnosis of pyrexia of unknown origin. In Pract 6. Dunn JK, Gorman NT. Fever of unknown origin in dogs and 1995;17:470-481. cats. J Small Anim Pract 1987;28:167-181. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 19

FREE CE The Diagnostic Approach to FUO in Dogs 7. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of Disease. 5th ed. Philadelphia: Saunders; 1997:1077. fever in dogs: laboratory testing, diagnoses and influence prior to 23. Lelièvre H, Gimenez M, Vandenesch F, et al. Multicenter clinical treatment. J Small Anim Pract 2006;47:370-376. comparison of resin-containing bottles with standard aerobic and 8. Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with anaerobic bottles for culture of microorganisms from blood. Eur J pyrexia of unknown origin. J Small Anim Pract 1998;39:574-580. Clin Microbiol Infect Dis 1997;16(9):669-674. 9. Mourad O, Palda V, Detsky AS. A comprehensive evidence- 24. MacDonald KA, Chomel BB, Kittleson MD, et al. A prospective based approach to fever of unknown origin. Arch Intern Med study of canine infective endocarditis in Northern California (1999– 2003;163:545-551. 2001): emergence of Bartonella as a prevalent etiologic agent. J Vet 10. Roth AR, Basello GM. Approach to the adult patient with fever Intern Med 2004;18:56-64. of unknown origin. Am Fam Phys 2003;68:2223-2228. 25. Gebert S, Siegel D, Wellinghausen N. Rapid detection of patho- 11. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am gens in blood culture bottles by real-time PCR in conjunction with 1996;10:85-91. the pre-analytic tool MolYsis. J Infect 2008;57:307-316. 12. Wess G, Unterer S, Haller M, et al. Recurrent fever as the only 26. Greene CE, Budsberg SC. Musculoskeletal infections. In: Greene or predominant clinical sign in four dogs and one cat with con- CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: genital portosystemic vascular anomalies. Schweiz Arch Tierheilkd Elsevier Saunders; 2006:823-841. 2003;145(8):363-368. 27. Goldstein RE. Swollen joints and lameness. In: Ettinger SJ, 13. Mattoon JS, Nyland TG. Thorax. In: Nyland TG, Mattoon JS, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 1. eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: 6th ed. St. Louis: Elsevier Saunders; 2005:83-87. Saunders; 2002:325-353. 28. Houser G, Ayoob A, Greene CE. Laboratory testing for infec- 14. Samii VF, Long CD. Musculoskeletal system. In: Nyland TG, tious diseases of dogs and cats. Appendix 5. In: Greene CE, ed. Mattoon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Philadelphia: Saunders; 2002:267-284. Saunders; 2006:1139-1168. 15. Mattoon JS, Nyland TG. Eye. In: Nyland TG, Mattoon JS, eds. 29. Moon ML, Hinkle GN, Krakowka GS. Scintigraphic imaging Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: Saun- of technetium 99m-labeled neutrophils in the dog. Am J Vet Res ders;2002:305-324. 1988;49(6):950-955. 16. Wisner ER, Mattoon JS, Nyland TG. Neck. In: Nyland TG, Mat- 30. Peremans K, DeWinter F, Janssens L, et al. An infected hip toon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadel- prosthesis in a dog diagnosed with a 99mTC-ciprofloxacin (infec- phia: Saunders; 2002:285-304. tion) scan. Vet Radiol Ultrasound 2002;43(2):178-182. 17. MacDonald KA. Infective endocarditis. In: Bonagura JD, Twedt 31. Berry CR, DeGrado TR, Nutter F, et al. Imaging of pheochromo- DC, eds. Kirk’s Current Veterinary Therapy XIV (Small Animal Prac- cytoma in 2 dogs using p-[18F]fluorobenzylguanidine. Vet Radiol tice). St. Louis: Elsevier Saunders; 2009:786-791. Ultrasound 2002;43(2):183-186. 18. Hirsh DC, Jang SS, Biberstein EL. Blood culture of the canine 32. Ballegeer EA, Forrest LJ, Jeraj R, et al. PET/CT following inten- patient. JAVMA 1984;184(2):175-178. sity-modulated radiation therapy for primary lung tumor in a dog. 19. Haggstrom J, Kvart C, Pedersen HD. Acquired valvular heart Vet Radiol Ultrasound 2006;47(2):228-233. disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary 33. LeBlanc AK, Jakoby B, Townsend DW, et al. Thoracic and ab- Internal Medicine. Vol 2. 6th ed. St. Louis: Elsevier Saunders; dominal organ uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) 2005:1022-1039. with positron emission tomography in the normal dog. Vet Radiol 20. Calvert CA, Wall M. Cardiovascular infections. In: Greene CE, Ultrasound 2008;49(2):182-188. ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: El- 34. Lappin MR. Practical antimicrobial chemotherapy. In: Nelson sevier Saunders; 2006:841-865. RW, Couto CG, eds. Small Animal Internal Medicine. 4th ed. St. 21. Li J, Plorde JJ, Carlson LG. Effects of volume and periodicity on Louis: Elsevier; 2009:1291-1301. blood cultures. J Clin Microbiol 1994;32(11):2829-2831. 35. Klein NC, Cunha BA. Treatment of fever. Infect Dis Clin North 22. Karchmer A. Infective endocarditis. In: Braunwald E, ed. Heart Am 1996;10(1):211-216. 3 CE CREDITS CE TEST 1 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. Which statement regarding the investi- 2. What is the correct definition of a true 3. Which statement regarding fever in dogs gation of FUO in dogs is false? fever? is true? a. Two-view abdominal and three-view a. increase in body temperature due to an a. The cause of fever in most dogs is thoracic radiographs are recommended. elevation of the thermal set point in the neoplasia. b. Joint radiographs can aid in the diag- anterior hypothalamus b. Most FUOs in dogs are caused by a nosis of an erosive immune-based b. increase in body temperature due to an common disease presenting in an polyarthritis. elevation of the thermal set point in the obscure fashion. c. Thoracic ultrasonography should anterior pituitary gland c. Dogs with true fevers commonly always be conducted, especially if c. a marked, rapid rise in body tempera- have prolonged body temperatures abnormalities are not detected on tho- ture without adjustment of the thermal above 106°F. racic radiographs. set point in the anterior hypothalamus d. Prolonged body temperatures d. Dogs with infective endocarditis are d. a marked, rapid rise in body tempera- above 106°F are not dangerous. usually medium to large breeds that ture without adjustment of the do not tend to have myxomatous valve thermal set point in the anterior degeneration. pituitary gland 20 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE The Diagnostic Approach to FUO in Dogs CE 4. FUO in dogs is commonly the result 7. Which statement regarding blood cul- 9. Which statement is true with regard to of ____________ disease. tures for dogs with FUO is false? dogs with FUO? a. infectious a. Blood cultures can be conducted for a a. Antibiotics should never be started b. neoplastic dog currently on antibiotics. unless the definitive cause of FUO is c immune-mediated b. It is rare for dogs with positive blood determined. d. all of the above cultures to have isolation of the same b. A negative fungal antibody titer rules organism from other sites. out infection with that organism. 5. Which statement regarding sample c. Obtaining a larger blood sample c. Initial improvement after the start culture is true? volume is more important than of corticosteroids does not equate a. A negative urine culture can rule the timing of the sample. to successful treatment because out pyelonephritis. d. Bartonella spp are emerging as many diseases can respond favorably b. A negative blood culture can rule an important cause of culture-negative initially. out bacteremia. infective endocarditis in dogs. d. Bone marrow aspiration is only indi- c. A negative joint culture can rule out cated if the CBC is abnormal. septic arthritis. 8. Which statement regarding arthrocente- d. none of the above sis in the evaluation of a dog with FUO is 10. Which statement is false with regard to true? dogs with FUO? 6. When evaluating a dog with FUO, a. Only one joint should be tapped a. Using a logical approach usually results a. it is usually not necessary to evaluate to decrease the chance of septic in a definitive diagnosis. a blood smear in conjunction with contamination. b. It is important to run as many diagnos- the CBC. b. Immune-mediated polyarthropathies tic tests as quickly as possible when b. a urine culture is only indicated tend to involve larger joints such as the evaluating a stable dog with FUO. when there is an active urine stifles, elbows, and shoulders. c. Conduct fecal centrifugation and fecal sediment. c. Degenerate neutrophils are not always cytology, if indicated. c. repeated neurologic and fundic exami- seen with septic joints. d. If fever persists beyond 72 hours nations are important. d. Immune-mediated polyarthritis is after a medication has been discontin- d. a joint tap is recommended only for extremely rare in asymptomatic dogs ued, a drug-induced fever can be dogs presenting with lameness. with FUO. ruled out. Clinical Snapshot Answers and Explanations Case Presentation #1 SEE PAGE 11 FOR CASE PRESENTATION. common differentials include pem- warm weather, can occur in approx- 1. This is an example phigus, sterile eosinophilic pus- imately 50% of patients. of superficial bacte- tulosis, and pustular demodicosis. 3. Fluoroquinolone antibiotics prevent rial infection of the However, bacterial folliculitis is most bacterial DNA synthesis by partly skin involving the commonly confused with dermato- inhibiting bacterial DNA gyrase. hair follicles, hence phytosis or urticaria. Demodicosis, This class of drugs is primarily the name superficial concurrent Malassezia infection, active against gram-negative aero- bacterial folliculitis. and other infections should be bic and facultative anaerobic bac- Close examination ruled out by skin scrapings, impres- teria. Although they are effective of the skin reveals small papules at sion smears, and dermatophyte cul- against many gram-positive organ- the base of the hairs. These papules/ tures, respectively. isms (e.g., staphylococci), the mini- pustules may rupture, causing the The diagnosis of a bacterial pyo- mum inhibitory concentrations are formation of tiny epidermal collar- derma is often a clinical diagnosis usually higher than for gram-nega- ettes, which may be seen encircling supported by ruling out demodi- tive bacteria. Fluoroquinolone anti- the base of the hairs. cosis and dermatophytosis, the biotics are contraindicated in this 2. The major diagnostic differentials two most common follicular dis- particular patient because they are are dermatophytosis, demodico- eases. Concurrent bacterial and known to cause erosive arthropathy sis, and Malassezia dermatitis. Less Malassezia infections, especially in in young dogs. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 21

Using a Diet History to Improve Adherence to Dietary Recommendations ❯❯ Kathryn E. Michel, DVM, MS, DACVN,* University of Pennsylvania Proper dietary management is essential to pet health, yet changing pet owners’ feeding practices is often difficult. Taking a diet history provides an opportunity to open a dialogue about animals’ dietary needs as well as invaluable information that will aid in tailoring specific dietary interventions to the needs and preferences of patients and their caregivers. ommunicating effectively with people the household? Do any of them spend all day C about the nutrition and dietary manage- with the pet? Inquire whether there are other ment of their pets can be difficult, par- pets in the home and whether they are—or ticularly when the goal is to persuade them to can be—fed separately from the patient. Can alter their feeding practices. However, circum- the patient get into the other pets’ food? Ask stances frequently arise in which a change in whether the pet is confined indoors or is feeding management may be in the best inter- allowed outside. If the pet is allowed out, is ests of a pet. Obtaining a complete diet history is it supervised while it is outside? Does it have the essential first step in the process of altering the opportunity to steal food, get into garbage, feeding practices to suit a pet’s needs. The diet scavenge, or hunt? history provides information about what the pet is being fed and whether this food is complete, The Principal Diet, Feeding Routines, balanced, and appropriate to the pet’s life stage and Eating Behaviors QuickNotes and health status. Just as important, the history Obtain the precise names (including flavor, if provides information about how food is used appropriate) and brands of all commercial pet Information from in interactions between the pet and the other foods that the patient is receiving and the spe- the diet history is members of the household. Understanding this cific amounts fed. Often, caregivers cannot pro- essential for deter- relationship is a key element when designing vide this information accurately by recall alone mining whether a dietary interventions that meet the health and and need to check labels and measure feeding patient is receiving nutritional needs of the patient and are accept- portions. Also, pet owners who use a scoop to an appropriate and able to the pet’s caregivers. measure dry food often do not realize the true adequate diet. size of their measuring device. If the pet is eat- Elements of the Diet History ing a canned diet, ask what size can the owner A complete diet history gives an accurate account buys. Some varieties of pet food are sold in of all foods fed to a pet on a typical day. It is an multiple can sizes (e.g., 5.5 and 12 oz), so the opportunity to evaluate all the ways that food size used by the client is important informa- is involved in interactions between the pet and tion. Make sure to ask whether the food the pet the other members of its household. It should is currently eating is its usual diet and, if not, also be an opportunity for the pet’s caregivers when the diet change was implemented. to offer their viewpoints regarding the propo- If the pet is eating a commercial pet food, sition of modifying their feeding practices. ask if the diet is being supplemented with any *Dr. Michel discloses that human foods. If this is the case, it is important she has received financial support from Nestlé The Household to get accurate details, including measured Purina PetCare Company Begin by asking about who lives with the amounts of all foods routinely given to the and Royal Canin. pet. How many adults and children are in pet. If the pet is being fed a home-prepared 22 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

CONTRIBUTED BY THE AMERICAN COLLEGE OF VETERINARY NUTRITION About ACVN diet, ask for the recipe, including measured consider such items treats, and many of the Founded in 1988, the primary amounts of all the ingredients. Some owners products and foods used for these purposes objective of the American College do not use a standard recipe when making a are high in calories. of Veterinary Nutrition (ACVN) is home-prepared diet. It is useful to ask these It is important to remember to inquire to advance the specialty area of owners to keep a diary of all food fed to the pet whether the pet routinely receives any supple- veterinary nutrition and increase the competence of those who for 5 to 7 days. Be certain to inquire whether ments or medications that are disguised with practice in this field by establish- the pet is receiving any dietary supplements. food. Human foods that are typically used to ing requirements for certification If possible, have the client bring in the supple- pill a dog or cat, such as cheese, lunch meats, in veterinary nutrition, encour- ments—or at least the label information—so or peanut butter, are often high in sodium, fat, aging continuing professional you can see exactly which nutrients are being and calories. For example, one study evalu- education, promoting research, supplemented and in what quantities. ating dogs with cardiac disease showed that and enhancing the dissemination Ask about the daily routine of feeding the 62% of the owners used human or pet food of new knowledge of veterinary nutrition through didactic teaching pet. Is the pet fed at certain times of the day, for pill administration and that many of these and postgraduate programs. or is food always available? If the pet is fed foods were high-sodium table foods such as with other pets, are the meals supervised? cheese or lunch meats.1 For more information, contact: Does one person assume responsibility for One further point to ask about is the pet’s American College of Veterinary feeding the pet, or can it vary day-to-day? This level of activity and opportunity to exercise. Is Nutrition, c/o Dawn Cauthen, is important information, especially when you the pet walked regularly? How often, and how Administrative Assistant, are making dietary recommendations, because far? Find out whether the pet goes outside, School of Veterinary Medicine: Dept. of Molecular Biosciences the person who brings the pet to the office may has a fenced-in yard—and if so, how large— One Shields Avenue not be the person who will be implementing or participates in regular activities that involve Davis, California 95616-8741 the new plan. Ask about how and where the exercise, such as going to a dog park or an food is stored (e.g., in a sealed container, in agility class. See if you can gauge whether Telephone: 530-752-1059 Fax: 530-752-4698 the refrigerator). If the pet is fed a dry food, is increasing the opportunity to exercise would Email: dawncauthen@yahoo.com the food bought in large quantities, and how be feasible in the household. This information Web: acvn.org long does it take to use up a bag of food? Food is especially valuable when you are designing can lose its freshness over time, especially if it a weight reduction program for a patient. is not stored under optimal conditions. Inquire about the pet’s normal feeding Gathering the Information behavior. Is the pet an “easy keeper” or a picky This may seem like a great deal of information eater? Does the pet eat the food as soon as it to gather in a routine office visit, but the pro- is offered, or is it content to graze through- cess can be expedited by having a diet history out the day? Does the pet usually eat all the form available for clients to fill out while they food that is offered? Does the pet beg for food are in the waiting room. As previously men- between meals? If the pet is not eating as it tioned, the client may not be able to recall all normally does, find out what has changed and of the information in the office and may need for how long the behavior has been altered. to take the form home. If your practice has a Web site, you can have a link to a download- Treats, Supplements, and Exercise able version of the form so that clients can When inquiring about treats, ask the question fill it out before the office several times in different ways. Ask specifically visit. To help expedite the about which commercial treats are used—not process, a veterinary techni- WEB EXCLUSIVE just the brand name but also the flavor, variety, cian familiar with taking diet and size. Ask about human foods and table histories can either gather scraps. Ask about products or foods that are the pertinent information Photocopy the diet history form used to promote chewing and dental hygiene directly from a client during on pages 47 and 48 for your clients, or to alleviate boredom. Also inquire about the visit or review the diet or download a customizable PDF different ways food may be used as a reward, history form for complete- of the same form from such as for performing tricks or for good ness and accuracy once the CompendiumVet.com. behavior during walks. Owners do not always client has filled it out. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 23

Negotiating a Diet Change The information obtained in the diet history HEALTHY BITES will be invaluable for making appropriate and, hopefully, acceptable dietary recommendations To get an accurate account of for your patients. Knowing a pet’s current diet the foods fed to a pet on a and any recent changes to it will inform your decision about what kind of dietary modifica- typical day: tion may be necessary to address the pet’s health Find out if you are speaking to the person condition and what kind of diet the pet may find responsible for feeding the pet. most acceptable. Being aware of owner prefer- Have a diet history form available that the ences and potential obstacles to change will help client can take home so he or she can check you tailor your recommendations not only to the the labels and measure the amounts of food pet but also to the entire household to ensure that the pet is fed (see pages 47 and 48 or the greatest probability of success and adherence. CompendiumVet.com for a sample diet Understanding the client’s attitude toward, and history form). concerns about, the dietary management of pet Request that dry pet foods be measured dogs and cats will present you with the oppor- with an 8-oz kitchen measuring cup. tunity to open a dialogue with the client about Ask specifically about the different treats pet nutrition and educate him or her about the and supplemental foods a pet might receive (e.g., commercial treats, table foods and QuickNotes reasons for your recommendations. scraps, oral hygiene products, foods used as Investigations in human medicine have Making an effort found that when physicians make an effort rewards, foods used for administering pills, to talk with pet dietary supplements). to talk with patients about their knowledge, owners about their beliefs, concerns, and expectations about beliefs, concerns, their condition, the result is better adherence Conclusion and expectations to treatment regimens.2 Exploration of all of The information that can be obtained from a can result in bet- these issues from a patient’s perspective on diet history can greatly facilitate the process ter adherence to his or her illness permits the attending health of implementing dietary therapy for a patient. professional to address deficiencies in knowl- It can help not only in making an appropri- recommendations. edge or understanding of the condition and its ate diet selection and accurate feeding recom- treatment and the patient’s ability and willing- mendations but also in understanding the pet ness to pursue a particular course of therapy. owner’s rationale for current feeding practices In veterinary medicine, the owner speaks for and assessing any concerns that may arise the patient, but the same principle applies. from a diet change. By anticipating problems, With regard to dietary practices, despite a you should be able to craft the dietary inter- basic uniformity in nutritional requirements vention in a way that will be acceptable to the and physiologic needs, there is considerable pet’s household or, at the very least, to com- variation in what humans eat. In the case of pet municate more effectively with the pet owner dogs and cats, their owners largely determine about the rationale for the changes in feeding what they eat on a daily basis. Yet in many, management. You will be in a better position if not most, cases, client education alone will to explain why you feel the changes you are not succeed in changing habits and behaviors proposing are in the pet’s best interest and to relating to how a pet is fed. Just as a person’s look for compromise when your recommen- social and cultural context will influence his dations and the pet owner’s preferences are or her own dietary habits, it will also have an in conflict. impact on how and what that person feeds a pet. Therefore, it is important to consider References the social and cultural aspects of owners’ food 1. Freeman LM, Rush JE, Markwell PJ. Dietary patterns of dogs with cardiac disease. J Nutr 2002;132:1632S-1633S. consumption in order to communicate effec- 2. The “why”: a rationale for communication skills teaching and tively with them about their pets’ nutritional learning. In: Kurtz S, Silverman J, Draper J. Teaching and Learning needs and appropriate dietary management, Communication Skills in Medicine. 2nd ed. San Francisco: Radcliffe Publishing; 2005:13-27. particularly if you are attempting to change 3. Michel KE. Unconventional diets for dogs and cats. Vet Clin current feeding practices.3 North Am Small Anim Pract 2006;36:1269-1281. 24 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

Letters The Curious Case of the Cat with the Munchies We found the article “Five Common Toxins Ingested by Dogs and Cats” extremely in- teresting and practical. We recently treated a 5-month-old domestic shorthaired cat for CE Article #1 Five Common Toxins Ingested marijuana toxicity following ingestion of a by Dogs and Cats Julie Ann Luiz, DVM “hash brownie.” The cat presented with per- University of Hawaii at Hilo Johanna Heseltine, DVM, MS, DACVIM Oklahoma State University plexing sudden-onset neurologic signs and ABSTRACT: Substances that are toxic to pets are present in most households. Early identification of intoxication is crucial to preventing or minimizing gastrointestinal absorption of toxins.The history, clinical signs, and laboratory test results can be used to make a presumptive diagnosis and begin therapy. hypothermia (temperature 94.5°F [34.7°C]). O nce absorbed from the gastrointestinal (GI) tract, many toxins lack a specific antidote and are associated with severe systemic effects that are difficult to treat. in veterinary medicine are derived from the human medical literature. Decontamination and treatment strategies for the toxins discussed in this article are summarized in Table 1. Therefore, prompt decontamination is the first With gentle coaxing, the owners admitted step in managing patients that have ingested toxic materials. If the toxin ingested is known, therapy should be initiated before clinical signs develop. This article discusses the general prin- Emesis Induction If the owner suspects toxicosis and calls the clinic before presenting the animal, the veterinarian must consider the risks and benefits ciples for minimizing GI absorption of ingested of instructing the owner to administer an the source of the problem. (The brownie had toxins and the clinical presentation and management of toxicosis caused by five commonly ingested household substances: anticoagulant rodenticides, ethylene glycol (EG), marijuana, emetic.1 Productive emesis requires the presence of food or liquid in the stomach, especially for retrieval of small volumes of toxin.2 Removal of the poison from the stomach is chocolate, and metaldehyde. most effective within 1 hour of ingestion, is been carefully wrapped in plastic film and useful up to 2 hours after ingestion, and is of DECONTAMINATION STRATEGIES limited benefit more than 4 hours after inges- FOR ORALLY INGESTED TOXINS tion.2,3 Early emesis may remove up to 80% of GI decontamination techniques are used to pre- the ingested material.3 vent or limit the absorption of ingested toxins. Induction of emesis is contraindicated for Because many toxins lack a specific antidote, corrosive and caustic materials, as well as for hidden but had disappeared while the patient • Take CE tests decreasing the amount of toxin absorbed may be life - saving, and decontamination strategies should begin as soon petroleum distillates and other volatile materials that may result in aspiration pneumonia. 2,3 Vomiting should not be induced in patients that are depressed or have decreased conscious- • See full-text articles as possible after ingestion of a ness or those that have seizures or are likely to was alone in the house. Clawed plastic and CompendiumVet.com toxic substance. Most decontamination methods practiced seizure.2,3 Emetics should not be administered if the patient has already vomited.2 COMPENDIUM 578 November 2008 crumbs were found at the scene.) At the time, we found little informa- Drs. Luiz and Heseltine mentioned are rare and—when they do occur— tion in the literature specifically on drug testing as a means of confirming carry a good prognosis. Nonetheless, we cases of feline marijuana ingestion. To the diagnosis. We did not do this at the encourage colleagues treating known or our knowledge (and anecdotally), mari- outset due to the client’s financial con- strongly suspected cases of marijuana juana toxicity in cats is more likely to straints. When we undertook a detailed toxicity to submit samples for toxicol- occur via inhalation when owners blow literature search and realized so little ogy screening and to share their data. smoke in the cat’s face, rather than via was known about feline toxicity due to Drs. Anne Fawcett dietary indiscretion, as is more com- Cannabis sativa, we offered to cover and Angela Phillips mon in dogs. In this case, we did not the cost of toxicology testing. The own- Sydney Animal Hospitals Inner West ascertain the ingested dose and did not ers allowed us to collect a urine sample Stanmore, NSW know how long the patient would take from the patient via cystocentesis; how- Australia to recover. ever, the sample, collected 14 days after Hypothermia persisted for approxi- ingestion, returned a negative result. mately 24 hours. One of the signs not THC may be detectable in human urine DO YOU HAVE mentioned in the article by Drs. Luiz samples for 4 to 6 weeks, but the time SOMETHING TO SAY? and Heseltine was marked polyphagia. frame in which it remains detectable During hospitalization, our patient ate in samples from companion animal Send your letters, suggestions, ravenously. At one point, the patient species is not known, according to the comments, or questions to defecated, passing a piece of a shoelace. pathologist at the laboratory to which E-MAIL editor@ This may have been ingested as a result we submitted the sample (Dr. Bruce CompendiumVet.com of the cat’s marijuana-enhanced appetite Duff at Symbion Vetnostics). The recom- FAX 800-556-3288 before hospitalization, suggesting that mended time frame for submission of WRITE Compendium, gastrointestinal foreign bodies are a samples is within 48 hours of exposure Veterinary Learning Systems potential side effect of marijuana toxic- to the toxin. 780 Township Line Road, ity (as is chocolate toxicity, if marijuana In this case, we are confident the Yardley, PA 19067 is ingested in a brownie). The patient patient was suffering from marijuana was discharged 3 days later when the toxicity. The negative urinalysis result More letters are online at neurologic signs resolved, although the may be due to the fact that a young, CompendiumVet.com owner reported that the cat had a “lazy lean cat can metabolize marijuana rela- eye” for 2 weeks after discharge. tively rapidly. Fortunately, these cases CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 25

3 CE CREDITS CE Article 2 The Diagnostic Approach to Fever of Unknown Origin in Cats* ❯❯ 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. Infection 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 addresses the potential diagnostic tests for, and the differential diagnosis and treatment of, FUO in cats. T 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 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 hyperthermia occurs when heat spective studies. Fevers 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 which are usually seen with nonfebrile fashion.8 BOX 1 lists some causes of FUO in Staged Diagnostic Approach to Fever of causes of hyperthermia.3 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 Page 28 ful in cats and may be somewhat benefi- thorough diagnostic evaluation.4 cial because they constitute a protective Treatment a Page 30 response to inflammation.1,4 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 virus 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 tick 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. ehrlichiosis, bartonellosis, cytauxzoonosis), and contact with other cats is also impor- BOX 1 tant as many FUO causes are transmissable.5 Knowledge of ingestion of prey species may Potential Causes of Fever be helpful because songbirds can carry sal- of Unknown Origin in Cats2,4 monellosis, rabbits can carry tularemia, and rodents can carry plague or toxoplasmosis.5 Bacterial infection (focal or systemic): Bac- Cats are frequently affected by stress hyper- teremia, infective endocarditis, septic arthritis, thermia, which must be ruled out before an osteomyelitis, diskospondylitis, septic menin- extensive diagnostic evaluation is pursued. As gitis, pyothorax, pyelonephritis, prostatitis, in dogs, FUO diagnostic clues in cats are gen- stump pyometra, peritonitis, abscess Bacterial diseases: Bartonellosis, borrelio- erally not readily apparent on physical exami- sis(?), mycoplasmosis (hemotrophic and non- nation, so repeated detailed examinations are hemotrophic), tuberculosis and other myco- essential.9 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, anaplasmosis, formed because numerous infectious diseases QuickNotes Rocky Mountain spotted fever (e.g., FIP, FIV, FeLV) cause ocular changes. Fungal: Histoplasmosis, blastomycosis, cryp- Absence of ocular changes does not rule out Infectious diseases tococcosis, coccidioidomycosis infection with these diseases. Repeated neu- are the most com- Protozoal infections: Toxoplasmosis, cytaux- rologic and orthopedic examinations should mon causes of zoonosis, neosporosis(?), babesiosis(?), try- be performed, although they can be difficult fever and fever of panosomiasis(?) to interpret in an uncooperative cat. unknown origin in Immune-mediated diseases: Polyarthritis, systemic lupus erythematosus, rheumatoid cats. Feline Leukemia and Feline arthritis, vasculitis, meningitis, steroid-re- Immunodeficiency Virus sponsive neutropenia and fever FeLV antigen and FIV antibody blood tests Neoplastic: Lymphoma, 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- pancreatitis, granulomatosis tive results.13,14 Miscellaneous: Portosystemic shunt, drug reaction, toxin, hyperthyroidism, idiopathic Fecal Examinations causes Fecal samples should be obtained from cats with FUO. If diarrhea is discovered, rectal a Hurley KE, Pesavento PA, Pedersen NC, et al. An cytology should also be conducted. Other outbreak of virulent systemic feline calicivirus dis- diagnostic tests to consider include fecal flota- ease. JAVMA 2004;224(2):241-249. tion with centrifugation, direct fecal examina- CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 27

FREE CE The Diagnostic Approach to FUO in Cats BOX 2 tion, and fecal cultures. Cats can be bacteremic Staged Diagnostic Approach to Fever from Salmonella (and possibly Campylobacter) of Unknown Origin in Cats2,3 infection without diarrhea, so fecal cultures should be submitted, especially if neutrophils 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 Typically, the changes seen on the CBC and chemistry profile. 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 heart murmur 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 blood culture. for urinalysis and culture and sensitivity on mul- Perform arthrocentesis. tiple occasions because a negative urine culture Conduct fecal cultures, if indicated. 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 (previously known as feline syncytium-forming virus) can be conducted for cats with FUO and suspected joint disease.20 Courtesy of Dr.Ty McSherry Blood Cultures Blood culture should be conducted for cats with FUO and suspected bacteremia. Typical signs of bacteremia in cats include anorexia, pyrex ia, and shi f ti ng leg lameness. 21,22 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 rheumatoid arthritis, 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 bronchoalveolar 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 marrow disease are present (FIGURE 2). It should be considered later if no definitive diagnosis Courtesy of Dr. Robin Allison 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 bacte- HISTOPLASMA ORGANISMS in a bone marrow rial infection, and FeLV with feline foamy virus aspirate from a cat. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 29

FREE CE The Diagnostic Approach to FUO in Cats 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 malaise, dehydration, and anorexia; therefore, clinicians must decide in each case whether NSAIDs could be beneficial.3 If an antipyretic is considered necessary, Courtesy of Dr. Robin Allison 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 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 complications 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 defi nitive 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 Acknowledgments on immune responses by causing hypothermia special tests that can be The author thanks Robin W. Allison, DVM, used in diagnosing the and impairing host immune defenses.3,4,31 PhD, DACVP, of the Department of Veterinary cause of FUO in cats, please visit the Web b For more information on the treatment of cats with Pathobiology at Oklahoma State University and Leo Exclusives section of FUO, please refer to the treatment section in the “Ty” McSherry, DVM, DACVP, clinical pathologist CompendiumVet.com. article starting on page 14. Many of the treatments at Antech Diagnostics in Irvine, California, for the used in dogs can also be used in cats. cytology images. References 1. Miller JB. Hyperthermia and fever of unknown origin. In: Etting- 5. Lappin MR. Fever of unknown origin I and II. Proc Western Vet er SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Conf 2003. Vol 1. 6th ed. St. Louis: Elsevier Saunders; 2005:9-13. 6. Wolfe AM. Fever of undetermined origin in the cat. Proc Atl 2. Lunn KF. Fever of unknown origin: a systematic approach to Coast Vet Conf 2002. diagnosis. Compend Contin Educ Pract Vet 2001;23(11):976-992. 7. Feldman BF. Fever of undetermined origin. Compend Contin 3. Johannes DM, Cohn LA. A clinical approach to patients with Educ Pract Vet 1980;2(12):970-977. fever of unknown origin. Vet Med 2000;95(8):633-642. 8. Dunn JK, Gorman NT. Fever of unknown origin in dogs and 4. Couto CG. Fever of undetermined origin. In: Nelson RW, Couto cats. J Small Anim Pract 1987;28:167-181. CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; 9. Roth AR, Basello GM. Approach to the adult patient with fever 2009:1274-1277. of unknown origin. Am Fam Phys 2003;68:2223-2228. 30 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE The Diagnostic Approach to FUO in Cats CE 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. Feline leukemia virus 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 greater than 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. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 31

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CE Article 3 3 CE CREDITS Immunosuppressive Therapy for Canine Immune-Mediated Hemolytic Anemia ❯❯ Suliman Al-Ghazlat, BVSc, Abstract: The mortality for dogs with severe immune-mediated hemolytic anemia (IMHA) is unaccept- DACVIMa ably high, and better immunosuppressive regimens are needed to increase survival. Understanding NYC Veterinary Specialists the basic immunology of the disease and the mechanisms of action of the available immunosuppres- Forest Hills, New York sive therapies will help clinicians choose an appropriate immunosuppressive protocol. Prospective, randomized clinical studies must be conducted to evaluate the efficacy and safety of different combined immunosuppressive modalities to treat canine IMHA and improve patients’ outcomes. T he pathogenesis of canine immune- Treatment Options mediated hemolytic anemia (IMHA) Current immunosuppressive therapies for At a Glance involves the production of immuno- IMHA act by a variety of mechanisms, Treatment Options globulin (Ig) that recognizes either a self but ultimately they all suppress antibody Page 33 (autoimmune) antigen or a foreign (immune- production by lymphocytes and/or inhibit mediated) antigen associated with red blood the clearance of opsonized RBCs by mac- Suggested cells (RBCs). This results in sensitization or rophages or lysis by the complement sys- Immunosuppressive opsonization of the RBCs and their subse- tem.5,12–14 Because the half-life of IgG (the Protocol Page 35 quent destruction by the complement system, antibody class involved in most cases of the mononuclear phagocyte system, or both.1–3 canine IMHA) in dogs is approximately 1 Management of Relapse The interaction of RBC surface-bound Ig with week, therapies directed only at suppres- Page 40 protein crystallizable fragment receptors (FcRs) sion of antibody production are unlikely on different cells in the immune system leads to affect the outcome in the acute phase to a wide range of immune responses, includ- of the disease.13,14 ing antibody-dependent cellular cytotoxicity, Over the past 25 years, great advances phagocytosis, complement activation, mast cell have been made in the field of immu- degranulation, lymphocyte proliferation, anti- nology, especially in the development body secretion, and enhancement of antigen of new immunosuppressive agents (e.g., presentation. These responses also promote cyclosporine, leflunomide, mycopheno- phagocytosis and clearance of opsonized late mofetil) that are more potent, more RBCs by the mononuclear phagocyte system selective, and less toxic than glucocorti- cells and lead to intravascular hemolysis by coids.5,14,15 The wide array of new drugs full activation of complement.1,2,4,5 In severe offers the opportunity to use combinations cases, clinical signs of anemia progress that block different pathways of immune rapidly, and animals may present in shock. activation while selecting agents with non- Most dogs that succumb to IMHA do so overlapping toxicity profiles. Nonetheless, within the first 2 weeks after onset (acute IMHA mortality remains high, ranging phase).3,6–11 A retrospective study of 60 dogs from 22% to 80%.2,3,6–11,16–18 Moreover, mul- with IMHA showed a mortality of 52%, with tiple retrospective studies have shown that a good long-term outcome in dogs that sur- the addition of cyclosporine, azathioprine, vived the first 2 weeks of the disease.11 or cyclophosphamide to glucocorticoids CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 33

FREE CE Immunosuppressive Therapy for Canine IMHA did not improve mortality.8,11 gastrointestinal (GI) signs at presentation. For IMHA and its therapy can be divided into induction, the recommended dose is 2 mg/kg three phases: induction of remission, mainte- bid for dogs weighing less than 6 kg and 1.1 nance of remission and prevention of relapse, mg/kg or 30 mg/m2 bid for those weighing and management of relapse. The causes of more than 30 kg.2,17 Remission is signaled by a death in dogs that die during the acute phase stable or rising packed cell volume (PCV) with of IMHA are not well documented, but in addi- no clinical signs of decreased oxygen-carrying tion to lack of response to immunosuppressive capacity over a period of 7 to 14 days. At this agents, they include thromboembolic disease, time, the dose may be decreased by 25% to sepsis, and other side effects of therapy, as 50% (depending on the severity of side effects) well as reactions to antithrombotic therapy and and then by 25% every 2 weeks thereafter.2 blood transfusions.8,9,18 One way to improve Once a dose of 0.5 mg/kg sid is reached, outcomes in the acute phase of IMHA is to the patient can be switched to alternate-day focus the induction of immunosuppression prednisone therapy. As the side effects of pred- on manipulating FcR/Ig interactions, reducing nisone at this point are typically mild, decreas- phagocytosis, and inhibiting complement. The ing the dose by 25% every 4 to 6 weeks rather causes of death during the maintenance phase than every 2 weeks is generally advisable. of IMHA therapy are also unclear, but they may Prednisone administration can be completely be related to disease recurrences or side effects discontinued if there are no signs of relapse of immunosuppression. To improve outcomes while the patient is receiving 0.25 mg/kg every and minimize relapses in this phase, mainte- other day for 4 to 6 weeks (TABLE 1). A com- nance immunosuppressive therapy should be plete blood count (CBC) should be obtained potent, specific, and associated with few or no before any decrease in the dose of immuno- side effects. suppressive agents. A less aggressive tapering protocol may be advised when glucocorti- Glucocorticoids coids are used as the sole immunosuppressive Glucocorticoids remain the mainstay of immu- agent. Although most dogs can be completely nosuppressive therapy for canine IMHA. Their weaned from glucocorticoids, a few patients activity is largely derived from their ability may require lifelong, low-dose therapy to QuickNotes to repress the transcription of many genes maintain remission.2,11 This prednisone proto- responsible for encoding proinflammatory col is based solely on my clinical experience, The mortality for cytokines and adhesion molecules that influ- and there are no published studies establish- dogs with severe ence immune cell trafficking and cellular inter- ing its superiority. IMHA is high, with actions. The molecular basis of glucocorticoid Adverse effects of glucocorticoids include most deaths occur- action lies in the capacity to diffuse through iatrogenic hyperadrenocorticism, GI ulcer- ring within the first the cell membrane and bind to cytosolic ste- ation and perforation, recurrent infections, 2 weeks of clinical roid receptors, which subsequently undergo sepsis, and thromboembolic disease.21–23 disease. nuclear translocation and modulate tran- Glucocorticoids may also predispose patients scriptional activation.5,12,19,20 The main effect to pancreatitis, although this has not been of glucocorticoids in the treatment of IMHA proven.24 Based on clinical experience, large- is to suppress complement and phagocytosis and giant-breed dogs are especially sensitive of opsonized RBCs by interfering with the to adverse effects of glucocorticoids. In con- expression and function of macrophage FcRs, trast, most dogs weighing less than 6 kg gen- which is an immediate effect.5,20 erally experience only mild adverse effects. Prednisone (2 mg/kg bid) is commonly Dexamethasone is considered by some clini- used to induce remission in IMHA, and a vari- cians to be superior to prednisone in induc- ety of dosages and protocols have been advo- ing IMHA remission, but there are no studies cated.1–3,5–11,16–18 There have been no studies to to support this opinion, and (anecdotally) GI evaluate the effect of different prednisone dos- ulceration and pancreatitis are more common ages on short- or long-term outcomes. Factors with dexamethasone than with prednisone.13,14 that may influence dosing include patient In addition, due to its longer duration of effect size, body condition, breed, disease sever- in suppressing the hypothalamic–pituitary– ity, concurrent illnesses, and the presence of adrenal axis, dexamethasone is not appropri- 34 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE FREE Immunosuppressive Therapy for Canine IMHA CE CE TABLE 1 Suggested Immunosuppressive Protocol This protocol is for a 25-kg dog with a body condition score of 5/9, using prednisone for induction of remission and azathioprine to help with maintenance, and is based on clinical experience. Day Protocol Day 1 Prednisone at 30 mg PO bid or, if the dog cannot tolerate oral medication, dexamethasone at 9 mg IV sid Day 5 No GI disturbance for at least 48 hr Maintain prednisone at 30 mg bid and add azathioprine at 50 mg PO sid Day 7 PCV is stable or rising for the previous 48 hr and there Discharge the patient from the hospital and continue the same medications are no signs of GI disturbance Day 14 PCV is rising but subnormal, with no signs of Obtain a CBC and chemistry profile myelotoxicity/hepatotoxicity or serious glucocorticoid side Maintain prednisone at 30 mg bid effects Decrease azathioprine to 50 mg q48h Day 21 PCV is normal, with no signs of myelotoxicity or Obtain a CBC serious glucocorticoid side effects Decrease prednisone to 20 mg bid Maintain azathioprine at 50 mg q48h Day 28 (week 4) PCV is normal, with no signs of Obtain a CBC myelotoxicity or serious glucocorticoid side effects Maintain prednisone at 20 mg bid Maintain azathioprine at 50 mg q48h Week 5 No signs of relapse, myelotoxicity, or hepatotoxicity Obtain a CBC and chemistry profile Decrease prednisone to 15 mg bid Maintain azathioprine at 50 mg q48h Week 7 No signs of relapse or myelotoxicity Obtain a CBC Decrease prednisone to 10 mg bid Maintain azathioprine at 50 mg q48h Week 9 No signs of relapse or myelotoxicity Obtain a CBC Decrease prednisone to 15 mg sid Maintain azathioprine at 50 mg q48h Week 11 No signs of relapse or myelotoxicity/hepatotoxicity Obtain a CBC and chemistry profile. Decrease prednisone to 10 mg sid Maintain azathioprine at 50 mg q48h Week 13 No signs of relapse or myelotoxicity Obtain a CBC Decrease prednisone to 5 mg q48h Maintain azathioprine at 50 mg q48h Week 17 No signs of relapse or myelotoxicity/hepatotoxicity Obtain a CBC and chemistry profile Discontinue prednisone Maintain azathioprine at 50 mg q48h Week 23 No signs of relapse or myelotoxicity/hepatotoxicity Obtain a CBC and chemistry profile Decrease azathioprine dose to 50 mg q 3 days Week 27 No signs of relapse Obtain a CBC Discontinue azathioprine Week 30 No signs of relapse Recommend a CBC q 2 mo for the first year and biannually to triennially thereafter CBC = complete blood count; PCV = packed cell volume. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 35

FREE FREE CE Immunosuppressive Therapy for Canine IMHA CE ate for alternate-day therapy. Because the main Danazol effect of glucocorticoids in treating IMHA is Danazol is an androgen derivative used in the to suppress complement and FcR-mediated early 1990s as an adjunctive treatment for canine clearance of opsonized RBCs, glucocorticoids immune-mediated thrombocytopenia.33,34 Similar are the drugs of choice in the induction phase to glucocorticoids, danazol (10 to 15 mg/kg sid) of treatment. However, as glucocorticoids can may inhibit binding of the Fc portion of immu- have severe side effects when used chronically noglobulin to FcRs and hence prevent phago- at high doses, they are not ideal for maintain- cytosis of opsonized RBCs.33,35 However, in one ing remission and preventing relapse. preliminary report of a small, prospective study in dogs with IMHA, adding danazol did not Human Intravenous Immunoglobulin show any significant beneficial effects compared Human IV immunoglobulin (hIVIG) is a ster- with prednisone alone.35 Danazol is an anabolic ile, purified IgG preparation manufactured steroid and can cause dramatic weight gain in a from pooled human plasma that typically short time, especially when used in combination contains more than 95% unmodified IgG, with prednisone. Furthermore, danazol is expen- which has intact Fc-dependent effector func- sive and may be hepatotoxic.36 Due to these side tions, and only trace amounts of IgA and IgM. effects of chronic use, danazol is not recom- Several mechanisms of action have been pro- mended to maintain remission. posed, including antiidiotypic activity, inhibi- tion of autoantibody production, acceleration Splenectomy of autoantibody breakdown and removal, and Splenectomy may be considered for patients suppression of complement activation.25–32 Most with IMHA that fail to respond to, or have severe importantly, hIVIG may reduce Fc-mediated adverse effects from, immunosuppressive ther- phagocytosis of IgG-coated RBCs.25,26 One apy or that require long-term, high-dose therapy study showed that hIVIG binds to canine lym- to remain in remission. The spleen is a major phocytes and monocytes and inhibits RBC site of autoantibody production and of seques- phagocytosis.26 tration and destruction of IgG-sensitized RBCs. hIVIG has been used successfully in mul- A thorough search for an underlying infection tiple studies to treat a small number of dogs is mandatory before proceeding with splenec- QuickNotes with IMHA.31,32 A total infusion of 0.5 to 2 g/ tomy. Preliminary results of a small, prospective, kg administered in a divided dose on 2 con- unpublished study showed that splenectomy Glucocorticoids secutive days over a period of 6 to 12 hours as an adjunctive therapy is superior to medical are the mainstay of has been beneficial in some refractory cases therapy alone in reducing mortality and short- immunosuppressive of canine nonregenerative IMHA.31 No signifi- ening the interval to normal PCVs in dogs with therapy for canine cant side effects were reported in these lim- severe IMHA.37 In fact, splenectomy may be IMHA, but they can ited samples.31,32 effective for both remission induction and main- cause serious side Due to its rapid onset of action and poten- tenance therapy for severe IMHA. It may also effects. tial to block the phagocytosis of sensitized be helpful in dogs with multiple acute relapses RBCs, hIVIG may be useful in the induction or in those that only partially respond to medi- of remission in dogs with severe IMHA. In the cal immunosuppression. However, as the site few reported cases, the response was often of clearance of IgM-sensitized RBCs appears rapid but transient, suggesting that hIVIG is to be the hepatic Kupffer cells, splenectomy is not ideal for maintaining remission.31,32 Indeed, unlikely to be beneficial in dogs with positive it is potentially immunogenic in dogs, and Coombs’ test results or IgM autoantibodies.38 repeated infusions could induce acute anaphy- No large-scale studies have evaluated the laxis. There are no studies on the efficacy and short- and long-term safety of splenectomy in the safety of repeated hIVIG infusions in dogs. dogs. Due to the cost of surgery and risk of Although hIVIG is expensive ($600 for a 5-g complications, splenectomy is rarely recom- bottle), it may be practical and economical to mended as a first-line therapy for severe IMHA. use for induction of remission if it significantly On the other hand, given the encouraging pre- decreases hospitalization time and transfusion liminary data, further studies to evaluate the requirements. Repeated maintenance infusions safety and efficacy of splenectomy in the treat- are currently not recommended. ment of canine IMHA are warranted. 36 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE FREE Immunosuppressive Therapy for Canine IMHA CE CE Plasmapheresis on reducing levels of circulating antierythro- Plasmapheresis is a process whereby the com- cyte antibodies. As such, it is probably inef- ponents in plasma believed to cause or exac- fective for remission induction during the erbate disease are removed. The remaining acute phase of IMHA. blood components are then combined with One retrospective study showed no ben- replacement plasma or an inert substitute and eficial effect of adding cyclophosphamide returned to the patient.39,40 The clinical effec- to prednisone in 60 dogs with IMHA,11 and tiveness of plasmapheresis in the treatment of another study showed higher mortality in dogs autoimmune disease may be due to the partial so treated compared with dogs that received removal of autoantibodies, immune complexes, prednisone alone.8 Interpretation of these complement components, proinflammatory studies is complicated by their retrospective agents, and soluble adhesion molecules.39 nature, and it is likely that cyclophosphamide Plasmapheresis is most useful for rapidly was used only in the more severe cases. reducing plasma concentrations of autoan- However, a small, randomized, prospective tibodies or immune complexes while other trial found no beneficial effects from adding immunosuppressive measures are applied cyclophosphamide to prednisone in the man- to prolong the effect.39 One study reported agement of acute IMHA and even suggested encouraging results for plasmapheresis in dogs that cyclophosphamide may adversely affect with systemic immune-mediated diseases.40 outcome.10 Indeed, several in vitro and in vivo The study suggested that any dog with an experimental studies suggest that cyclophos- acute immune-mediated disease refractory to phamide may paradoxically augment immune conventional immunosuppressive therapy can responses through a toxic effect on T regula- be considered for plasmapheresis.40 Although tory cells.43 Cyclophosphamide also has seri- there are no reported clinical trials of plas- ous adverse effects, including gastroenteritis, mapheresis for IMHA, it may be helpful in myelosuppression, sterile hemorrhagic cystitis, acute, refractory cases or cases complicated and secondary neoplasia.5,44,45 Based on this by concurrent systemic infection.41 However, evidence, cyclophosphamide is not recom- availability of plasmapheresis is limited in vet- mended for induction of remission in dogs erinary medicine, and experience with its use with IMHA, and the risk–benefit profile should for treating animals with immune-mediated be considered carefully before it is used for QuickNotes diseases is minimal. maintenance therapy. Due to its rapid Cyclophosphamide Azathioprine onset of action, Cyclophosphamide is a cytotoxic, myelosup- Azathioprine is a cy totoxic antimetabo- human intravenous pressive alkylating agent. It cross-links DNA lite that is conver ted to 6 -mercaptopu- immunoglobulin helixes to prevent their separation, thus pre- rine in the liver. It is a purine analogue may be a good venting the formation of a DNA template.5,42 that functions as a competitive purine choice in the initial Cyclophosphamide is toxic to both resting antagonist, thereby inhibiting cellular pro- management of and dividing cells, particularly proliferating liferation.5,12,46 Azathioprine is less toxic to severe IMHA. immune cells (lymphocytes).5 It suppresses resting cells than cyclophos phamide and both cell-mediated and humoral immunity, therefore has fewer side effects. It primarily and it may suppress mononuclear phago- suppresses lymphocyte activation and pro- cytic function.5,12 Historically and anecdot- liferation, reducing antibody production. In ally, cyclophosphamide has been effective in vivo experimental studies have shown that inducing and maintaining remission in dogs azathioprine may help to establish antigen- with fulminant IMHA. Several authors have specific tolerance and decrease the risk of recommended using cyclophosphamide in relapse.47 Azathioprine also suppresses mac- cases in which intravascular hemolysis or rophage function, which reduces inflamma- autoagglutination is present, suggesting that it tory cytokine production and phagocytic is especially effective in IgM-mediated hemol- efficiency.4,5 The onset of action of azathio- ysis.5 However, cyclophosphamide principally prine is slow in people but appears to be targets lymphocyte proliferation and, there- faster in dogs, with immunosuppressive fore, is unlikely to have an immediate effect effects evident in 2 to 4 weeks. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 37

FREE CE Immunosuppressive Therapy for Canine IMHA Several studies have suggested a benefi- properties through its blockage of transcrip- cial effect of azathioprine in the treatment of tion of cytokine genes in activated T cells. canine IMHA.6,11,17 However, as these studies CsA inhibits the phosphatase activity of cal- are retrospective and lack data on azathio- cineurin, thereby preventing activation of the prine timing and dosing and because mul- nuclear factor of activated T cells (NFAT).5,12,52 tiple concurrent immunosuppressive and NFAT activation and nuclear translocation are antithrombotic agents were used, it is difficult required for the transcription of many cytok- to attribute the improved survival directly to ines, particularly interleukin-2 (IL-2), which use of azathioprine. A large, retrospective is necessary for the proliferation and matura- study showed that in dogs treated for IMHA tion of T cells.5,52,53 CsA also enhances expres- with the combination of prednisone, azathio- sion of transforming growth factor-β (TGF-β), prine, and ultralow-dose aspirin (0.5 mg/kg which is a potent inhibitor of IL-2–stimulated sid), the survival rates at discharge, 1 month, T cell proliferation and generation of antigen- and 1 year were 88%, 82%, and 69%, respec- specific cytotoxic lymphocytes.5,52 Studies indi- tively, which compared favorably with rates in cate that CsA blocks the activation of C-Jun N previously reported studies (57%, 58%, 34%).17 terminal kinases and p38 signaling pathways Due to azathioprine’s slow onset of action, it triggered by antigen recognition, making CsA is unlikely to play any role in improving short- a highly specific inhibitor of T cell activation.12 term survival. The recommended canine load- In addition, by suppressing the production of ing dose is 2 mg/kg sid for 5 to 7 days, followed interferon γ, CsA may inhibit the phagocytic by 2 mg/kg every other day for maintenance.17 capabilities of macrophages.5,53 I generally continue azathioprine maintenance The efficacy of CsA has been demonstrated until the patient has been weaned off predni- in cats and dogs undergoing renal transplan- sone for 4 weeks. There is no well-established tation and in dogs with immune-mediated dose-tapering protocol for azathioprine, but I disorders.54 One retrospective study showed taper the dose gradually over 2 to 3 months by improved outcome in dogs with IMHA that extending the period of time between doses received CsA and glucocorticoids compared by 1 day every 4 weeks (TABLE 1). with glucocorticoids alone, but the difference The most common adverse effects of azathi- did not reach statistical significance.8 This QuickNotes oprine therapy are GI disturbances and myelo- finding suggests that CsA may be superior to suppression, particularly in large dogs.46,48,49 glucocorticoids alone, as CsA was likely added Cyclophosphamide Acute pancreatitis and cholestatic hepatopa- only in the more severe cases. Preliminary is not recom- thy have been anecdotally reported in dogs results from a prospective study showed no mended for induc- receiving azathioprine.48,50,51 The prognosis beneficial effect from combining CsA with tion of remission in for azathioprine-induced bone marrow toxic- prednisone on the survival of dogs with IMHA dogs with IMHA. ity is good if the drug is discontinued before in the first 28 days after onset.55 However, four severe myelofibrosis occurs.49 Therefore, a of the 19 dogs in the prednisone-only group CBC should be obtained every week for the experienced relapses compared with none in first month of azathioprine therapy and every the combination group. This study has not 4 weeks for the duration of therapy, and the yet been published, and the number of sub- drug should be discontinued immediately if jects was small. In addition, a relatively small the neutrophil count declines significantly. dose of CsA was used (4 mg/kg sid), and there Due to its slow onset of immunosuppressive was no mention of monitoring drug levels. action, azathioprine is not a drug of choice for Generally, a dosing regimen of 5 to 10 mg/kg induction of remission. Conversely, due to its sid is recommended for dogs, and plasma con- selective immunosuppressive effects, few side centrations should be periodically monitored effects, availability, and relatively low cost, it is to achieve an effective but safe trough level a good choice for maintenance therapy. (400 to 500 ng/mL); an optimal level has not been established.5 Cyclosporine A The most common side effects of CsA in Cyclosporine A (CsA) is a cyclic polypep- dogs include GI irritation, gingival hyper- tide metabolite of the fungus Tolypocladium plasia, antibiotic-responsive dermatitis, and inflatum. It has potent immunosuppressive papillomatosis.5,54,56 Malignancies, including 38 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

FREE Immunosuppressive Therapy for Canine IMHA CE lymphoma and squamous cell carcinoma, dogs are especially sensitive to the adverse GI have been noted as well.57,58 In addition, effects (e.g., diarrhea, vomiting) of this drug.61 anaphylaxis has been reported in people There are no reports on the use of MMF to and dogs receiving IV CsA.59 CsA-associated manage canine IMHA, but based on its mech- nephrotoxicosis is a well known complica- anism of immunosuppressive action, it should tion in people but appears to be rare in dogs be investigated for maintenance of remission. and cats whose serum CsA levels are maintained within the therapeutic range (400 to Leflunomide 500 ng/mL).54 CsA is expensive and requires Leflunomide is a synthetic isoxazole derivative blood level monitoring, which usually makes that is metabolized in the gut and liver.60 The it cost-prohibitive for large dogs. However, active metabolite of leflunomide, A77 1726, due to its potent and specific suppressive reversibly inhibits dihydro-orotate dehydro- effects on lymphocyte proliferation and genase, the rate-limiting enzyme in the de autoantibody production and tolerable side novo synthesis of pyrimidines.12,52,60,65–67 Again, effects even when used chronically, it may be lymphocytes need both the salvage and the a good choice for maintenance. In addition, de novo pathways of pyrimidine synthesis to due to its suppression of phagocytosis, it may meet the high demand for pyrimidines dur- be beneficial during the induction phase of ing lymphocyte activation and proliferation. therapy. 5,53 Leflunomide specifically suppresses activated T and B cells while other cells maintain their Mycophenolate Mofetil basal cell division. Experimental transplanta- Mycophenolate mofetil (MMF) is a fermenta- tion studies showed that A77 1726 prevents tion product of several Penicillium spp that antibody production.60 Leflunomide also inhib- is metabolized completely in the plasma and its the production of proinflammatory cytok- liver into its active metabolite, mycophenolic ines (e.g., IL-1, tumor necrosis factor α) and acid (MPA).60–62 MPA is an effective, reversible augments the production of the antiinflamma- inhibitor of inosine monophosphate dehy- tory cytokine TGF-β, culminating in significant drogenase (IMPDH), which is a key enzyme antiinflammatory effects.43,52,61,65 in de novo purine biosynthesis.12,52,60–62 Most One study reported promising results of the other cell lines can maintain their function use of leflunomide for treatment of immune- QuickNotes through the salvage pathway of purine bio- mediated and inflammatory diseases in dogs synthesis alone, but proliferating lymphocytes refractory to conventional therapy.65 In this An immunosuppres- depend on both the salvage pathway and the study, 26 dogs with different immune-medi- sive regimen is only de novo pathway. Due to the high specific- ated diseases were treated with leflunomide, one part of a com- ity of MPA for IMPDH, MPA is a very selec- including six dogs with IMHA. Five of these six prehensive thera- tive lymphocyte inhibitor.60,61,63 Blockade of dogs responded well to leflunomide therapy, peutic approach to IMPDH by MPA was shown to deplete the and the one dog that died had severe myelofi- improve the out- guanosine pool in lymphocytes and to inhibit brosis that was probably related to the primary come of dogs with T- and B-cell proliferation, differentiation of disease. The initial dose of leflunomide was IMHA. alloreactive cytotoxic T cells, and antibody 4 mg/kg/day, but the dose was adjusted to responses.60–62 Other mechanisms that may obtain a target trough A77 1726 plasma level contribute to the immunosuppressive effects of 20 μg/mL.67 Most of the dogs had mild to of MPA include induction of apoptosis of acti- moderate disease or partial response to con- vated T cells and impairment of the matura- ventional therapy, affording sufficient time for tion of dendritic cells.64 leflunomide to exert its immunosuppressive MMF has been shown to be safe and effec- effects. tive in prolonging the survival of canine Leflunomide is not commonly used in vet- experimental renal allografts and, anecdotally, erinary medicine, so adverse effects are not has been used successfully in several cases of well documented. Adverse effects reported canine immune-mediated disease.61,62 The rec- in a small number of dogs were rare and ommended starting MMF dose for dogs is 20 mild, including decreased appetite, lethargy, to 40 mg/kg/day PO divided into two or three mild anemia, and self-limiting GI signs.65 doses.62 Experimental studies showed that However, most of the dogs in the study were CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 39

FREE CE Immunosuppressive Therapy for Canine IMHA concurrently receiving other immunosup- can be managed by increasing the dose to the pressive agents that may have contributed to previous level. This dog can be managed as these effects. Based on this single study of an outpatient if it is asymptomatic for anemia, dogs with IMHA, it seems that leflunomide but its CBC should be reevaluated in 1 week may be an effective immunosuppressive drug to assess the efficacy of therapy. Importantly, with minimal side effects and should be inves- a drop in PCV for a dog with IMHA does not tigated for maintenance of remission of canine always signal a relapse. Other causes of a IMHA. decreased PCV in dogs receiving immunosuppressive therapy for IMHA include sepsis and Mizoribine GI hemorrhage. Failure to identify patients Mizoribine is an imidazole nucleoside, and its with these complications can be detrimental active metabolite (mizoribine monophosphate) and potentially fatal. is a potent inhibitor of IMPDH.52,68 Therefore, like MMF, it blocks purine biosynthesis in B Conclusion and T cells and inhibits their proliferation. Canine patients with severe IMHA have a The antiproliferative effect of mizoribine is guarded prognosis. Despite the introduction of linked to a decrease in guanine ribonucle- several new immunosuppressive agents, mor- otide pools. Mizoribine has been approved in tality remains high.2,3,5–7,12–16 Glucocorticoids Japan for renal transplant recipients and is cur- are the mainstay of IMHA therapy for induc- rently undergoing clinical testing in Europe as tion of remission, but the addition of more a substitute for azathioprine in human renal potent immunosuppressive agents to pred- transplant recipients. It appears to be safe and nisone therapy may be warranted in severe (unlike azathioprine) to have minimal myelo- cases and in patients with major adverse toxicity or hepatotoxicity. The availability of glucocorticoid effects. Because azathioprine, this drug is very limited, and little is known CsA, leflunomide, and MMF are unlikely to about its safety and efficacy in veterinary med- have immediate beneficial effects in dogs icine, but theoretically, it could be employed with IMHA but may have immediate adverse for the maintenance of IMHA remission. reactions, I generally wait to add one of these agents to glucocorticoid therapy until the PCV Management of Relapse is stable and the dog exhibits no GI distur- The relapse rate for canine IMHA is not well bances. At my institution, the most common documented, but retrospective studies suggest immunosuppressive agents used in combina- that it is relatively high (13% to 20%).8,9,11,16,17 tion with prednisone for severe IMHA are CsA Clinicians must monitor patients for relapse and azathioprine. CsA is faster acting and has (Table 1), make a prompt diagnosis, assess the fewer side effects than azathioprine, but it can severity and the acuteness of the relapse, and be cost prohibitive in large dogs. Preliminary institute an appropriate immunosuppressive results seem promising for leflunomide and protocol. The choice of regimen depends on discouraging for cyclophosphamide, but there the severity of the relapse. A patient with an are few published prospective, randomized acute relapse (e.g., drop in PCV from normal trials evaluating the use of various immuno- to 25% or lower) should be hospitalized for suppressive agents used in combination with supportive care and aggressively treated to prednisone versus prednisone alone. reinduce remission. Immunosuppressive doses Immunosuppressive therapy is only one part of glucocorticoids are the mainstay of therapy of a comprehensive approach to improving the for relapse; adjunctive induction therapies for outcome of IMHA. Other therapies being stud- severe, refractory cases include hIVIG, sple- ied include antithrombotic agents; one large, nectomy, and plasmapheresis. retrospective study showed improved survival On the other hand, a patient with a mild in dogs with IMHA that were treated with relapse while being weaned off immunosup- ultralow-dose aspirin to prevent thromboem- pressive therapy can be managed less aggres- bolic complications.17 The timing, volume, and sively. For example, a dog in which the PCV type of oxygen-carrying support provided by drops from 40% to 35% after the prednisone blood products or blood substitutes is another dose is decreased from 1.5 to 1 mg/kg/day area that requires further investigation. 40 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

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Abnormalities of von related cholestatic jaundice in heart transplant patients. J Heart Willebrand factor are also part of the prothrombotic state of Cush- Transplant 1990;9(5):577-578. ing’s syndrome. Blood Coagul Fibrinolysis 1999;10:145-151. 51. King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncolo- 24. Moriello KA, Bowen D, Meyer DJ. Acute pancreatitis in two dogs gist 2001;6:162-176. given azathioprine and prednisone. JAVMA 1987;191(6):695-696. 52. Halloran PF. Molecular mechanisms of new immunosuppres- 25. Knezevic-Maramica I, Kruskall MS. Intravenous immune globu- sants. Clin Transplant 1996;10:118-123. lins: an update for clinicians. Transfusion 2003;43:1460-1480. 53. Salom RN, Maquire JA, Hancock WW. Mechanism of a clinically 26. Reagan WJ, Scott-Moncrieff JC, Christian J, et al. Effects of hu- relevant protocol to induce tolerance of cardiac allografts. 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Quick Course Factors to Consider When Choosing Kitten Vaccines At no time are cats at greater risk for of age.3 Studies have also shown that for adult cats, the AAFP strongly disease than in the first few months of maternal antibody interference may recommends vaccinating kittens against life.1 That’s why it’s important to vaccinate persist beyond 14 weeks of age.2–4 this disease. In an experimental study, kittens early to induce immunity before To compensate for variations in susceptibility to FeLV decreased with they are exposed to pathogens. maternal immunity, initial kitten age, but young kittens were most “Maternal antibodies can block the vaccinations should begin at 6 to 8 vulnerable.6 Persistent viremia occurred kitten’s ability to respond to a vaccine,”2 weeks of age and continue at 3- to 4- with 100% of cats infected with FeLV as according to Alice Wolf, DVM, DACVIM, week intervals until the kitten is at least newborns, 85% of cats exposed between DABVP, emeritus/adjunct professor 16 weeks of age.5 Practitioners are 2 weeks and 2 months of age, and 15% at Texas A&M University College of encouraged to consult the 2006 of cats infected at 4 months to 1 year of Veterinary Medicine and chief medical American Association of Feline age.6 Even though owners may claim a consultant for the Veterinary Practitioners (AAFP) feline vaccination kitten is a strictly indoor pet, kittens can Information Network. “Every kitten has guidelines for complete vaccine escape or owners may eventually allow a different level of maternal antibodies— recommendations. them outdoors. even kittens from the same litter—and these antibodies can persist for different The Case for FeLV Vaccination Choosing the Right Vaccines periods of time.” Some kittens have very Although vaccination for feline leukemia Some vaccine components, such as low or no maternal antibodies at 6 weeks virus (FeLV) is considered noncore preservatives, adjuvants, or pH, can contribute to local inflammation.2 Chronic inflammation has been POSTINJECTION LUMPS: THE 3-2-1 RULE implicated as a potential factor in the Most postvaccination lumps development of vaccine-associated usually resolve within a few weeks. sarcomas (VAS).7 Although the precise However, lumps that persist for more cause of VAS is not known, the AAFP than 3 months after the injection, Feline Vaccine Advisory Panel suggests are larger than 2 cm in diameter, using less inflammatory products or continue to increase in size 1 month after injection should be whenever possible.5 investigated.5 In these cases, a Most products today are killed, biopsy and chest radiographs can modified-live virus (MLV), or recombinant help determine the diagnosis and canarypox-vectored vaccines. Killed virus prognosis. Cats with vaccine-associated vaccines generally require an adjuvant to sarcomas require aggressive treatment, bolster the immune response. Most MLV and, if possible, injectable vaccines and recombinant feline vaccines, on the should be discontinued in the future other hand, are capable of stimulating in these cats.5 an effective immune response without Sponsored by an educational grant from Merial © 2009 Merial Limited, Duluth, GA. All rights reserved. ® VET JET is a registered trademark of Merial.

Primary Kitten Vaccine Series5 Vaccine Initial Dosea Booster Intervals Considerations Core Vaccines Feline panleukopenia As early as 6 weeks of age Every 3 to 4 weeks virus (FPV) Feline herpesvirus-1 As early as 6 weeks of age Every 3 to 4 weeks (FHV-1) Feline calicivirus As early as 6 weeks of age Every 3 to 4 weeks (FCV) Rabies As early as 8 weeks of age Single dose in the first year; or 12 to 16 weeks of age follow state or local statutes Recommended Vaccine Feline leukemia virus As early as 8 weeks One booster 3 to 4 Kittens should test negative (FeLV) of age weeks later for FeLV before vaccination aDepends on the vaccine. adjuvants. The canarypox-vectored a few weeks. However, a lump that 2006, pp. 1069–1119. recombinant vaccines, for example, persists or grows can be a sign of VAS. 3. Dawson S, Willoughby K, Gaskell R, et al: A field trial to assess the effect of vaccination stimulate protective immunity and Although the risk of VAS is relatively against feline herpesvirus, feline calicivirus and reduce the potential risks associated low (approximately one to two cases per feline panleukopenia virus in 6-week-old kittens. J Feline Med Surg 3:17–21, 2001. with an adjuvant. 10,000 vaccinated cats 8,9), the probability 4. Reese MJ, Patterson EV, Tucker SJ, et al: The Another way to potentially reduce that a kitten will be exposed to a effect of anesthesia and surgery on serological responses to vaccination in kittens. JAVMA inflammation at the injection site is with potentially fatal disease is considerably 233(1):116–121, 2008. the needle-free VET JET® transdermal higher.10 5. AAFP Advisory Panel: The 2006 American delivery system. Compared with Still, vaccines are important, even for Association of Feline Practitioners Feline Vaccine Advisory Panel Report. JAVMA conventional needles and syringes, this indoor kittens. “It’s possible for owners 9(1):1405–1441, 2006. system disperses a smaller volume of to track the panleukopenia virus into the 6. Hoover EA, Olsen RG, Hardy WD Jr, et al: Feline leukemia virus infection: Age-related variation in vaccine (0.25 ml) into the tissue through house,” according to Dr. Wolf, “and response of cats to experimental infection. J Natl a tiny orifice (about the diameter of a 36- while less likely, owners can bring Cancer Inst 57:365–369, 1976. gauge needle). respiratory viruses home on their 7. Macy DW, Hendrick MJ: The potential role of inflammation in the development of postvacci- clothing.”11 Kittens may also be exposed nal sarcomas in cats. Vet Clin North Am 26(1): Discussing Vaccine Issues to sick cats through porch screens or 103–108, 1996. with Clients when boarded, groomed, or traveling 8. Kass PH, Barnes WG Jr, Spangler WL, et al: Epidemiologic evidence for a causal relation Owners should be instructed to monitor with their owners. “Certainly, all kittens between fibrosarcoma and tumorgenesis in their kittens for signs of possible vaccine need to receive their core vaccines,” says cats. JAVMA 203:396–405, 1993. 9. Esplin DG, McGill LD, Meininger AC, et al: reactions. “The most common reaction Dr. Wolf. Postvaccination sarcomas in cats. JAVMA is a mild malaise or fever that may last 202:1245–1247, 1993. for 24 hours,” explains Dr. Wolf. “That’s REFERENCES 10. Tizard IR: The uses of vaccines, in Veterinary 1. Richards J, Rodan I: Feline vaccination guide- Immunology: An Introduction, St. Louis, Saun- simply the immune system responding lines. Vet Clin North Am Small Anim Pract ders Elsevier, 2009, pp. 270−285. to the vaccine.” (31)3:455−472, 2001. 11. Gaskell RM, Dawson S, Radford A: Feline respira- 2. Greene CE, Schultz RD: Immunophylaxis, in tory disease, in Greene CE (ed): Infectious Dis- Mild swelling at the vaccine site may Greene CE (ed): Infectious Diseases of the Dog eases of the Dog and Cat, ed. 3. St. Louis, also occur and generally resolves within and Cat, ed. 3. St. Louis, Saunders Elsevier, Saunders Elsevier, 2006, pp. 145−154. This information has not been peer reviewed and does not necessarily reflect the opinions of, nor constitute or imply endorsement or recommendation by, the Publisher or Editorial Board. The Publisher is not responsible for any data, opinions, or statements provided herein. VAC08PBKITTENVACQCR

FREE CE Immunosuppressive Therapy for Canine IMHA 56. Ryffel B. Experimental toxicological studies with cyclosporine A. anaemia and auto-immune thrombocytopenia purpura. Br J Hae- In: White CE, White DJG, eds. Cyclosporin A. Amsterdam: Elsevier matol 2002;117:712-715. Biomedical Press; 2003:45-75. 64. Mehling A, Grabbe S, Voskort M, et al. Mycophenolate mofetil 57. Blackwood L, German AJ, Stell AJ, O’Neil T. Multicentric lymphoma in impairs the maturation and function of murine dendritic cells. J Im- a dog after cyclosporine therapy. J Small Anim Pract 2004;45:259-262. munol 2000;165:2374-3281. 58. Callan MB, Preziosi D, Mauldin E. Multiple papillomavirus-as- 65. Gregory CR, Stewart A, Sturges B, et al. Leflunomide effective- sociated epidermal hamartomas and squamous cell carcinoma in ly treats naturally occurring immune-mediated and inflammatory situ in a dog following chronic treatment with prednisone and cy- diseases of the dog that are unresponsive to conventional therapy. closporine. Vet Derm 2005;16:338-345. Transplant Proc 1998;30:4143-4148. 59. Kuiper RAJ, Malingre MM, Beijnen JH, et al. Cyclosporine-in- 66. Cohen S, Cannon GW, Schiff M, et al. Two-year, blinded, ran- duced anaphylaxis. Ann Pharmacother 2000;34:858-861. domized, controlled trial of treatment of active rheumatoid arthri- 60. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive tis with leflunomide compared with methotrexate. Arthritis Rheum drugs: a review. J Am Soc Nephrol 1999;10:1366-1380. 2001;44:1984-1992. 61. Platz KP, Sollinger HW, Hullett DA, et al. RS-61443—a new, po- 67. Gregory CR, Silva HT, Patz JD, Morris RE. Comparative effects tent immunosuppressive agent. Transplantation 1991;51:27-31. of malononitriloamide analogs of leflunomide on whole blood lym- 62. Dewey CW, Boothe DM, Rinn KL, et al. Treatment of a myasthenic dog phocyte stimulation in humans, rhesus macaques, cats, dogs, and with mycophenolate mofetil. J Vet Emerg Crit Care 2000;10:177-187. rats. Transplantation Proc 1998;30:1047-1048. 63. Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycopheno- 68. Yokota S. Mizoribine: mode of action and effects in clinical use. late mofetil for the treatment of refractory autoimmune haemolytic Pediatr Intl 2002;44:196-198. 3 CE CREDITS CE TEST 3 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. Which statement regarding dogs with of cyclophosphamide. b. increased risk of infection IMHA is correct? c. Secondary malignancies have been c. bone marrow suppression a. Most dogs die during the maintenance reported in dogs receiving cyclosporine. d. increased risk of thromboembolic phase of disease management. d. Cyclosporine is a potent cytotoxic disease b. All dogs can be successfully weaned off immunosuppressive drug. immunosuppressive therapy. 8. Which patient is the most suitable candi- c. Dogs that survive the first 2 weeks of 4. Which statement regarding the mecha- date for hIVIG treatment? the disease generally have a good long- nism of action of immunosuppressive a. a dog with a 3-day history of mild weak- term prognosis. agents is incorrect? ness, a PCV of 26%, total bilirubin of 1.5 d. To avoid relapses, dogs should never a. Azathioprine is a competitive purine mg/dL, and 2+ spherocytes be weaned off immunosuppressive antagonist. b. a dog experiencing an IMHA relapse medications. b. Mizoribine blocks the purine biosyn- with PCV of 24% and a history of thetic pathway. receiving an hIVIG dose 1 month earlier 2. Which statement regarding glucocorti- c. Leflunomide blocks the biosynthesis of c. a dog that has been hospitalized for coid therapy for treating IMHA is correct? pyrimidine. IMHA for 3 days and received pred- a. Prednisone at 2 mg/kg bid is a good d. Cyclosporine works by blocking the nisone 2 mg/kg bid and three blood dose for large- and giant-breed dogs, biosynthesis of pyrimidine. transfusions whereas small-breed dogs should not d. a dog presenting with acute IMHA, a receive more than 1.2 mg/kg bid. 5. Which is not a reported side effect of PCV of 20%, and a history of conges- b. It has been proven that dexamethasone cyclosporine therapy in dogs? tive heart failure is superior to prednisone for inducing a. GI disturbances remission. b. infection 9. Which immunosuppressive therapy c. Dexamethasone is not appropriate for c. development of secondary neoplasia is unlikely to be effective in the first 2 alternate-day therapy. d. aplastic anemia weeks of treating IMHA? d. Prednisone at doses higher than 2 a. glucocorticoids c. azathioprine mg/kg bid is associated with better 6. Which is not a side effect of azathioprine b. splenectomy d. hIVIG outcomes. therapy in dogs? a. pancreatitis 10. In dogs with IMHA, administration of 3. Which statement regarding immunosup- b. bone marrow toxicity which immunosuppressive drug has pressive agents used to treat canine c. gingival hyperplasia been associated with a worse outcome IMHA is correct? d. GI disturbances in retrospective studies? a. Azathioprine is a good drug to induce a. cyclosporine remission, but it can cause bone mar- 7. Which is not a side effect of b. leflunomide row suppression. glucocorticoids? c. cyclophosphamide b. Hepatotoxicity is a common side effect a. GI ulceration and perforation d. mycophenolate mofetil 44 Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

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Save thousands on high- quality name-brand equipment, including your ideal job! ance, vacation, sick time, CE, license fees, uniform al- lowance, etc.). Interested candidates can email their Shor-Line, Abaxis, InnoVet, and more. Please call 305-205-6959 for resumes to aecwh.aecwh@hotoffice.net or fax to details and full equipment list. 832-593-8388. CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians® 45

CLASSIFIED ADVERTISING Do you want to place an ad? VetClassiﬁeds.com Download our complete classified advertising rate card and order form at www.VetClassifieds.com/pdf No Internet Access? Call 800-920-1695, or fax your request to 201-231-6373. Index to Advertisers Abbott Animal Health SevoFlo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3, 4 Eli Lilly and Company Comfortis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46, Back cover Hill’s Pet Nutrition Prescription Diet t/d Canine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Inside front cover (Canada only) Merial Quick Course: Kitten Vaccinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42–43 Nestlé Purina PetCare EN Gastroenteric Canine Dry Formula . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12–13 Northgate Veterinary Supply Glass cage doors and rod gates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 ProLabs LTCI: Lymphocyte T-Cell Immunomodulator . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Inside front cover (US only) Vetstreet Pet Portal Service. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Inside back cover 46 CompendiumVet.com

DIET HISTORY FORM Date: _______________________________________________ Stamp clinic information below: Case Number: ________________________________________ Owner Information Name: _______________________________________________ Email address: ________________________________________ Phone (home): ________________________________________ Phone (cell):__________________________________________ Best time to call:_______________________________________ Pet Information Is food left out for your pet during the day? ❏ Yes ❏ No Name: __________________________________ Age: ________ Does your pet have access to other, unmonitored food sources Species: _____________________ Breed: ___________________ Gender: ❏ Male ❏ Female Neutered/spayed: ❏ Yes ❏ No (e.g., treats fed by neighbor, food left for outdoor cats)? Current weight: _____________ Usual weight: _____________ ❏ Yes ❏ No Body condition score (1–9): _____ If yes, please describe:________________________________ Evidence of muscle wasting ❏ None ❏ Mild ❏ Severe ____________________________________________________ ____________________________________________________ Reason for Visit ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ If you have more than one pet, do they have access to each other’s ____________________________________________________ food? ❏ Yes ❏ No If yes, please describe: ____________________________________________________ Household Demographics ____________________________________________________ How many adults are in your household? ___________________ ____________________________________________________ How many children are in your household, and how old are they? ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ How do you store your pet’s food? ________________________ Where is your pet housed? ❏ Indoors ❏ Outdoors ❏ Both Do you have other pets? ❏ Yes ❏ No If so, please list species ____________________________________________________ and specify if they live indoors or outdoors. ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Activity ____________________________________________________ How active is your pet? ____________________________________________________ ❏ Hyperactive ❏ Very active ❏ Average ____________________________________________________ ❏ Not very active ❏ Hardly moves Feeding Management How often is your pet walked? Who typically feeds your pet? ____________________________ ❏ At least 3 times/day ❏ 1-2 times/day ❏ Once a day ____________________________________________________ ❏ Seldom ❏ Never ____________________________________________________ Do you have access to a yard? ❏ Yes ❏ No When is your pet fed? __________________________________ Is it difﬁcult to exercise your pet? ❏ Yes ❏ No ____________________________________________________ Can exercise be increased? ❏ Yes ❏ No ____________________________________________________ Has your pet participated in training? ❏ Yes ❏ No ____________________________________________________ Has your pet participated in competition? ❏ Yes ❏ No ©2009 Veterinary Learning Systems

DIET HISTORY FORM Behavior Table foods or scraps; home-prepared foods How does your pet act toward food? ____________________________________________________ ❏ Greedy ❏ Indifferent ❏ Shows avoidance ____________________________________________________ Has your pet’s attitude toward food changed? If so, describe: ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Dietary supplements; food used to give pills ____________________________________________________ ____________________________________________________ If you have other pets, is this pet dominant or submissive to them? ____________________________________________________ ❏ Dominant ❏ Submissive ____________________________________________________ Has your pet recently lost or gained weight? If so, please describe: ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ List anything else given by mouth (e.g., medications): ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Have there been any recent changes in activity level? __________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Have you observed any of the following: Is your pet’s current diet a change from its typical diet? Nausea/salivation ❏ Yes ❏ No ❏ Yes ❏ No Difﬁculty chewing ❏ Yes ❏ No If so, please describe the change and why the diet was changed. Difﬁculty swallowing ❏ Yes ❏ No ____________________________________________________ Vomiting ❏ Yes ❏ No ____________________________________________________ Diarrhea ❏ Yes ❏ No ____________________________________________________ Constipation ❏ Yes ❏ No ____________________________________________________ Have there been any changes in urination? ❏ Yes ❏ No ____________________________________________________ ____________________________________________________ Diet Are you open to making a change in your pet’s diet? For each of the following categories, list the brand names (if appli- cable) and amounts of all foods your pet eats daily, as well as how ❏ Yes ❏ No often each food is fed (e.g., twice a day). What are your pet’s food preferences?______________________ Commercial foods ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ What foods does your pet refuse? _________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Commercial treats; dental hygiene products ____________________________________________________ ____________________________________________________ Are there foods to which your pet is allergic? ❏ Yes ❏ No ____________________________________________________ If so, which foods? ____________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ©2009 Veterinary Learning Systems

Raising the level of care “AAHA is continually looking for ways to help member practices run better. AAHA endorses Vetstreet because it offers clinics an important client outreach tool. The Vetstreet Pet Portal® service allows us to better connect with and educate our clients, increase compliance and, most importantly, raise the level of health care for our patients. ” Anna Worth, DVM 2008-2009 AAHA President West Mountain Veterinary Hospital Shaftsbury, VT Recommended by Easy to set up and easy to use, Vetstreet™ is a powerful practice communication and management tool that keeps you in touch with your clients via Pet Portals. To discover how Vetstreet can help you increase client satisfaction, build compliance, and enhance your bottom line, visit Vetstreet.com, call toll-free 888-799-8387 or email info@vetstreet.com. , Visit us at NAVC/Booth #927and WVC/Booth #1951 Vetstreet is a trademark of VetInsite.com, Inc. Pet Portal is a registered trademark of VetInsite.com, Inc.

Month-long ﬂea protection in a chewable tablet Fast-acting Convenient Family-friendly Doesn’t wash off • Starts killing ﬂeas in 30 minutes • 100% effective within 4 hours in a controlled laboratory study • Approved by the FDA and available by prescription only To learn more about Comfortis®, see your Lilly representative or distributor representative, call 1 (888) LillyPet or visit www.comfortis4dogs.com The most common adverse reaction recorded during clinical trials was vomiting. Other adverse reactions were decreased appetite, lethargy or decreased activity, diarrhea, cough, increased thirst, vocalization, increased appetite, redness of the skin, hyperactivity and excessive salivation. For product label, including important safety information, see page 46. ©2009 Eli Lilly and Company CF00305 010109

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