Compendium | January 2009 by davidpsu

VOLUME 31 NUMBER 1 JANUARY 2009

Compendium CompendiumVet.com | Peer Reviewed | Listed in MEDLINE

9 CE Contact Hours

CONTI N U I NG EDUCATION FOR VETERI NARIANS ®

Refereed Peer Review

Fever of Unknown Origin

Diagnostic Approaches NEW W

Focus on Nutrition

PAGES 1–48

IImproving i Adherence Ad to Recommendations Understanding Behavior: Patient Assessment

FO New CU Nu S trit O ion Se N Co e Pa NU lu ge T m 22 R IT n! IO N

COMPENDIUM CONTINUING EDUCATION FOR VETERINARIANS®

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Vol 31(1) January 2009

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TREATMENT EA ATTMENT AI AID D FOR F OR FeLV eLLV / FIV FI FV INFECTIONS FECTION NS LTCI

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Approved Treatment Aid for: f or : FeLV and/or FIV infections ections ti

Including Associated Symptoms of: Oppor tunistic infection ction Lymphopenia Anemia Granulocytopenia Thrombocytopenia

www.ProLabsAnimalhealth.com. 800-367-6359 LTCI has received a conditional license by the USDA; additional potency and efficacy studies are in progress. LTCI is manufactured by T-Cyte Therapeutics, Inc. and distributed by IMULAN BioTherapeutics and ProLabs Animal Health

January 2009 Vol 31(1) CompendiumVet.com | Peer Reviewed | Listed in MEDLINE

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January 2009 Vol 31(1) CompendiumVet.com | Peer Reviewed | Listed in MEDLINE

EDITORIAL BOARD Anesthesia Nora S. Matthews, DVM, DACVA Texas A&M University

Internal Medicine Dana G. Allen, DVM, MSc, DACVIM Ontario Veterinary College

Cardiology Bruce Keene, DVM, MSc, DACVIM North Carolina State University

Internal Medicine and Emergency/ Critical Care Alison R. Gaynor, DVM, DACVIM (Internal Medicine), DACVECC North Grafton, Massachusetts

Clinical Chemistry, Hematology, and Urinalysis Betsy Welles, DVM, PhD, DACVP Auburn University

EDITOR IN CHIEF Douglass K. Macintire, DVM, MS, DACVIM, DACVECC

Department of Clinical Sciences College of Veterinary Medicine Auburn University, AL 36849

Dentistry Gary B. Beard, DVM, DAVDC Auburn University R. Michael Peak, DVM, DAVDC The Pet Dentist—Tampa Bay Veterinary Dentistry Largo, Florida Emergency/Critical Care and Respiratory Medicine Lesley King, MVB, MRCVS, DACVECC, DACVIM University of Pennsylvania Endocrinology and Metabolic Disorders Marie E. Kerl, DVM, ACVIM, ACVECC University of Missouri-Columbia

EXECUTIVE ADVISORY BOARD MEMBERS Behavior Sharon L. Crowell-Davis, DVM, PhD, DACVB The University of Georgia Dermatology Craig E. Grifﬁn, DVM, DACVD Animal Dermatology Clinic San Diego, California Wayne S. Rosenkrantz, DVM, DACVD Animal Dermatology Clinic Tustin, California Nutrition Kathryn E. Michel, DVM, MS, DACVN University of Pennsylvania Surgery Elizabeth M. Hardie, DVM, PhD, DACVS North Carolina State University

CompendiumVet.com

Epidemiology Philip H. Kass, DVM, MPVM, MS, PhD, DACVPM University of California, Davis Exotics Avian Thomas N. Tully, Jr, DVM, MS, DABVP (Avian), ECAMS Louisiana State University Reptiles Douglas R. Mader, MS, DVM, DABVP (DC) Marathon Veterinary Hospital Marathon, Florida Small Mammals Karen Rosenthal, DVM, MS, DABVP (Avian) University of Pennsylvania Feline Medicine Michael R. Lappin, DVM, PhD, DACVIM (Internal Medicine) Colorado State University Margie Scherk, DVM, DAVBP (Feline Medicine) Cats Only Veterinary Clinic Vancouver, British Columbia Gastroenterology Debra L. Zoran, DVM, MS, PhD, DACVIM (Internal Medicine) Texas A&M University Infectious Disease Derek P. Burney, PhD, DVM Gulf Coast Veterinary Specialists Houston, Texas

Nephrology Catherine E. Langston, DVM, ACVIM Animal Medical Center New York, New York Neurology Curtis W. Dewey, DVM, MS, DACVIM (Neurology), DACVS Cornell University Hospital for Animals Oncology Ann E. Hohenhaus, DVM, DACVIM (Oncology and Internal Medicine) Animal Medical Center New York, New York Gregory K. Ogilvie, DVM, DACVIM (Internal Medicine and Oncology) CVS Angel Care Cancer Center and Special Care Foundation for Companion Animals San Marcos, California Ophthalmology David A. Wilkie, DVM, MS, DACVO The Ohio State University Parasitology Byron L. Blagburn, MS, PhD Auburn University David S. Lindsay, PhD Virginia Polytechnic Institute and State University Pharmacology Katrina L. Mealey, DVM, PhD, DACVIM, DACVCP Washington State University

AMERICAN BOARD OF VETERINARY PRACTITIONERS (ABVP) REVIEW BOARD Eric Chafetz, DVM, DABVP (Canine/Feline) Vienna Animal Hospital Vienna, Virginia Canine and Feline Medicine Henry E. Childers, DVM, DABVP (Canine/Feline) Cranston Animal Hospital Cranston, Rhode Island Canine and Feline Medicine David E. Harling, DVM, DABVP (Canine/Feline), DACVO Reidsville Veterinary Hospital Reidsville, North Carolina Canine and Feline Medicine, Ophthalmology Jeffrey Katuna, DVM, DABVP Wellesley-Natick Veterinary Hospital Natick, Massachusetts Canine and Feline Medicine Robert J. Neunzig, DVM, DABVP (Canine/Feline) The Pet Hospital Bessemer City, North Carolina Canine and Feline Medicine

Rehabilitation and Physical Therapy Darryl Millis, MS, DVM, DACVS University of Tennessee Surgery Philipp Mayhew, BVM&S, MRCVS, DACVS Columbia River Veterinary Specialists Vancouver, Washington C. Thomas Nelson, DVM Animal Medical Center Anniston, Alabama

Compendium is a refereed journal. Articles published herein have been reviewed by at least two academic experts on the respective topic and by an ABVP practitioner.

Surgery and Orthopedics Ron Montgomery, DVM, MS, DACVS Auburn University Toxicology Tina Wismer, DVM, DABVT, DABT ASPCA National Animal Poison Control Center Urbana, Illinois

Any statements, claims, or product endorsements made in Compendium are solely the opinions of our authors and advertisers and do not necessarily reﬂect the views of the Publisher or Editorial Board.

Service... SevoFlo® (sevoflurane) anesthesia—with expert service, support and training—is smart, efficient and profitable for your practice. Only SevoFlo— available through all major distributors —provides four unique benefits: 1. A minimum of 300 ppm water 2. Shatter-resistant PEN bottles 3. Local Abbott representatives and expert advice 4. Commitment to training and education

You’re probably familiar with SevoFlo. But, do you realize how Abbott Animal Health’s exceptional service and product support helps you, your patients and your practice? SevoFlo and Abbott Animal Health can help your surgical suite run efficiently and profitably. Our team of local representatives provides support and advice. In addition, our technical support department and panel of anesthesiologists are standing by to discuss techniques and equipment. Abbott Animal Health also helps educate you and your staff by providing “lunch-and-learns,” in-clinic training materials and CE sponsorships—we’re committed to the veterinary community. To learn more about SevoFlo, our other anesthetics and our commitment to serving you, contact Abbott Animal Health Customer Service at 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

SevoFlo®

5458

(sevoflurane) Inhalation Anesthetic For Use in Dogs Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian. DESCRIPTION: SevoFlo (sevoflurane), a volatile liquid, is a halogenated general inhalation anesthetic drug. Its chemical name is fluoromethyl 2,2,2trifluoro-l- (trifluoromethyl) ethyl ether, and its structural formula is:

Sevoflurane Physical Constants are: Molecular weight 200.05 Boiling point at 760 mm Hg 58.6°C Specific gravity at 20°C 1.520-1.525 g/mL Vapor pressure in mm Hg at 20°C 157 at 25°C 197 at 36°C 317 Distribution Partition Coefficients at 37°C: Blood/Gas 0.63-0.69 Water/Gas 0.36 Olive Oil/Gas 47-54 Brain/Gas 1.15 Mean Component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications: Conductive rubber 14.0 Butyl rubber 7.7 Polyvinyl chloride 17.4 Polyethylene 1.3 Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13. Sevoflurane is a clear, colorless, stable liquid containing no additives or chemical stabilizers. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform and petroleum benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting condition according to instructions. INDICATIONS: SevoFlo is indicated for induction and maintenance of general anesthesia in dogs. DOSAGE AND ADMINISTRATION: Inspired Concentration: The delivered concentration of SevoFlo should be known. Since the depth of anesthesia may be altered easily and rapidly, only vaporizers producing predictable percentage concentrations of sevoflurane should be used. Sevoflurane should be vaporized using a precision vaporizer specifically calibrated for sevoflurane. Sevoflurane contains no stabilizer. Nothing in the drug product alters calibration or operation of these vaporizers. The administration of general anesthesia must be individualized based on the patient’s response. WHEN USING SEVOFLURANE, PATIENTS SHOULD BE CONTINUOUSLY MONITORED AND FACILITIES FOR MAINTENANCE OF PATENT AIRWAY, ARTIFICIAL VENTILATION, AND OXYGEN SUPPLEMENTATION MUST BE IMMEDIATELY AVAILABLE. Replacement of Desiccated CO2 Absorbents: When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced. An exothermic reaction occurs when sevoflurane is exposed to CO2 absorbents. This reaction is increased when the CO2 absorbent becomes desiccated (see PRECAUTIONS). Premedication: No specific premedication is either indicated or contraindicated with sevoflurane. The necessity for and choice of premedication is left to the discretion of the veterinarian. Preanesthetic doses for premedicants may be lower than the label directions for their use as a single medication.1 Induction: For mask induction using sevoflurane alone, inspired concentrations up to 7% sevoflurane with oxygen are employed to induce surgical anesthesia in the healthy dog. These concentrations can be expected to produce surgical anesthesia in 3 to 14 minutes. Due to the rapid and dose dependent changes in anesthetic depth, care should be taken to prevent overdosing. Respiration must be monitored closely in the dog and supported when necessary with supplemental oxygen and/or assisted ventilation. Maintenance: SevoFlo may be used for maintenance anesthesia following mask induction using sevoflurane or following injectable induction agents. The concentration of vapor necessary to maintain anesthesia is much less than that required to induce it. Surgical levels of anesthesia in the healthy dog may be maintained with inhaled concentrations of 3.7-4.0% sevoflurane in oxygen in the absence of premedication and 3.3-3.6% in the presence of premedication. The use of injectable induction agents without premedication has little effect on the concentrations of sevoflurane required for maintenance. Anesthetic regimens that include opioid, alpha2-agonist, benzodiazepine or phenothiazine premedication will allow the use of lower sevoflurane maintenance concentrations. CONTRAINDICATIONS: SevoFlo is contraindicated in dogs with a known sensitivity to sevoflurane or other halogenated agents. WARNINGS: Sevoflurane is a profound respiratory depressant. DUE TO THE RAPID AND DOSE DEPENDENT CHANGES IN ANESTHETIC DEPTH, RESPIRATION MUST BE MONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITH SUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION. In cases of severe cardiopulmonary depression, discontinue drug administration, ensure the existence of a patent airway and initiate assisted or controlled ventilation with pure oxygen. Cardiovascular depression should be treated with plasma expanders, pressor agents, antiarrhythmic agents or other techniques as appropriate for the observed abnormality. Due to sevoflurane’s low solubility in blood, increasing the concentration may result in rapid changes in anesthetic depth and hemodynamic changes (dose dependent decreases in respiratory rate and blood pressure) compared to other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be corrected by decreasing or discontinuing the inspired concentration of sevoflurane. Potassium hydroxide containing CO2 absorbents (e.g. BARALYME®) are not recommended for use with sevoflurane. ADVERSE REACTIONS: The most frequently reported adverse reactions during maintenance anesthesia were hypotension, followed by tachypnea, muscle tenseness, excitation, apnea, muscle fasciculations and emesis. Infrequent adverse reactions include paddling, retching, salivation, cyanosis, premature ventricular contractions and excessive cardiopulmonary depression. Transient elevations in liver function tests and white blood cell count may occur with sevoflurane, as with the use of other halogenated anesthetic agents.

PRECAUTIONS: Halogenated volatile anesthetics can react with desiccated carbon dioxide (CO2) absorbents to produce carbon monoxide (CO) that may result in elevated carboxyhemoglobin levels in some patients. To prevent this reaction, sevoflurane should not be passed through desiccated soda lime or barium hydroxide lime. Replacement of Desiccated CO2 Absorbents: When a clinician suspects that the CO2 absorbent may be desiccated, it should be replaced before administration of sevoflurane. The exothermic reaction that occurs with sevoflurane and CO2 absorbents is increased when the CO2 absorbent becomes desiccated, such as after an extended period of dry gas flow through the CO2 absorbent canisters. Extremely rare cases of spontaneous fire in the respiratory circuit of the anesthesia machine have been reported during sevoflurane use in conjunction with the use of a desiccated CO2 absorbent, specifically those containing potassium hydroxide (e.g. BARALYME). Potassium hydroxide containing CO2 absorbents are not recommended for use with sevoflurane. An unusually delayed rise in the inspired gas concentration (decreased delivery) of sevoflurane compared with the vaporizer setting may indicate excessive heating of the CO2 absorbent canister and chemical breakdown of sevoflurane. The color indicator of most CO2 absorbent may not change upon desiccation. Therefore, the lack of significant color change should not be taken as an assurance of adequate hydration. CO2 absorbents should be replaced routinely regardless of the state of the color indicator. The use of some anesthetic regimens that include sevoflurane may result in bradycardia that is reversible with anticholinergics. Studies using sevoflurane anesthetic regimens that included atropine or glycopyrrolate as premedicants showed these anticholinergics to be compatible with sevoflurane in dogs. During the induction and maintenance of anesthesia, increasing the concentration of sevoflurane produces dose dependent decreases in blood pressure and respiratory rate. Due to sevoflurane’s low solubility in blood, these changes may occur more rapidly than with other volatile anesthetics. Excessive decreases in blood pressure or respiratory depression may be related to depth of anesthesia and may be corrected by decreasing the inspired concentration of sevoflurane. RESPIRATION MUST BE MONITORED CLOSELY IN THE DOG AND SUPPORTED WHEN NECESSARY WITH SUPPLEMENTAL OXYGEN AND/OR ASSISTED VENTILATION. The low solubility of sevoflurane also facilitates rapid elimination by the lungs. The use of sevoflurane in humans increases both the intensity and duration of neuromuscular blockade induced by nondepolarizing muscle relaxants. The use of sevoflurane with nondepolarizing muscle relaxants has not been evaluated in dogs. Compromised or debilitated dogs: Doses may need adjustment for geriatric or debilitated dogs. Because clinical experience in administering sevoflurane to dogs with renal, hepatic and cardiovascular insufficiency is limited, its safety in these dogs has not been established. Breeding dogs: The safety of sevoflurane in dogs used for breeding purposes, during pregnancy, or in lactating bitches, has not been evaluated. Neonates: The safety of sevoflurane in young dogs (less than 12 weeks of age) has not been evaluated. HUMAN SAFETY: Not for human use. Keep out of reach of children. Operating rooms and animal recovery areas should be provided with adequate ventilation to prevent the accumulation of anesthetic vapors. There is no specific work exposure limit established for sevoflurane. However, the National Institute for Occupational Safety and Health has recommended an 8 hour time-weighted average limit of 2 ppm for halogenated anesthetic agents in general. Direct exposure to eyes may result in mild irritation. If eye exposure occurs, flush with plenty of water for 15 minutes. Seek medical attention if irritation persists. Symptoms of human overexposure (inhalation) to sevoflurane vapors include respiratory depression, hypotension, bradycardia, shivering, nausea and headache. If these symptoms occur, remove the individual from the source of exposure and seek medical attention. The material safety data sheet (MSDS) contains more detailed occupational safety information. For customer service, adverse effects reporting, and/or a copy of the MSDS, call (888) 299-7416. CLINICAL PHARMACOLOGY: Sevoflurane is an inhalational anesthetic agent for induction and maintenance of general anesthesia. The Minimum Alveolar Concentration (MAC) of sevoflurane as determined in 18 dogs is 2.36%.2 MAC is defined as that alveolar concentration at which 50% of healthy patients fail to respond to noxious stimuli. Multiples of MAC are used as a guide for surgical levels of anesthesia, which are typically 1.3 to 1.5 times the MAC value. Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient at 37°C = 0.63-0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. During sevoflurane induction, there is a rapid increase in alveolar concentration toward the inspired concentration. Sevoflurane produces only modest increases in cerebral blood flow and metabolic rate, and has little or no ability to potentiate seizures.3 Sevoflurane has a variable effect on heart rate, producing increases or decreases depending on experimental conditions.4,5 Sevoflurane produces dose-dependent decreases in mean arterial pressure, cardiac output and myocardial contraction.6 Among inhalation anesthetics, sevoflurane has low arrhythmogenic potential.7 Sevoflurane is chemically stable. No discernible degradation occurs in the presence of strong acids or heat. Sevoflurane reacts through direct contact with CO2 absorbents (soda lime and barium hydroxide lime) producing pentafluoroisopropenyl fluoromethyl ether (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether (PMFE, C5H6F6O), also known as Compound B. Compound A: The production of degradants in the anesthesia circuit results from the extraction of the acidic proton in the presence of a strong base (potassium hydroxide and/or NaOH) forming an alkene (Compound A) from sevoflurane. Compound A is produced when sevoflurane interacts with soda lime or barium hydroxide lime. Reaction with barium hydroxide lime results in a greater production of Compound A than does reaction with soda lime. Its concentration in a circle absorber system increases with increasing sevoflurane concentrations and with decreasing fresh gas flow rates. Sevoflurane degradation in soda lime has been shown to increase with temperature. Since the reaction of carbon dioxide with absorbents is exothermic, this temperature increase will be determined by the quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthetic circle system, metabolic status of the patient and ventilation. Although Compound A is a dose-dependent nephrotoxin in rats, the mechanism of this renal toxicity is unknown. Two spontaneously breathing dogs under sevoflurane anesthesia showed increases in concentrations of Compound A as the oxygen flow rate was

SEVO-152 January 2007

page 1 of 1

decreased at hourly intervals, from 500 mL/min (36 and 18 ppm Compound A) to 250 mL/min (43 and 31 ppm) to 50 mL/min (61 and 48 ppm).8 Fluoride ion metabolite: Sevoflurane is metabolized to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Fluoride ion concentrations are influenced by the duration of anesthesia and the concentration of sevoflurane. Once formed, HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In humans, the fluoride ion half-life was prolonged in patients with renal impairment, but human clinical trials contained no reports of toxicity associated with elevated fluoride ion levels. In a study in which 4 dogs were exposed to 4% sevoflurane for 3 hours, maximum serum fluoride concentrations of 17.0-27.0 mcmole/L were observed after 3 hours of anesthesia. Serum fluoride fell quickly after anesthesia ended, and had returned to baseline by 24 hours post-anesthesia. In a safety study, eight healthy dogs were exposed to sevoflurane for 3 hours/day, 5 days/week for 2 weeks (total 30 hours exposure) at a flow rate of 500 mL/min in a semi-closed, rebreathing system with soda lime. Renal toxicity was not observed in the study evaluation of clinical signs, hematology, serum chemistry, urinalysis, or gross or microscopic pathology. DRUG INTERACTIONS: In the clinical trial, sevoflurane was used safely in dogs that received frequently used veterinary products including steroids and heartworm and flea preventative products. Intravenous Anesthetics: Sevoflurane administration is compatible with barbiturates, propofol and other commonly used intravenous anesthetics. Benzodiazepines and Opioids: Benzodiazepines and opioids would be expected to decrease the MAC of sevoflurane in the same manner as other inhalational anesthetics. Sevoflurane is compatible with benzodiazepines and opioids as commonly used in surgical practice. Phenothiazines and Alpha2-Agonists: Sevoflurane is compatible with phenothiazines and alpha2- agonists as commonly used in surgical practice. In a laboratory study, the use of the acepromazine/oxymorphone/ thiopental/sevoflurane anesthetic regimen resulted in prolonged recoveries in eight (of 8) dogs compared to recoveries from sevoflurane alone. CLINICAL EFFECTIVENESS: The effectiveness of sevoflurane was investigated in a clinical study involving 196 dogs. Thirty dogs were mask-induced with sevoflurane using anesthetic regimens that included various premedicants. During the clinical study, one hundred sixty-six dogs received sevoflurane maintenance anesthesia as part of several anesthetic regimens that used injectable induction agents and various premedicants. The duration of anesthesia and the choice of anesthetic regimens were dependent upon the procedures that were performed. Duration of anesthesia ranged from 16 to 424 minutes among the individual dogs. Sevoflurane vaporizer concentrations during the first 30 minutes of maintenance anesthesia were similar among the various anesthetic regimens. The quality of maintenance anesthesia was considered good or excellent in 169 out of 196 dogs. The table shows the average vaporizer concentrations and oxygen flow rates during the first 30 minutes for all sevoflurane maintenance anesthesia regimens: Average Vaporizer Concentrations among Anesthetic Regimens

Average Vaporizer Concentrations among Individual Dogs

3.31 - 3.63%

1.6 - 5.1%

Average Oxygen Flow Rates among Anesthetic Regimens 0.97 - 1.31 L/minute

Average Oxygen Flow Rates among Individual Dogs 0.5 - 3.0 L/minute

During the clinical trial, when a barbiturate was used for induction, the times to extubation, sternal recumbency and standing recovery were longer for dogs that received anesthetic regimens containing two preanesthetics compared to regimens containing one preanesthetic. Recovery times were shorter when anesthetic regimens used sevoflurane or propofol for induction. The quality of recovery was considered good or excellent in 184 out of 196 dogs. Anesthetic regimen drug dosages, physiological responses, and the quality of induction, maintenance and recovery were comparable between 10 sighthounds and other breeds evaluated in the study. During the clinical study there was no indication of prolonged recovery times in the sighthounds. HOW SUPPLIED: SevoFlo (sevoflurane) is packaged in amber colored bottles containing 250 mL sevoflurane, List 5458. STORAGE CONDITIONS: Store at controlled room temperature 15°-30°C (59°-86°F). REFERENCES: 1. Plumb, D.C. ed., Veterinary Drug Handbook, Second Edition, University of Iowa Press, Ames, IA: p. 424 (1995). 2. Kazama, T. and Ikeda, K., Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology. 68: 435-437 (1988). 3. Scheller, M.S., Nakakimura, K., Fleischer, J.E. and Zornow, M.H., Cerebral effects of sevoflurane in the dog: Comparison with isoflurane and enflurane. Brit. J. Anesthesia 65: 388-392 (1990). 4. Frink, E.J., Morgan, S.E., Coetzee, A., Conzen, P.F. and Brown, B.R., Effects of sevoflurane, halothane, enflurane and isoflurane on hepatic blood flow and oxygenation in chronically instrumented greyhound dogs. Anesthesiology 76: 85-90 (1992). 5. Kazama, T. and Ikeda, K., The comparative cardiovascular effects of sevoflurane with halothane and isoflurane. J. Anesthesiology 2: 63-8 (1988). 6. Bernard, J. M., Wouters, P.F., Doursout, M.F., Florence, B., Chelly, J.E. and Merin, R.G., Effects of sevoflurane on cardiac and coronary dynamics in chronically instrumented dogs. Anesthesiology 72: 659-662 (1990). 7. Hayaski, Y., Sumikawa, K., Tashiro, C., Yamatodani, A. and Yoshiya, I., Arrhythmogenic threshold of epinephrine during sevoflurane, enflurane and isoflurane anesthesia in dogs. Anesthesiology 69: 145-147 (1988). 8. Muir, W.W. and Gadawski, J., Cardiorespiratory effects of low-flow and closed circuit inhalation anesthesia, using sevoflurane delivered with an in-circuit vaporizer and concentrations of compound A. Amer. J. Vet. Res. 59 (5): 603-608 (1998). NADA 141-103, Approved by FDA SevoFlo® is a registered trademark of Abbott Laboratories. Manufactured by Abbott Laboratories, North Chicago, IL 60064, USA Product of Japan Under license from Maruishi Pharmaceutical Co., LTD 2-3-5, Fushimi-Machi, Chuo-Ku, Osaka, Japan For customer service call (888) 299-7416. ©Abbott 8/2006 Taken from Commodity Number 03-5474/R6, SevoFlo, sevoflurane, package insert, January 11, 2007

EEach CE article is accredited for 3 contact hours by A Auburn University College of Veterinary Medicine.

Section Name January 2009 Vol 31(1)

Features 8

Understanding Behavior Behavior Assessment: The First Appointment ❯❯ Sharon L. Crowell-Davis Once a behavior problem has been identiﬁed and described, the circumstances in which it occurs must be clariﬁed. This is the second article in this series on behavior patient assessment.

CompendiumVet.com | Peer Reviewed | Listed in MEDLINE

An In-Depth Look FREE 14 The Diagnostic Approach to CE Fever of Unknown Origin in D Dogs ❯❯ Julie Flood FREE

Focus on Nutrition NEW Using a Diet History to Improve Adherence to Dietary Recommendations i

26 The Diagnostic Approach to CE Fever of Unknown Origin in C Cats t ❯❯ Julie Flood Fever is a common clinical sign in dogs and cats, but its cause is not always apparent. These articles present a thorough overview of physical examination ﬁndings and diagnostic tests that can help guide diagnosis of the underlying condition.

❯❯ Kathryn E. Michel The ﬁrst article in this quarterly series explains how to effectively use diet history forms and what information is most important.

Immunosuppressive Therapy for Canine ine Immune-Mediated Hemolytic Anemia FREE

CE ❯❯ Suliman Al-Ghazlat The author describes the range of current treatment options for dogs with this potentially deadly condition.

Focus on Nutrition Sample Diet History Form This form is also downloadable from CompendiumVet.com.

Departments 6

Editorial: Focus on Nutrition ❯❯ Kathryn E. Michel

CompendiumVet.com

Clinical Snapshot A Dog with “Bumps” on its Skin ❯❯ Karen A. Moriello

Clinical Snapshot PAGE 11

Letters

Product Forum

Market Showcase

On the Cover

45 46

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Starting on page 14, Dr. Julie Flood describes the diagnostic approach to fever of unknown origin in dogs and cats. Supplemental material to both articles is available at CompendiumVet.com. CompendiumVet.com

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.

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 on this subject and feel more conconcern to many pet owners and one about informed fident when entering into a dialogue on diet and dietary management with their clients which people often hold strong opinions. to ensure the best possible outcome for their In order to help practitioners meet this patients. challenge, this issue of Compendium is launching the Focus on Nutrition series in collaboration 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-ofFAX 800-556-3288 the-art information on best practices for the nutritional management of companion animals, both to maintain wellness and to treat disease.

Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

January 2009 Vol 31(1)

WEB EXCLUSIVES

FEATURES

❯❯ Supplements: The Diagnostic Approach to Fever of Unknown Origin in Dogs and Cats ❯❯ Julie Flood Diagnosing the cause of fever of unknown origin (FUO) can require a battery of tests. This supplemental material elaborates on some of the diagnostic tools that can be used or may become available for patients with FUO, the differential diagnosis, and tips on safe sedation of fractious febrile cats. CE ARTICLES

❯❯ The Renin–Angiotensin–Aldosterone System: Approaches to Cardiac and Renal Therapy ❯❯ Melanie Otte and Alan Spier The renin–angiotensin–aldosterone system (RAAS) plays a signiﬁcant role in preserving hemodynamic stability in response to the loss of blood volume, salt, and water. Manipulation of the RAAS is the mainstay of therapy for cardiac and renal diseases. ❯❯ Lead and Zinc Intoxication in Companion Birds ❯❯ Birgit Puschner and Robert H. Poppenga Although the toxicity of lead and zinc to birds is widely recognized by veterinarians

and bird owners, these metals are frequently found in the environments of pet and aviary birds, and intoxications are common. Once diagnosed, intoxication can be effectively treated by (1) preventing further exposure, (2) administering chelating drugs, and (3) providing symptomatic and supportive care.

WEB EXCLUSIVE

VIDEO

DIET HISTO

HANDOUTS

Date: __________ RY FORM __________ __________ Case Number: __________ Behavior _______ DIET HIS __________ __________ __________ TORY What is__________ Owner Information FORM your pet’s attitude toward P Greedd P Gree Name: __________ food? P Indifference __________ Table foods __________ Has your Email address: or scaps; __________ P Avoi P Avoidan pet’s __________ attitude dance _______ home-p ce ______ __________ toward ______ repared ______ Phone (home): __________ food change ______ foodss ______ __________ __________ ______ d? If so, ______ __________ ______ ______ ______ describe: ______ Phone (cell): __________ ______ ______ ______ ______ ___________ __________ __________ ______ ______ ______ ______ __________ ______ ______ ______ ______ ______ ______ __________ Best time to ______ ______ ______ ______ ____ ______ __________ call:________________ ______ _____ ____ ______ ______ ______ ______ __ ______ ______ ______ ______ ______ __________ ______ ______ ______ ______ ______ ______ __________ ______ ___ ____ ______ ____ ______ ______ ______ ______ Pet Information ______ ______ ______ ______ _ ______ ______ If you have ______ ______ ______ ______ ____ ____________ ____ other pets, ______ ______ Name: __________ _______ ______ ______ is this pet Dietary ______ P Dom ______ __________ ______ supplem domina ____ inant ____ __________ ____________ ents; food Species: __________ nt or submis ____ Age: ________ _______ P Submis P Subm ______ Has used to Is ______ food left out issive __________ your pet sive ______ to give pills ____ for your petsive _ Breed: __________ recently Gender: P Male ______ duringthem? the day? ______ ______ _________lost orDoes ______ P Female P Yes______ your pet have gained ______ ______ P No Neutered/spayed: weight? access ______ Current weight: ______ ______ to other, unmonitored ______ _________ P Yes ______ ______ (e.g., treats If so, please __________ ______ ______ food ______ ______ ___ Usual ____________ P No sources ______ fed by neighbor,describe: ____ Body condition ______ ______ weight: __________ ______ ______ food _______ score (1–9): ____________ ______ ______ ______ cats)? _______________ P Yes P No ____________ left for outdoor _ _____ ______ ______ ______ ____ ____ Evidence of muscle ______ ______ ______ ______ _______ ____________ ______ If yes, please ____________ wasting P ______ ______ __ ____ ______ ______ None P______ ______ ____ Mild ______ ______describe:____________ ______ ______ P ____________ ______ _______ ____________ __________ Have there Severe List anythin______________________ Reason for Visit __ ____ ______ ____________________ __________ been any ______ __________ g else given ______ ______ __________ recent change ______ _______ __________ ______ _____________ ______ __________ by mouth ______ ____________________ ___ ____ ______ ______ s in activity __________ (e.g., medica __ __________ ______ ______ ________________ __________ level? ______ ations): __________________________ ttions): __________ __________ ______ __________ ____________ ______ __________ ______ _________ ______ ____ __________ ______ __________ ______ ______ ________ __________ ______ __________ ______ __ __________ ______ __________ ________________ ______ ________________________ ______ __________ ______ _____ ______ __________ ______ ______ ____ __________ ____ ______ __________ ________ ______ ______ __________ __________ you have more____________ ______ __ _______ Have you __________ ______If______ ______ ______ ____________ ______ ________ ______ observe ____ ______ ______ than one pet, do Household Demograph ______ they have access d any__ ______ ______ food? P Yes ______ _________ of the followin ______ ics Nausea/salivat ______ to each other’s ______ P______ _________ ______ No If____ ______ How many adults g: yes, please describe: ______ ion ______ __________ are in your household? Difﬁcul ______ _________ ______ __________ ______ _________ ______ __________ ____________ ty chewin How many children __________ ______ __________ __________ ______ g _________ P Yes are in your household, Dyspha ______ ___ ____________ __________ ______ Is your ____________ P No __________ __________ ______ __________ and gia pet’s how _ old are they? __________ current ______ __________ __________ P Yes __________ diet a change ______ __________ __________ __________ Vomitin P No __ P Yes ______ __________ __________ __________ g _____ from its ____ __________ __________ P No __________ __________ P Yes typical __ __________ __________ P al diet? If so, please____________ Diarrhea __________ __________ __________ No __________ __________ describe __________ __________ P __ __________ __________ Yes P the__change __________ ______ Constip __________ __________ __________ No ______ ation and why __________ __________ __________ How do you P ______ the diett __ __________ Have __________ store Yes ______ ______ your pet’s was change __________ there been __ ______ Where is your P No food? __________ ______ __________ pet housed? d. ______ __________ P any change ______ __ __________ ______ ____ __________ P Yes ______ Indoors P ______ ______ s in urinatio ____ Do you have ______ P__________ ______ Outdoors No ______ ______ other pets? _____ __________ n? ______ __________ P Both ______ P Yes PDiet __________ P Yes ______ __________ __________ ______ ______ No If so, please __ ______ and specify if ______ P__________ No ______ ______ _____ __________ they live indoors list species __________ ______ For each ______ __________ __________ ______ __________ or outdoors. ______ of __________ __ ______ __________ ____________ ______ ______ cable) and the following categor __________ __________ __________ ______ _____ ______ __________ amounts __________ __________ ______ _____ ______ __________ ______ __________ often __ ______ ______________________ of all foods ies, list the brand ______ __________ each food ______ __________ __________ ______ _____ __________ ______ __ __________ your names (if ______ ___________ pet eats __________ ______ __________ is fed (e.g., twice __________ appli- Are you open __________ __ ______ Comme __________ ______ daily, as __________ __________ ______ rcial foods __________ to making a day). ____ ______ well as __ __________ __________ ______ ___________ how __________ __________ a __ change ______ P Yes ______ Activity __________ ______ in your __________________ ____ P No __________ pet’s diet? __________ ____________ __________ What are ? ______ How active is __________ your pet’s __________________ ______ __________ ______ your pet? food prefere __________ ____________ ______ ______ ______ Hyperactive __________ nces?_______ ______ __________________ ______P Feeding Manageme ______ ______ ______ ______ ___________ ______ ______ P Very active ______ ______ P Average nt ______ ______ ______ ______ ______ ______ P Not very active _____ ______ ___ Who typically ______ ____ ______ ______ P ______ Hardly ______ feeds your pet? ______ moves ______ ______ ______ ______ How often is ______ ___________ ______ ______ __________ ______ ______ ______ ____ __________ ______ ____ __________ ______ ______ your pet walked? ______ __________ ____________ ________ ______ ______ What foods ______ __________ Comme ___________ ______ ______ ______ P At least 3 times/day __________ ____ rcial treats; __________ does your ______ ____ ______ __________ __________ P 1-2 times/day ____________ pet dental hygiene ______ ______ __ __________ ______ _ ______ P Seldom P Once a day refuse? ______ ______ __________ _____ When is your ____ ______ __________ P______ products Never ____ ______ ______ pet fed? __________ ______ ______ ______ ______ __________ __ ______ Do you have ______ ______ ______ ______ __________ ______ __________ _____ ________________ ______ ______ ______ access to a yard? __________ ______ ____ ______ ______ ______ P ______ __________ Is it difﬁcult ______ ______ _______ ______ ______ ______Yes P No ______ __________ __________ to exercise ____ ______ __________ ____________ ___ ______ ______ ____pet? your __________ ______ ______ ______ __________ Are there P Yes ______ Can exercise ________ ______ _______ ______ ______ __________ ______ __________ foods to P No be increased? ____ ___ ______ __________ ____________ ______ ____ __________ ______ ______ __________ If so, which P Yes which your pet Has your____________ ________ _______ ______ ______ __________ is allergic ____ ___ ______ __________ ____________ pet participated foods? P No ____ in training? ? P ______ ______ Has your______ Yes P ______ ________ P Yes P No ____________ pet participated ______ ______ ______ No ____ in competition ______ ______ ______ ? ______ ______ ______ __________ P Yes P______ ______ ______ ______ ______ ___ ______ ____ ______ No ______ ______ ______ ______ _________ ______ ______ ____ ______ __ ______ ______ ______ ______ __________ ______ _____ ______ ______ ______ __________ _____

❯❯ Focus on Nutrition: Sample Diet History Form This downloadable form can be given to clients to gather important information about their diet.t h i pet’t’s diet di NEWS BITES

❯❯ What Makes Ticks Tick? Studies of tick salivary glands may reduce incidence of Lyme disease.

❯❯ CAPC 2008 Road Show Presentations Drs. Byron L. Blagburn and Dwight D. Bowman present current data and personal experience to demonstrate the importance of preventing parasitic infections and related disease in companion animals. ❯❯ Laparoscopic OVH and OVE

❯❯ Compendium Board Member Talks to ABC News About Feline Cancer Gregory K. Ogilvie is interviewed about a cancer diagnosis for Socks the cat. ❯❯ Winn Foundation Announces Grants for Feline Health Studies ❯❯ “Workaholic” Dolphins are Spongers ❯❯ AVMA Calls for More Veterinary Oversight of Meat Production E-NEWSLETTER ❯❯ COMPENDIUM EXTRA Our monthly e-newsletter service provides Web Exclusive articles and news, as well as a preview of this month’s journal. Sign up at CompendiumVet.com.

Four videos from Dr. Philipp Mayhew demonstrate some of the techniques described in the August 2008 Surgical Views article by Dr. Sara Gower and Dr. Mayhew, “Canine Laparoscopic and Laparoscopic-Assisted Ovariohysterectomy and Ovariectomy.”

CompendiumVet.com

Understanding

Behavior About This Column Behavior problems are a signiﬁcant cause of death (euthanasia) in companion animals. While most veterinary practices are necessarily geared toward the medical aspect of care, there are many opportunities to bring behavior awareness into the clinic for the beneﬁt of the pet, the owner, and ourselves. This column acknowledges the importance of behavior as part of veterinary medicine and speaks practically about using it effectively in daily practice.

Behavior Assessment: The First Appointment* ❯❯ Sharon L. Crowell-Davis, DVM, PhD, DACVB,a The University of Georgia *The ﬁrst article in this series on patient evaluation, “Behavior Assessment: History Forms and Interviews,” was published in the December 2008 issue of Compendium and is available at CompendiumVet.com.

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 description. The circumstances in which the behavior occurs must also be clarified, along with any treatments the owner has already attempted, either alone or with advice from a veterinarian, animal trainer, or other source. The pet’s signalment, environment, and background may all affect its behavior and should be discussed with the owner. Some of this information can be gathered in advance through the use of history forms; some may be better obtained through interviews and conversation with the owner during the first 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.

CompendiumVet.com | January 2009

The history of the behavior is also important. How long has the animal been exhibiting this behavior? While there are exceptions, it is often the case that problems of long duration will take longer to resolve than problems of short duration. This is especially true of behaviors that have developed as a consequence of operant conditioning, such as persistently waking the owners during the night, because the undesirable behavior has been reinforced hundreds or even thousands of times, rather than a few dozen times. Also, in attempts to treat the problem, the owners may have reinforced the undesirable behavior on a variable-ratio or variable-interval schedule by trying to ignore the behavior for a while but eventually acknowledging it. If this is the case, the behavior will have become very resistant to extinction.

History of Treatment Another critical piece of the history is how the owners have already attempted to correct the behavior. There is a tremendous amount of information about animal behavior on the Internet. Some is excellent. Some is mediocre. Some is unclear or confusing, and some will actually make behavior problems worse. Clients are likely to have tried various treatment protocols they have found on the Internet or in books. As with terms describing behaviors, this is a potential area of misunderstanding. Just because a client knows the word desensitization does not mean that the Web site or book where he or she read about it described it accurately or that the client understood the description correctly. Even if the original resource is accurate, the client may have conducted the protocol improperly and attempted a different treatment, such as flooding, instead. Thus, if a client says that he or she has already tried “treatment X,” ask for an exact, detailed description of what he or she did. In some cases, the client has identified the correct behavior modification treatment and conducted it appropriately, and it is helping, but not enough. In this circumstance, confirm that the treatment should be continued. However, it will be necessary to build on the current protocol, perhaps with a new variation of the established behavior modification plan or with medication. In other cases, the treatment may be a reasonable option, and the client may be conducting it accurately, but it is having no effect. In these cases, an entirely different approach is needed. If medications prescribed by other veterinarians have not been effective, verify the medication, the dose, and how long it was given to determine whether it was genuinely not beneficial or was simply not given at an adequate dose for an adequate time. For example, if a client discontinued fluoxetine

after administering it for just 1 week, the medication did not have time to take effect.

Other Behavior Problems The animal may have other behavior problems in addition to the chief complaint. Sometimes these problems come up in the discussion of the chief complaint, but not always. Before proceeding to issues other than the animal’s presenting behavior, ask if the owner has noticed QuickNotes any other behavior problems that have The duration, frenot been mentioned yet. Occasionally, it turns out that the owner considers a quency, intensity, problem other than the presenting com- and context of the plaint to be of more concern but had problem behavnot previously mentioned it because ior need to be he or she believes it to be untreatable. identified. For example, a dog may be aggressive, but the owner has brought it in for storm phobia because of a recent news story about treatments for storm phobia. If the animal has multiple behavior problems, it may be necessary to prioritize treatments. It is rare that the treatments for multiple problems are mutually exclusive. More typically, there are simply limitations to how much time and effort a client can put into treating a pet’s behavior problems. Thus, if a dog has fear aggression toward men, moderate storm phobia, mild separation anxiety, and a nuisance habit of jumping up on women as a form of friendly greeting, and the client can spend approximately 20 minutes a day conducting specific behavior modification, it will be impossible to address all these problems at once. It therefore makes sense to prioritize them in the order presented.

Owner Commitment For some owners, the amount of time and effort necessary to treat one problem, let alone several, is daunting. Therefore, one of the most important pieces of information to obtain at the ﬁrst appointment, in addition to a complete description of any problem behavTO LEARN ior, is a full understanding of how MORE motivated the owner is to treat the problem and keep the pet. At one For more information about end of the spectrum are owners clarifying the correct terms who intend to keep the pet, regardin conversations with less of the success of treatment. At owners, see the December the other end are those who intend 2008 article “Behavior to euthanize or give away the pet Assessment: History Forms if resolution of the behavior proband Interviews” at lem is not quick and easy. If the CompendiumVet.com. owners are considering giving the

CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians®

Understanding

Behavior pet away, it is important to in which the pet lives. The apprise them of the difficul-same information should Previously attempted treatties of finding an alternative be gathered for all the ments need to be identihome for a pet with a majorr other pets in the household. behavior problem. This is Finally, ask for a complete fied. It is important to especially the case with description of the pet’s physverify that these treatments aggressive pets. Sometimes ical environment, including owners think the police orr the house and yard. How were carried out correctly armed forces will want theirr big is the house? Are there aggressive dog as a guard parts of the house in which and appropriately. The dog. However, for guard and the pet is not allowed? Is the fact that someone knows attack work, police and mili-yard fenced in, and does the tary organizations want onlyy fencing adequately contain a word characteristic of k dogs that are trained to attack the pet? Is the pet walked on the jargon of learning and in a specific way at a spe-a leash? If so, how often and cific command. They do not for how long? What is the behavior modifi cation want dogs that have behaviorr neighborhood like? Is there problems and are likely to a problem with encoundoes not mean that he or infl ict bites because of such tering other pets while on she knows how to conduct issues as fear. walks? Are pedestrians and Beyond the extremes off cars rare, common, or conthe treatment correctly. willingness to keep a pet orr 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 idencan and will put into treating a pet. Major behavior tified as contributing to the existence and exacerproblems 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 boisterowner 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 atmoand 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 considernot 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 which the pet’s behavior problem exists. To properly identify and treat the problem, it is important to understand all the aspects of the pet’s environment, both social and physical. The social environment includes the people and animals with which the pet regularly interacts. All the humans who either live in the same household as the pet or visit frequently, either as guests or employees (e.g., gardener, maid), need to be identiﬁed. In addition to their names, sexes, and ages, their relationship and interactions with the pet are critical to understanding the world

Signalment Signalment is a basic information set that veterinarians are already accustomed to collecting. As with many medical conditions, signalment often gives us information about the relative likelihood of a given behav-

Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

TO LEARN MORE For more information about cognitive dysfunction, see the February 2008 article “Cognitive Dysfunction in Senior Pets” at CompendiumVet.com.

ior problem. In cases of older pets presenting with behavior problems, it is essential to identify whether the current problem is actually of recent onset. Sometimes owners have tolerated a given behavior problem in a pet for years, but changes in the family circumstances, rather than any substantial changes in the pet, have made the problem less tolerable. If the problem is of recent onset, or if there has been a signiﬁcant change in the intensity or frequency of the problem in an older pet, cognitive dysfunction, analogous to Alzheimer disease, should be considered. However, cognitive dysfunction should not be considered as a possible diagnosis in a young animal. If the complaint is aggression in a dog, aggressively “herding” people or other animals should be a diagnostic differential for herding breeds, but it is unlikely in nonherding breeds. If possible, ﬁnd out about the early history of the pet. Sometimes this is not possible because the owners adopted the pet at several months to several years of age. However, if background information is available, it can be useful in helping the owners understand the problem, even if it does not help

with treatment. Dogs and cats that were born and raised in puppy or kitten mills where they received little to no socialization with humans may be excessively shy around humans and susceptible to developing a variety of anxiety disorders as a consequence of their early experience. QuickNotes Extra effort will be required to help them Signalment will overcome these problems. Likewise, pets that have spent time as strays, fending for assist in prioritizthemselves to survive, may have become ing the differential very aggressive around food, especially diagnosis. if their ability to obtain food while stray was not very successful and they became underweight. Owners who find problem behaviors very frustrating are often more tolerant of them if they understand why their pet behaves in an undesirable fashion.

Conclusion The third article in this series will complete the discussion of the history that needs to be reviewed at the first visit and address direct assessment of 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 presentation of superficial bacterial pyoderma in dogs. Note the “goose bumps” or hive-like lesions on the skin. 1. What is the name of this condition, and what is seen upon close examination of the skin? 2. What are the diagnostic differentials, and what diagnostic tests should be conducted to confirm the diagnosis? 3. What is the mechanism of action of fluoroquinolone antibiotics, and why would this drug class not be an appropriate antibiotic choice in this dog?

TO LEARN MORE

Clinical Snapshot presents illustrated case histories and challenges you to answer the questions posed. This case is part of the series of Self-Assessment Colour Review books on multiple topics from Manson Publishing Ltd., London, available from Blackwell Publishing Professional. For more information or to obtain any of the books in the series, call 800-862-6657 or visit BlackwellProfessional.com

SEE PAGE 21 FOR ANSWERS AND EXPLANATIONS.

CompendiumVet.com | January 2009 | Compendium: Continuing Education for Veterinarians®

L:7

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FOR CANINE INTESTINAL HEALTH AND IMMUNE SYSTEM SUPPORT Arleigh Reynolds, DVM, PhD, DACVN Ebenezer Satyaraj, PhD

While veterinarians have long recognized the connection between colostrum and enhanced immunity in newborns, recent research shows dogs of all ages can benefit from colostrum’s supportive effects on gastrointestinal (GI) health. The findings demonstrate that, while colostral antibodies are not absorbed by older puppies and adult dogs as in 1- or 2-day-old pups, the immunoglobulin-rich substance contains elements that support proper GI tract development, nutrient absorption, growth and healthy intestinal microflora.1 GI TRACT KEY TO IMMUNE FUNCTION The GI tract plays a vital role in protecting the body from pathogens. With gut-associated lymphoid tissue (GALT), the intestinal tract is the body’s largest immune organ.2,3 The intestinal mucosa provides a protective barrier and secretes immunoglobulin A (IgA), which helps neutralize potential pathogens and stabilize intestinal microflora.

COLOSTRUM BENEFITS SHOWN Research shows dietary colostrum may benefit growing puppies and adult dogs. Weaned puppies fed a bovine colostrum–supplemented diet for 10 days after arrival at pet stores had significantly improved fecal quality compared to the control group.4 In a 40-week study, bovine colostrum was fed to adult Alaskan sled dogs under exercise stress.5 Compared to controls, colostrum-supplemented dogs had: • Increased intestinal microflora diversity,5 which reduces the risk of bacterial pathogens colonizing the GI tract.6 • More stable microbial populations following stress, which helps reduce risk of diarrhea and GI upset.5 • Increased fecal IgA levels, indicating improved GI mucosal immune status.5 • Greater, persistent antibody levels following canine distemper virus (CDV) vaccination, suggesting enhanced systemic immune status. The immune systems of colostrum-supplemented dogs were not hyperactive, based on normal C-reactive protein levels. 5

Measure of microﬂora stability 90

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*e<0.05 During stress, dogs fed a colostrum-supplemented diet had more stable gut microflora.

GI TRACT KEY TO IMMUNE FUNCTION (1) Immunoglobulin (Ig) binds to an immune cell in the GI mucosa. (2) Ig binding activates the immune cell. (3) Cytokines are secreted into the circulatory system, enabling communication with other immune cells. (4a) Activated systemic immune cells release IgG into the circulatory system in response to immune system challenges. (4b) Mucosal immune cells release IgA into the GI tract lumen, leading to increased levels of fecal IgA.

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1. Edwards, Christine. Interactions between nutrition and the intestinal microflora. Proc Nutr Soc. 1993;52(2):375–82. 2. Hall EJ. Mucosal immunity—Why it’s important [Internet]. In: The 32nd Congress of the World Small Animal Veterinary Association Proceedings Online; 2007 Aug 19–23; Sydney, Australia. Available at: http://www.vin.com/proceedings/Proceedings.plx?CID=WSAVA 2007&PID=18137&Print=2986&O=Generic. Accessed April 25, 2008. 3. Tizard IR. Immunity at body surfaces. In: Tizard IR, ed. Veterinary Immunology: An Introduction. 7th ed. Philadelphia, Pa: Saunders; 2004:234–246. 4. Giffard CJ, Seino MM, Markwell PJ, Bektash RM. BeneÀts of bovine colostrum on fecal quality in recently weaned puppies. J Nutr. 2004;134:2126S–2127S. 5. Data on Àle, 2006. Nestlé Purina PetCare Company. 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. 2005;73:6952–6961.

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CE Article 1

The Diagnostic Approach to Fever of Unknown Origin in Dogs* ❯❯ Julie Flood, DVM, DACVIM Antech Diagnostics Irvine, California

Abstract: Identifying the cause of a fever of unknown origin (FUO) in dogs presents a considerable diagnostic challenge. The diagnostic workup can be frustrating for veterinarians and clients, especially when it fails to reach a ﬁnal diagnosis after extensive testing. Fortunately, most causes of FUO can be found or treated successfully. This article discusses FUO in dogs and provides information about common causes, the diagnostic approach, and potential treatments.

T At a Glance Differential Diagnosis Page 14

Clinical Approach Page 14

Potential Causes of Fever of Unknown Origin in Dogs Page 15

Staged Diagnostic Approach to Fever of Unknown Origin in Dogs Page 16

Treatment Page 19

WEB EXCLUSIVE Supplemental material to this article is available at CompendiumVet.com.

rue fever (pyrexia) is defined as an increase in body temperature due to an elevation of the thermal set point in the anterior hypothalamus secondary to the release of pyrogens.1 With hyperthermic conditions other than true fever, the hypothalamic set point is not adjusted.1 Nonfebrile hyperthermia occurs when heat gain exceeds heat loss, such as with inadequate heat dissipation, exercise, and pathologic or pharmacologic causes.1 Dogs with true fever typically have body temperatures between 103°F and 106°F (39.5°C to 41.1°C).2 Prolonged body temperatures above 106°F are dangerous and can result in organ failure, disseminated intravascular coagulation, systemic inflammatory response syndrome, and death.1,3 Such temperatures are usually seen with nonfebrile causes of hyperthermia rather than with true fever.4 Temperatures less than 106°F are unlikely to be harmful and may be beneficial because they constitute a protective response to inflammation.1,5 The term fever of unknown origin (FUO) is used liberally in veterinary medicine.5 It should be used to identify a fever that does not resolve spontaneously, that does not respond to antibiotic treatment, and for which the diagnosis remains uncertain after an initial diagnostic workup.5 Along with a thorough history and physical examination, initial diagnostics should include a complete blood count (CBC),

*A companion article about fever of unknown origin in cats begins on page 26.

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serum biochemistry proﬁle, and urinalysis with antimicrobial culture. The cause of fever in most dogs is an infection that either is found during the initial workup or responds to antibiotic treatment; therefore, most dogs do not have a true FUO.5

Differential Diagnosis The differential diagnosis for FUO in dogs is extensive, and development of an algorithm covering all causes is not feasible. Some causes of FUO in dogs are listed in BOX 1.2,4,5 Most FUOs are caused by a common disease presenting in an obscure fashion.6 Current information in the veterinary literature regarding FUO in dogs is limited.1,5 Infectious, immune-mediated, and neoplastic diseases are all important and common causes.2,5,7,8 About 10% to 15% of FUOs in dogs remain undiagnosed despite thorough diagnostic evaluation.5 The prognosis for undiagnosed FUO in dogs is not known. However, a retrospective study7 revealed that in 13 of 14 dogs with undiagnosed FUO, the fever either resolved spontaneously or responded to antibiotics, NSAIDs, or corticosteroids.

Clinical Approach The diagnostic approach must be tailored to the patient. It should be guided by history and physical examination ﬁndings, simple laboratory testing, and the potential causes common to the geographic location.9,10 A three-stage approach, such as the one presented in BOX 2, is commonly

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The Diagnostic Approach to FUO in Dogs CE used.2,4,5 Communication with the owner is of utmost importance to ensure understanding of the time and ﬁnancial commitment that may be required to obtain a deﬁnitive diagnosis. Fortunately, a diagnosis can be obtained in most circumstances, and many causes are treatable or manageable.8 All medications should be discontinued to help rule out a drug-induced fever. If the fever persists beyond 72 hours after medication cessation, a drug reaction can be ruled out.11

History and Physical Examination Obtaining a thorough history is the ﬁrst step of a successful diagnostic approach. Clients should be questioned carefully about speciﬁc BOX 1

or subtle clinical signs (historical, intermittent, and current) because these may help localize the fever source. A history of stiffness may suggest joint disease, but fevers can present similarly.3 Often, diagnostic clues are not readily apparent on physical examination, so repeated detailed physical examinations are essential (by multiple clinicians, if possible).10 Careful attention should be paid to the whole body—pulses, skin, mucous membranes, oral cavity, lymph nodes, heart, abdomen, bones and joints, and rectum. Repeated fundic and neurologic examinations are also important to identify subtle changes. As the disease progresses, new clues may emerge to help guide the next diagnostic steps.

Complete Blood Count and Serum Biochemistry Profile

Bacterial infection (focal or systemic): Bacteremia, infective endocarditis, septic arthritis, osteomyelitis, diskospondylitis, septic meningitis, pyothorax, pyelonephritis, prostatitis, stump pyometra, peritonitis, deep pyoderma, abscess Bacterial diseases: Brucellosis, bartonellosis, borreliosis, leptospirosis, mycoplasmosis (hemotrophic and nonhemotrophic), tuberculosis and other mycobacterial diseases, diseases caused by L-form bacteria (e.g., cellulitis, synovitis) Viral: Canine distemper, parvovirus Rickettsial: Ehrlichiosis, anaplasmosis, Rocky Mountain spotted fever, salmon poisoning Fungal: Histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis Protozoal: Toxoplasmosis, neosporosis, babesiosis, trypanosomiasis, hepatozoonosis, leishmaniasis Immune-mediated diseases: Immunemediated hemolytic anemia, polyarthritis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, meningitis, steroidresponsive neutropenia and fever Neoplastic: Lymphoma, leukemia, multiple myeloma, malignant histiocytosis, necrotic solid tumors Noninfectious inﬂammatory diseases: Lymphadenitis, panniculitis, pansteatitis, panosteitis, pancreatitis, granulomatosis Miscellaneous: Portosystemic shunt, drug reaction, toxin, shar-pei fever, metabolic bone disorders, idiopathic causes

CBC and serum biochemistry profile abnormalities in dogs with FUO are generally nonspecific, but they may indicate a need for further diagnostic tests. Every CBC should be accompanied by a blood smear evaluation to detect morphologic changes and parasites. Frequently, multiple blood smears and careful scanning are necessary to find infectious organisms (FIGURE 1). Sometimes only one organism will be seen on an entire slide. It is wise to save serum for serologic testing or other special tests that may be crucial in the future. A serum bile acids assay may be indicated because fever may be the only predominant clinical sign in dogs with portosystemic shunts.12

QuickNotes Urine culture should be conducted for all dogs with fever of unknown origin.

Urinalysis with Culture A urine sample obtained via cystocentesis (unless contraindicated) should be submitted FIGURE 1

Courtesy of Dr.Ty McSherry

Potential Causes of Fever of Unknown Origin in Dogs2,5

HISTOPLASMA ORGANISMS found on a blood smear from a dog.

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BOX 2

Staged Diagnostic Approach to Fever of Unknown Origin in Dogs2,4 Stage 1 Take a thorough history. Stop all medications to rule out drug-induced fever. Perform a meticulous physical examination, including fundic and neurologic examinations. Obtain samples for CBC, blood smear, and serum chemistry profile. Save serum for serology or other testing. Obtain a urine sample for complete urinalysis and urine culture. Submit a sample for urine protein:creatinine ratio if proteinuria and inactive sediment are present. Conduct fecal centrifugation and fecal cytology, if indicated. Consider obtaining thoracic and abdominal radiographs. Consider trial antibiotics if bacterial infection is suspected (e.g., doxycycline if ehrlichiosis is suspected). If necessary, proceed to stage 2. Stage 2 Repeat stage 1 tests as indicated. Obtain thoracic and abdominal radiographs if not obtained in stage 1. Conduct abdominal and other ultrasonography as indicated. Conduct echocardiography if a heart murmur is present. Conduct heartworm testing, if indicated. Conduct fine-needle aspiration with cytology of masses, lymph nodes, and fluids (cyst, pleural, peritoneal, prostatic wash), if indicated. Conduct blood culture. Conduct arthrocentesis. Conduct fecal cultures, if indicated. Conduct bone marrow aspiration if warranted by CBC results. Conduct serology for infectious diseases. Obtain long bone and joint radiographs. Conduct protein electrophoresis, if indicated. Conduct an immune panel, if indicated. If necessary, proceed to stage 3. Stage 3 Repeat stage 1 and 2 tests as indicated. Conduct echocardiography even if no murmur is present. Conduct transesophageal echocardiography. Conduct bone marrow aspiration even if CBC results are normal. Perform biopsy as indicated. Conduct bronchoscopy and bronchoalveolar lavage as indicated. Conduct cerebrospinal fluid analysis. Conduct dental radiography. Consider computed tomography, magnetic resonance imaging, nuclear imaging, or positron emission tomography. Conduct laparoscopy or thoracoscopy as indicated. Consider exploratory celiotomy. Administer trial antibiotic or antifungal therapy. CBC = complete blood count

for a complete urinalysis with bacterial culture even if sediment is inactive. These tests should be repeated, especially if there is a history of lower urinary tract disease, as a negative urine culture does not rule out infection. Further diagnostic testing could include urine protein:creatinine ratio if proteinuria is present with inactive sediment.

Radiography Two-view abdominal and three-view thoracic radiographs should be obtained if the minimum database does not reveal the cause of the fever. Total body radiographs can help aid in the diagnosis of masses, pneumonia, pyothorax, or other infections. Joint radiographs can aid in the diagnosis of an erosive immunemediated polyarthritis.3 Other anatomic areas to radiograph include long bones (especially in young dogs), the spine, and dental structures (tooth root abscesses, masses). Special contrast radiographic studies can focus on other body systems (urogenital, spinal, gastrointestinal).

Ultrasonography Abdominal ultrasonography allows for evaluation of organ parenchyma and can detect lesions not apparent on survey radiographs. It can also assist with ﬁne-needle aspiration or biopsy if needed. Thoracic ultrasonography can be conducted if abnormalities (e.g., pleural effusion, cysts, masses) are detected on radiographs. When thoracic disease is not radiographically evident, ultrasonography is not rewarding because the lungs obscure intrathoracic anatomy.13 Ultrasonography can also be used to evaluate ocular (including retrobulbar), ventral cervical (thyroid/parathyroid, lymph node, salivary gland), and musculoskeletal (skin, subcutaneous, joint, muscle) regions if indicated.14–16

Echocardiography Echocardiography should be conducted in dogs with FUO and a heart murmur, especially a new or diastolic murmur. Vegetative lesions must be differentiated from proliferative myxomatous valve degeneration. Dogs with infective endocarditis are usually medium to large breeds that do not tend to have myxomatous valve degeneration.17 Echocardiography can also be used to evaluate for a heart base mass if one is clinically suspected.

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The Diagnostic Approach to FUO in Dogs CE Blood Culture

Courtesy of Dr.Ty McSherry

FIGURE 2

MORULAE in macrophages in a splenic aspirate from a dog infected with Ehrlichia canis. FIGURE 3

Courtesy of Dr.Ty McSherry

Blood cultures should be conducted (preferably during a pyrexic episode) for all dogs with FUO, especially those with a heart murmur, bounding pulses, lameness (polyarthritis), 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 sample is more important than the timing; larger volumes are associated with an increased diagnostic yield in human medicine.19,21,22 Patient 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 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 received antibiotics, blood culture vials with resins that bind antibiotics should be used.2,19 Evidence suggests that recovery is improved in samples from blood culture resin vials because the resins may absorb inhibitors other than antibiotics23; therefore, use of these vials for all blood samples may be warranted. Bartonella spp are emerging as an important cause of culture-negative infective endocarditis in dogs; therefore, submission of samples for Bartonella polymerase chain reaction (PCR) testing as well as serology is recommended in suspected cases.24 Blood culture PCR techniques are being used in human medicine and may be valuable for use in dogs for detecting other infections in the future.25

FINE-NEEDLE ASPIRATE from a spleen in a dog with malignant histiocytosis.

planum, skin, feces) can also be conducted if indicated. Fluid samples should be submitted for bacterial culture if the sample quantity is sufﬁcient.

Bone Marrow Evaluation Bone marrow aspiration should be conducted early in the evaluation of dogs with FUO if CBC abnormalities consistent with bone marrow disease are present. It should be considered in later diagnostic stages if no deﬁnitive diagnosis has been made, even if the CBC is normal, because neoplasia and infectious diseases can be common causes of FUO in dogs.2,8

QuickNotes Arthrocentesis can yield critical diagnostic information for many dogs with fever of unknown origin.

Arthrocentesis Cytologic Examination Fine-needle aspiration with cytology should be conducted on any suspicious masses or lymph nodes, ﬂuid accumulations, or abnormal organs. Cytology can be rewarding in the diagnosis of many infections as well as in the identiﬁcation of abnormal cells (FIGURES 2 AND 3). Impression cytology (nasal

Immune-mediated polyarthritis is a common cause of FUO in dogs even when no signs of arthritis are present (FIGURE 4).7,8 Arthrocentesis should be conducted on several joints and the samples submitted for cytologic evaluation (EDTA microcontainer) and possibly bacterial culture (aerobic, anaerobic, and mycoplasma). Infectious arthropathy needs to be ruled out

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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

FIGURE 4

Courtesy of Dr.Ty McSherry

Immunodiagnostic Screening Panels

JOINT FLUID from the tarsus of a dog with immune-mediated polyarthritis.

TO LEARN MORE For more information on special tests that can be used in diagnosing the cause of FUO in dogs, please visit the Web Exclusives section of CompendiumVet.com.

Immunodiagnostic panels (antinuclear antibody, rheumatoid factor, Coombs) are typically 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.

Other Diagnostic Tests

Other diagnostic tests, such as prostatic wash, if suppurative inflammation is seen on cytol- cerebrospinal fluid analysis, and bronchosogy 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-growwith 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 resmediated 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 scintigshoulder).27 If immune-mediated polyarthritis is raphy is being used more frequently in vetsuspected, 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 modalSerology 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 antibody titers for IgG and IgM should be sub- If fine-needle aspiration cytology cannot promitted if a diagnosis continues to be elusive. A vide a definitive diagnosis, a biopsy may be single high IgM indicates active or recent infec- helpful. In one study,7 biopsy samples submittion, and a fourfold IgG rising titer confirms ted for histopathology enabled a diagnosis in infection.28 It is important to remember that a 15 of 17 dogs with FUO. Tissue samples can negative antibody titer does not rule out infec- be obtained percutaneously (with or without tion and that a single positive titer implies either imaging assistance); via endoscopy, laparos-

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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 immuceliotomy 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 corticosTreatment 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 lymfluids 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 associchoice 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 administered, keeping in mind the potential and allowing new diagnostic clues to emerge side effects.5,7 Fever can result in considerable by revamping historical information (via reasmalaise, dehydration, and anorexia; therefore, sessing current information and possibly clinicians must decide in each case whether obtaining a more detailed history) and repeatNSAIDs could be beneficial.4 Antipyretics (e.g., ing physical examinations and simple laboraketoprofen, flunixin meglumine, dipyrone) tory tests is more desirable than proceeding should be used with caution because fever can with more invasive and expensive tests if the 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 abilthe 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.

QuickNotes The most common and important causes of FUO in dogs are infection, immune-mediated disease, and cancer.

4. Johannes DM, Cohn LA. A clinical approach to patients with fever of unknown origin. Vet Med 2000;95(8):633-642. 5. Couto CG. Fever of undetermined origin. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; 2009:1274-1277. 6. Dunn JK, Gorman NT. Fever of unknown origin in dogs and cats. J Small Anim Pract 1987;28:167-181.

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7. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of fever in dogs: laboratory testing, diagnoses and inﬂuence prior to treatment. J Small Anim Pract 2006;47:370-376. 8. Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of unknown origin. J Small Anim Pract 1998;39:574-580. 9. Mourad O, Palda V, Detsky AS. A comprehensive evidencebased approach to fever of unknown origin. Arch Intern Med 2003;163:545-551. 10. Roth AR, Basello GM. Approach to the adult patient with fever of unknown origin. Am Fam Phys 2003;68:2223-2228. 11. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85-91. 12. Wess G, Unterer S, Haller M, et al. Recurrent fever as the only or predominant clinical sign in four dogs and one cat with congenital portosystemic vascular anomalies. Schweiz Arch Tierheilkd 2003;145(8):363-368. 13. Mattoon JS, Nyland TG. Thorax. In: Nyland TG, Mattoon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: Saunders; 2002:325-353. 14. Samii VF, Long CD. Musculoskeletal system. In: Nyland TG, Mattoon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: Saunders; 2002:267-284. 15. Mattoon JS, Nyland TG. Eye. In: Nyland TG, Mattoon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: Saunders;2002:305-324. 16. Wisner ER, Mattoon JS, Nyland TG. Neck. In: Nyland TG, Mattoon JS, eds. Small Animal Diagnostic Ultrasound. 2nd ed. Philadelphia: Saunders; 2002:285-304. 17. MacDonald KA. Infective endocarditis. In: Bonagura JD, Twedt DC, eds. Kirk’s Current Veterinary Therapy XIV (Small Animal Practice). St. Louis: Elsevier Saunders; 2009:786-791. 18. Hirsh DC, Jang SS, Biberstein EL. Blood culture of the canine patient. JAVMA 1984;184(2):175-178. 19. Haggstrom J, Kvart C, Pedersen HD. Acquired valvular heart disease. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 2. 6th ed. St. Louis: Elsevier Saunders; 2005:1022-1039. 20. Calvert CA, Wall M. Cardiovascular infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:841-865. 21. Li J, Plorde JJ, Carlson LG. Effects of volume and periodicity on blood cultures. J Clin Microbiol 1994;32(11):2829-2831. 22. Karchmer A. Infective endocarditis. In: Braunwald E, ed. Heart

Disease. 5th ed. Philadelphia: Saunders; 1997:1077. 23. Lelièvre H, Gimenez M, Vandenesch F, et al. Multicenter clinical comparison of resin-containing bottles with standard aerobic and anaerobic bottles for culture of microorganisms from blood. Eur J Clin Microbiol Infect Dis 1997;16(9):669-674. 24. MacDonald KA, Chomel BB, Kittleson MD, et al. A prospective study of canine infective endocarditis in Northern California (1999– 2001): emergence of Bartonella as a prevalent etiologic agent. J Vet Intern Med 2004;18:56-64. 25. Gebert S, Siegel D, Wellinghausen N. Rapid detection of pathogens in blood culture bottles by real-time PCR in conjunction with the pre-analytic tool MolYsis. J Infect 2008;57:307-316. 26. Greene CE, Budsberg SC. Musculoskeletal infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:823-841. 27. Goldstein RE. Swollen joints and lameness. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 1. 6th ed. St. Louis: Elsevier Saunders; 2005:83-87. 28. Houser G, Ayoob A, Greene CE. Laboratory testing for infectious diseases of dogs and cats. Appendix 5. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:1139-1168. 29. Moon ML, Hinkle GN, Krakowka GS. Scintigraphic imaging of technetium 99m-labeled neutrophils in the dog. Am J Vet Res 1988;49(6):950-955. 30. Peremans K, DeWinter F, Janssens L, et al. An infected hip prosthesis in a dog diagnosed with a 99mTC-ciprofloxacin (infection) scan. Vet Radiol Ultrasound 2002;43(2):178-182. 31. Berry CR, DeGrado TR, Nutter F, et al. Imaging of pheochromocytoma in 2 dogs using p-[18F]fluorobenzylguanidine. Vet Radiol Ultrasound 2002;43(2):183-186. 32. Ballegeer EA, Forrest LJ, Jeraj R, et al. PET/CT following intensity-modulated radiation therapy for primary lung tumor in a dog. Vet Radiol Ultrasound 2006;47(2):228-233. 33. LeBlanc AK, Jakoby B, Townsend DW, et al. Thoracic and abdominal organ uptake of 2-deoxy-2-[18F]fluoro-D-glucose (18FDG) with positron emission tomography in the normal dog. Vet Radiol Ultrasound 2008;49(2):182-188. 34. Lappin MR. Practical antimicrobial chemotherapy. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; 2009:1291-1301. 35. Klein NC, Cunha BA. Treatment of fever. Infect Dis Clin North Am 1996;10(1):211-216.

3 CE CREDITS

CE TEST 1

2. What is the correct deﬁnition of a true fever? a. increase in body temperature due to an elevation of the thermal set point in the anterior hypothalamus b. increase in body temperature due to an elevation of the thermal set point in the anterior pituitary gland c. a marked, rapid rise in body temperature without adjustment of the thermal set point in the anterior hypothalamus d. a marked, rapid rise in body temperature without adjustment of the thermal set point in the anterior pituitary gland

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3. Which statement regarding fever in dogs is true? a. The cause of fever in most dogs is neoplasia. b. Most FUOs in dogs are caused by a common disease presenting in an obscure fashion. c. Dogs with true fevers commonly have prolonged body temperatures above 106°F. d. Prolonged body temperatures above 106°F are not dangerous.

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4. FUO in dogs is commonly the result of ____________ disease. a. infectious b. neoplastic c immune-mediated d. all of the above 5. Which statement regarding sample culture is true? a. A negative urine culture can rule out pyelonephritis. b. A negative blood culture can rule out bacteremia. c. A negative joint culture can rule out septic arthritis. d. none of the above 6. When evaluating a dog with FUO, a. it is usually not necessary to evaluate a blood smear in conjunction with the CBC. b. a urine culture is only indicated when there is an active urine sediment. c. repeated neurologic and fundic examinations are important. d. a joint tap is recommended only for dogs presenting with lameness.

7. Which statement regarding blood cultures for dogs with FUO is false? a. Blood cultures can be conducted for a dog currently on antibiotics. b. It is rare for dogs with positive blood cultures to have isolation of the same organism from other sites. c. Obtaining a larger blood sample volume is more important than the timing of the sample. d. Bartonella spp are emerging as an important cause of culture-negative infective endocarditis in dogs. 8. Which statement regarding arthrocentesis in the evaluation of a dog with FUO is true? a. Only one joint should be tapped to decrease the chance of septic contamination. b. Immune-mediated polyarthropathies tend to involve larger joints such as the stiﬂes, elbows, and shoulders. c. Degenerate neutrophils are not always seen with septic joints. d. Immune-mediated polyarthritis is extremely rare in asymptomatic dogs with FUO.

9. Which statement is true with regard to dogs with FUO? a. Antibiotics should never be started unless the deﬁnitive cause of FUO is determined. b. A negative fungal antibody titer rules out infection with that organism. c. Initial improvement after the start of corticosteroids does not equate to successful treatment because many diseases can respond favorably initially. d. Bone marrow aspiration is only indicated if the CBC is abnormal. 10. Which statement is false with regard to dogs with FUO? a. Using a logical approach usually results in a deﬁnitive diagnosis. b. It is important to run as many diagnostic tests as quickly as possible when evaluating a stable dog with FUO. c. Conduct fecal centrifugation and fecal cytology, if indicated. d. If fever persists beyond 72 hours after a medication has been discontinued, a drug-induced fever can be ruled out.

Clinical Snapshot Answers and Explanations Case Presentation #1 SEE PAGE 11 FOR CASE PRESENTATION.

1. This is an example

of superﬁcial bacterial infection of the skin involving the hair follicles, hence the name superﬁcial bacterial folliculitis. Close examination of the skin reveals small papules at the base of the hairs. These papules/ pustules may rupture, causing the formation of tiny epidermal collarettes, which may be seen encircling the base of the hairs. 2. The major diagnostic differentials are dermatophytosis, demodicosis, and Malassezia dermatitis. Less

common differentials include pemphigus, sterile eosinophilic pustulosis, and pustular demodicosis. However, bacterial folliculitis is most commonly confused with dermatophytosis or urticaria. Demodicosis, concurrent Malassezia infection, and other infections should be ruled out by skin scrapings, impression smears, and dermatophyte cultures, respectively. The diagnosis of a bacterial pyoderma is often a clinical diagnosis supported by ruling out demodicosis and dermatophytosis, the two most common follicular diseases. Concurrent bacterial and Malassezia infections, especially in

warm weather, can occur in approximately 50% of patients. 3. Fluoroquinolone antibiotics prevent bacterial DNA synthesis by partly inhibiting bacterial DNA gyrase. This class of drugs is primarily active against gram-negative aerobic and facultative anaerobic bacteria. Although they are effective against many gram-positive organisms (e.g., staphylococci), the minimum inhibitory concentrations are usually higher than for gram-negative bacteria. Fluoroquinolone antibiotics are contraindicated in this particular patient because they are known to cause erosive arthropathy in young dogs.

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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 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 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 in interactions between the pet and the other foods that the patient is receiving and the spemembers of the household. Understanding this cific amounts fed. Often, caregivers cannot prorelationship is a key element when designing vide this information accurately by recall alone dietary interventions that meet the health and and need to check labels and measure feeding nutritional needs of the patient and are accept- portions. Also, pet owners who use a scoop to measure dry food often do not realize the true able to the pet’s caregivers. size of their measuring device. If the pet is eatElements 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 informais 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 propoIf the pet is eating a commercial pet food, sition of modifying their feeding practices. ask if the diet is being supplemented with any human foods. If this is the case, it is important The Household to get accurate details, including measured Begin by asking about who lives with the amounts of all foods routinely given to the pet. How many adults and children are in pet. If the pet is being fed a home-prepared

QuickNotes Information from the diet history is essential for determining whether a patient is receiving an appropriate and adequate diet.

*Dr. Michel discloses that she has received ﬁnancial support from Nestlé Purina PetCare Company and Royal Canin.

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CONTRIBUTED BY THE AMERICAN COLLEGE OF VETERINARY NUTRITION About ACVN diet, ask for the recipe, including measured amounts of all the ingredients. Some owners do not use a standard recipe when making a home-prepared diet. It is useful to ask these owners to keep a diary of all food fed to the pet for 5 to 7 days. Be certain to inquire whether the pet is receiving any dietary supplements. If possible, have the client bring in the supplements—or at least the label information—so you can see exactly which nutrients are being supplemented and in what quantities. Ask about the daily routine of feeding the pet. Is the pet fed at certain times of the day, or is food always available? If the pet is fed with other pets, are the meals supervised? Does one person assume responsibility for feeding the pet, or can it vary day-to-day? This is important information, especially when you are making dietary recommendations, because the person who brings the pet to the ofﬁce may not be the person who will be implementing the new plan. Ask about how and where the food is stored (e.g., in a sealed container, in the refrigerator). If the pet is fed a dry food, is the food bought in large quantities, and how long does it take to use up a bag of food? Food can lose its freshness over time, especially if it is not stored under optimal conditions. Inquire about the pet’s normal feeding behavior. Is the pet an “easy keeper” or a picky eater? Does the pet eat the food as soon as it is offered, or is it content to graze throughout the day? Does the pet usually eat all the food that is offered? Does the pet beg for food between meals? If the pet is not eating as it normally does, ﬁnd out what has changed and for how long the behavior has been altered.

Treats, Supplements, and Exercise When inquiring about treats, ask the question several times in different ways. Ask speciﬁcally about which commercial treats are used—not just the brand name but also the ﬂavor, variety, and size. Ask about human foods and table scraps. Ask about products or foods that are used to promote chewing and dental hygiene or to alleviate boredom. Also inquire about different ways food may be used as a reward, such as for performing tricks or for good behavior during walks. Owners do not always

consider such items treats, and many of the products and foods used for these purposes are high in calories. It is important to remember to inquire whether the pet routinely receives any supplements or medications that are disguised with food. Human foods that are typically used to pill a dog or cat, such as cheese, lunch meats, or peanut butter, are often high in sodium, fat, and calories. For example, one study evaluating dogs with cardiac disease showed that 62% of the owners used human or pet food for pill administration and that many of these foods were high-sodium table foods such as cheese or lunch meats.1 One further point to ask about is the pet’s level of activity and opportunity to exercise. Is the pet walked regularly? How often, and how far? Find out whether the pet goes outside, has a fenced-in yard—and if so, how large— or participates in regular activities that involve exercise, such as going to a dog park or an agility class. See if you can gauge whether increasing the opportunity to exercise would be feasible in the household. This information is especially valuable when you are designing a weight reduction program for a patient.

Founded in 1988, the primary objective of the American College of Veterinary Nutrition (ACVN) is to advance the specialty area of veterinary nutrition and increase the competence of those who practice in this ﬁeld by establishing requirements for certiﬁcation in veterinary nutrition, encouraging continuing professional education, promoting research, and enhancing the dissemination of new knowledge of veterinary nutrition through didactic teaching and postgraduate programs. For more information, contact: American College of Veterinary Nutrition, c/o Dawn Cauthen, Administrative Assistant, School of Veterinary Medicine: Dept. of Molecular Biosciences One Shields Avenue Davis, California 95616-8741 Telephone: 530-752-1059 Fax: 530-752-4698 Email: dawncauthen@yahoo.com Web: acvn.org

Gathering the Information This may seem like a great deal of information to gather in a routine office visit, but the process can be expedited by having a diet history form available for clients to fill out while they are in the waiting room. As previously mentioned, the client may not be able to recall all of the information in the office and may need to take the form home. If your practice has a Web site, you can have a link to a downloadable version of the form so that clients can fill it out before the office visit. To help expedite the WEB EXCLUSIVE process, a veterinary technician familiar with taking diet histories can either gather Photocopy the diet history form the pertinent information on pages 47 and 48 for your clients, directly from a client during or download a customizable PDF the visit or review the diet of the same form from history form for completeness and accuracy once the CompendiumVet.com. client has filled it out.

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Negotiating a Diet Change

QuickNotes Making an effort to talk with pet owners about their beliefs, concerns, and expectations can result in better adherence to recommendations.

The information obtained in the diet history will be invaluable for making appropriate and, hopefully, acceptable dietary recommendations for your patients. Knowing a pet’s current diet and any recent changes to it will inform your decision about what kind of dietary modification may be necessary to address the pet’s health condition and what kind of diet the pet may find most acceptable. Being aware of owner preferences and potential obstacles to change will help you tailor your recommendations not only to the pet but also to the entire household to ensure the greatest probability of success and adherence. Understanding the client’s attitude toward, and concerns about, the dietary management of pet dogs and cats will present you with the opportunity to open a dialogue with the client about pet nutrition and educate him or her about the reasons for your recommendations. Investigations in human medicine have found that when physicians make an effort to talk with patients about their knowledge, beliefs, concerns, and expectations about their condition, the result is better adherence to treatment regimens.2 Exploration of all of these issues from a patient’s perspective on his or her illness permits the attending health professional to address deficiencies in knowledge or understanding of the condition and its treatment and the patient’s ability and willingness to pursue a particular course of therapy. In veterinary medicine, the owner speaks for the patient, but the same principle applies. With regard to dietary practices, despite a basic uniformity in nutritional requirements and physiologic needs, there is considerable variation in what humans eat. In the case of pet dogs and cats, their owners largely determine what they eat on a daily basis. Yet in many, if not most, cases, client education alone will not succeed in changing habits and behaviors relating to how a pet is fed. Just as a person’s social and cultural context will influence his or her own dietary habits, it will also have an impact on how and what that person feeds a pet. Therefore, it is important to consider the social and cultural aspects of owners’ food consumption in order to communicate effectively with them about their pets’ nutritional needs and appropriate dietary management, particularly if you are attempting to change current feeding practices.3

HEALTHY BITES

To get an accurate account of the foods fed to a pet on a typical day: Find out if you are speaking to the person responsible for feeding the pet. Have a diet history form available that the client can take home so he or she can check the labels and measure the amounts of food that the pet is fed (see pages 47 and 48 or CompendiumVet.com for a sample diet history form). Request that dry pet foods be measured with an 8-oz kitchen measuring cup. Ask speciﬁcally about the different treats and supplemental foods a pet might receive (e.g., commercial treats, table foods and scraps, oral hygiene products, foods used as rewards, foods used for administering pills, dietary supplements).

Conclusion The information that can be obtained from a diet history can greatly facilitate the process of implementing dietary therapy for a patient. It can help not only in making an appropriate diet selection and accurate feeding recommendations but also in understanding the pet owner’s rationale for current feeding practices and assessing any concerns that may arise from a diet change. By anticipating problems, you should be able to craft the dietary intervention in a way that will be acceptable to the pet’s household or, at the very least, to communicate more effectively with the pet owner about the rationale for the changes in feeding management. You will be in a better position to explain why you feel the changes you are proposing are in the pet’s best interest and to look for compromise when your recommendations and the pet owner’s preferences are in conﬂict. References 1. Freeman LM, Rush JE, Markwell PJ. Dietary patterns of dogs with cardiac disease. J Nutr 2002;132:1632S-1633S. 2. The “why”: a rationale for communication skills teaching and learning. In: Kurtz S, Silverman J, Draper J. Teaching and Learning Communication Skills in Medicine. 2nd ed. San Francisco: Radcliffe Publishing; 2005:13-27. 3. Michel KE. Unconventional diets for dogs and cats. Vet Clin North Am Small Anim Pract 2006;36:1269-1281.

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Letters The Curious Case of the Cat with the Munchies We found the article “Five Common Toxins Ingested by Dogs and Cats” extremely interesting and practical. We recently treated a 5-month-old domestic shorthaired cat for marijuana toxicity following ingestion of a “hash brownie.” The cat presented with perplexing sudden-onset neurologic signs and hypothermia (temperature 94.5°F [34.7°C]). With gentle coaxing, the owners admitted the source of the problem. (The brownie had been carefully wrapped in plastic ﬁlm and hidden but had disappeared while the patient was alone in the house. Clawed plastic and crumbs were found at the scene.) At the time, we found little information in the literature speciﬁcally on cases of feline marijuana ingestion. To our knowledge (and anecdotally), marijuana toxicity in cats is more likely to occur via inhalation when owners blow smoke in the cat’s face, rather than via dietary indiscretion, as is more common in dogs. In this case, we did not ascertain the ingested dose and did not know how long the patient would take to recover. Hypothermia persisted for approximately 24 hours. One of the signs not mentioned in the article by Drs. Luiz and Heseltine was marked polyphagia. During hospitalization, our patient ate ravenously. At one point, the patient defecated, passing a piece of a shoelace. This may have been ingested as a result of the cat’s marijuana-enhanced appetite before hospitalization, suggesting that gastrointestinal foreign bodies are a potential side effect of marijuana toxicity (as is chocolate toxicity, if marijuana is ingested in a brownie). The patient was discharged 3 days later when the neurologic signs resolved, although the owner reported that the cat had a “lazy eye” for 2 weeks after discharge.

Drs. Luiz and Heseltine mentioned drug testing as a means of confirming the diagnosis. We did not do this at the outset due to the client’s financial constraints. When we undertook a detailed literature search and realized so little was known about feline toxicity due to Cannabis sativa, we offered to cover the cost of toxicology testing. The owners allowed us to collect a urine sample from the patient via cystocentesis; however, the sample, collected 14 days after ingestion, returned a negative result. THC may be detectable in human urine samples for 4 to 6 weeks, but the time frame in which it remains detectable in samples from companion animal species is not known, according to the pathologist at the laboratory to which we submitted the sample (Dr. Bruce Duff at Symbion Vetnostics). The recommended time frame for submission of samples is within 48 hours of exposure to the toxin. In this case, we are confident the patient was suffering from marijuana toxicity. The negative urinalysis result may be due to the fact that a young, lean cat can metabolize marijuana relatively rapidly. Fortunately, these cases

CE Article #1

Five Common Toxins Ingested by Dogs and Cats Julie Ann Luiz, DVM University of Hawaii at Hilo

Johanna Heseltine, DVM, MS, DACVIM Oklahoma State University

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. 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. Therefore, prompt decontamination is the first 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 principles for minimizing GI absorption of ingested toxins and the clinical presentation and management of toxicosis caused by five commonly ingested household substances: anticoagulant rodenticides, ethylene glycol (EG), marijuana, chocolate, and metaldehyde.

DECONTAMINATION STRATEGIES FOR ORALLY INGESTED TOXINS GI decontamination techniques are used to prevent or limit the absorption of ingested toxins. Because many toxins lack a specific antidote, decreasing the amount of toxin absorbed may be life saving, and decontamination strategies should begin as soon • Take CE tests as possible after ingestion of a • See full-text articles toxic substance. Most decontCompendiumVet.com amination methods practiced COMPENDIUM

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.

Emesis Induction If the owner suspects toxicosis and calls the clinic before presenting the animal, the veterinarian must consider the risks and benefits of instructing the owner to administer an 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 most effective within 1 hour of ingestion, is useful up to 2 hours after ingestion, and is of limited benefit more than 4 hours after ingestion.2,3 Early emesis may remove up to 80% of the ingested material.3 Induction of emesis is contraindicated for corrosive and caustic materials, as well as for 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 consciousness or those that have seizures or are likely to seizure.2,3 Emetics should not be administered if the patient has already vomited.2

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are rare and—when they do occur— carry a good prognosis. Nonetheless, we encourage colleagues treating known or strongly suspected cases of marijuana toxicity to submit samples for toxicology screening and to share their data. Drs. Anne Fawcett and Angela Phillips Sydney Animal Hospitals Inner West Stanmore, NSW Australia

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CE Article 2

The Diagnostic Approach to Fever of Unknown Origin in Cats* ❯❯ Julie Flood, DVM, DACVIM Antech Diagnostics Irvine, California

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

T At a Glance Differential Diagnosis Page 26

Clinical Approach Page 26

Potential Causes of Fever of Unknown Origin in Cats Page 27

Staged Diagnostic Approach to Fever of Unknown Origin in Cats Page 28

Treatment Page 30

WEB EXCLUSIVE Supplemental material to this article is available at CompendiumVet.com.

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 retroNonfebrile 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 quate heat dissipation, exercise, and patho- in cats are infectious.5 Neoplasia is a less common cause of FUO in cats, and FUO logic or pharmacologic causes.1 Cats with true fever typically have body due to immune-mediated disease is rare in temperatures between 103°F and 106°F cats.6 FUO causes are often separated into (39.5°C to 41.1°C).2 Cats are less likely than groups based on the underlying disease dogs to succumb to the dangerous effects mechanism.2,3,7 Most FUOs are caused by a 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 causes of hyperthermia.3 Temperatures cats. It is thought that about 10% to 15% of less than 106°F are unlikely to be harm- FUOs in cats remain undiagnosed despite ful in cats and may be somewhat benefi- thorough diagnostic evaluation.4 cial because they constitute a protective a Clinical Approach response to inflammation.1,4 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 physinot 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 threeafter 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 estaba complete blood count (CBC), an FeLV lish a definitive diagnosis while minimizantigen 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 apin most cats is infection that either is found proach to cats with FUO, please refer to the

*A companion article about fever of unknown origin in dogs begins on page 14.

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clinical approach section in the article starting on page 14. Many of the same tests used in dogs can also be used in cats.

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The Diagnostic Approach to FUO in Cats CE and invasive diagnostic tests.2 Communication with the owner is of utmost importance to ensure understanding of the time and ﬁnancial commitment that may be required in order to obtain a deﬁnitive diagnosis. If possible, all medications should be discontinued early in the evaluation to help rule out a drug-induced fever. If the fever persists beyond 72 hours after cessation of the medication, a drug reaction can be ruled out.11 Drugs that are known to induce fever in cats include tetracycline, sulfonamides, penicillins, and levamisole. BOX 1

Potential Causes of Fever of Unknown Origin in Cats2,4 Bacterial infection (focal or systemic): Bacteremia, infective endocarditis, septic arthritis, osteomyelitis, diskospondylitis, septic meningitis, pyothorax, pyelonephritis, prostatitis, stump pyometra, peritonitis, abscess Bacterial diseases: Bartonellosis, borreliosis(?), mycoplasmosis (hemotrophic and nonhemotrophic), tuberculosis and other mycobacterial diseases, diseases caused by L-form bacteria (e.g., cellulitis or synovitis secondary to bite wounds or surgical incisions) Viral: FeLV, FIV, feline infectious peritonitis, feline calicivirusa Rickettsial: Feline ehrlichiosis, anaplasmosis, Rocky Mountain spotted fever Fungal: Histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis Protozoal infections: Toxoplasmosis, cytauxzoonosis, neosporosis(?), babesiosis(?), trypanosomiasis(?) Immune-mediated diseases: Polyarthritis, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, meningitis, steroid-responsive neutropenia and fever Neoplastic: Lymphoma, leukemia, multiple myeloma, necrotic solid tumors Noninfectious inﬂammatory diseases: Lymphadenitis, panniculitis, pansteatitis, pancreatitis, granulomatosis Miscellaneous: Portosystemic shunt, drug reaction, toxin, hyperthyroidism, idiopathic causes a Hurley KE, Pesavento PA, Pedersen NC, et al. An outbreak of virulent systemic feline calicivirus disease. JAVMA 2004;224(2):241-249.

History and Physical Examination Obtaining a thorough history is the first step to a successful diagnostic approach. The vaccination history should be ascertained because vaccines can cause immune-mediated fevers in cats during the immediate postvaccination period, and modified live virus vaccines can induce local lymphoid replication of the attenuated agent.5,12 Determining indoor/outdoor status, travel history, flea and tick control and potential exposure to diseases transmitted by parasites (e.g., hemotrophic mycoplasmosis, ehrlichiosis, bartonellosis, cytauxzoonosis), and contact with other cats is also important as many FUO causes are transmissable.5 Knowledge of ingestion of prey species may be helpful because songbirds can carry salmonellosis, rabbits can carry tularemia, and rodents can carry plague or toxoplasmosis.5 Cats are frequently affected by stress hyperthermia, which must be ruled out before an extensive diagnostic evaluation is pursued. As in dogs, FUO diagnostic clues in cats are generally not readily apparent on physical examination, so repeated detailed examinations are essential.9 The whole body should be carefully palpated to detect subtle swelling or discomfort, which may help localize the fever source. The thorax should be gently compressed to evaluate for a cranial mediastinal mass. Repeated fundic examination should be performed because numerous infectious diseases (e.g., FIP, FIV, FeLV) cause ocular changes. Absence of ocular changes does not rule out infection with these diseases. Repeated neurologic and orthopedic examinations should be performed, although they can be difficult to interpret in an uncooperative cat.

Feline Leukemia and Feline Immunodeficiency Virus

QuickNotes Infectious diseases are the most common causes of fever and fever of unknown origin in cats.

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

Fecal Examinations Fecal samples should be obtained from cats with FUO. If diarrhea is discovered, rectal cytology should also be conducted. Other diagnostic tests to consider include fecal ﬂotation with centrifugation, direct fecal examina-

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FREE CE The Diagnostic Approach to FUO in Cats

BOX 2

Staged Diagnostic Approach to Fever of Unknown Origin in Cats2,3 Stage 1 Take a thorough history. Stop all medications to rule out drug-induced fever. Perform a meticulous physical examination, including fundic and neurologic examinations. Conduct FeLV and FIV testing. Obtain samples for CBC, blood smear, and serum chemistry profile. Save serum for serology or other testing. Conduct a complete urinalysis and urine culture. Submit a sample for urine protein:creatinine ratio if proteinuria and inactive sediment are present. Conduct fecal centrifugation and fecal cytology, if indicated. Consider obtaining thoracic and abdominal radiographs. Consider trial antibiotics if bacterial infection is suspected (e.g., doxycycline if ehrlichiosis is suspected). If necessary, proceed to stage 2. Stage 2 Repeat stage 1 tests as indicated. Obtain thoracic and abdominal radiographs if not obtained in stage 1. Conduct abdominal and other ultrasonography as indicated. Conduct echocardiography if a heart murmur is present. Perform fine-needle aspiration with cytology of masses, lymph nodes, and fluids (cyst, pleural, peritoneal). Conduct blood culture. Perform arthrocentesis. Conduct fecal cultures, if indicated. Conduct bone marrow aspiration if warranted by CBC results. Conduct serology for infectious diseases. Obtain long bone and joint radiographs. Conduct an immune panel, if indicated. If necessary, proceed to stage 3. Stage 3 Repeat stage 1 and 2 tests as indicated. Conduct echocardiography even if no murmur is present. Conduct transesophageal echocardiography. Perform bone marrow aspiration even if CBC results are normal. Perform biopsy as indicated. Perform bronchoscopy and bronchoalveolar lavage as indicated. Conduct cerebrospinal fluid analysis. Perform dental radiography. Consider computed tomography, magnetic resonance imaging, nuclear imaging, or positron emission tomography. Perform laparoscopy or thoracoscopy as indicated. Consider exploratory celiotomy. Administer trial antibiotic or antifungal (if indicated) therapy.

tion, and fecal cultures. Cats can be bacteremic from Salmonella (and possibly Campylobacter) infection without diarrhea, so fecal cultures should be submitted, especially if neutrophils are evident on rectal cytology.15-17 If clostridial spores are seen on cytology, samples should be submitted for Clostridium perfringens enterotoxin testing.5

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

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

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

Serology Serum samples should be submitted for infectious disease testing (e.g., feline infectious peritonitis, bartonellosis, hemoplasmosis, rickettsiosis, anaplasmosis) if a disease is clinically suspected and if patient history suggests possible exposure. Toxoplasmosis serology (IgG and IgM) should be submitted for all cats with FUO. Natural clinical infections in cats with neosporosis have not been documented,

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The Diagnostic Approach to FUO in Cats CE FIGURE 1

Courtesy of Dr.Ty McSherry

so testing for this disease may not be warranted.19 Serology for feline foamy virus (previously known as feline syncytium-forming virus) can be conducted for cats with FUO and suspected joint disease.20

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

HISTOPLASMA ORGANISMS found in a pulmonary fine-needle aspirate from a cat. The organisms are located predominately in the macrophages.

are all associated with polyarthritis in cats.24–27 Other infective arthritides include fungal, rickettsial, and protozoal diseases.28

Immunodiagnostic Screening Panels

Immune panels (antinuclear antibody, rheumatoid factor [RF], Coombs) are thought to be unreTwo-view abdominal and three-view thoracic warding in cats with FUO, but in a recent study, radiographs should be obtained if the mini- 10 of 12 cats definitively diagnosed with rheumum 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 are frequently asymptomatic, so care must be for rheumatoid arthritis, it may be an important taken to rule out primary or secondary respi- diagnostic test in cats. The study also stated that four cats diagnosed with periosteal proliferative ratory problems. polyarthritis were negative for RF.30 Antiplatelet Ultrasonography antibody tests and serum protein electrophoreAbdominal 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 fluid analysis and bronchoscopy with bronchographic changes. alveolar lavage or transtracheal wash, should

Radiography

QuickNotes Urine culture should be conducted for every cat with fever of unknown origin regardless of the appearance of the urine sediment.

Bone Marrow Evaluation FIGURE 2

Courtesy of Dr. Robin Allison

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

Arthrocentesis Arthrocentesis should be conducted on cats even if there is no obvious evidence of joint disease. Calicivirus, mycoplasmosis, L-form bacterial infection, and FeLV with feline foamy virus

HISTOPLASMA ORGANISMS in a bone marrow aspirate from a cat.

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FREE CE The Diagnostic Approach to FUO in Cats

Courtesy of Dr. Robin Allison

FIGURE 3

TOXOPLASMA ORGANISMS in a bronchoalveolar lavage cytology sample from a cat.

QuickNotes Repeated fundic examinations are essential in cats with fever of unknown origin.

be considered if clinical abnormalities suggest neurologic or respiratory disorders, respectively. Samples should be submitted for cytologic evaluation and aerobic and anaerobic bacterial culture and sensitivity testing if quantity permits (FIGURE 3). Bronchoalveolar lavage samples should also be submitted for mycoplasma and slow-growing fungal cultures. Advanced imaging techniques and biopsy may be helpful in some cases, as in dogs.

Treatmentb

TO LEARN MORE For more information on special tests that can be used in diagnosing the cause of FUO in cats, please visit the Web Exclusives section of CompendiumVet.com.

Specific treatment is based on the definitive diagnosis, if found. A fan directed toward the cat’s cage or administration of intravenous fluids may be all that is necessary to lower the body temperature to a safer level. Antipyretics (e.g., ketoprofen, flunixin meglumine, dipyrone) are not typically advocated because the fever can be beneficial, and many argue that antipyretic therapy can have a negative impact on immune responses by causing hypothermia and impairing host immune defenses.3,4,31

Fevers may increase the bactericidal effect of antibiotics and serum and can also decrease the pathogenicity of some pathogens.3,31 Fever can result in considerable malaise, dehydration, and anorexia; therefore, clinicians must decide in each case whether NSAIDs could be beneﬁcial.3 If an antipyretic is considered necessary, aspirin dosed at 10 mg/kg q48–72h PO can be used.2,4 Empirical antibiotic therapy should be based on the organ system involved or the infectious agent suspected.5 Trial antifungal therapy should be considered for cats with suspected fungal infections that cannot be proven. Trial corticosteroids can be considered in cats with FUO for which the cause cannot be identiﬁed, making sure to discuss potential complications with the owner before use.

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

The author thanks Robin W. Allison, DVM, PhD, DACVP, of the Department of Veterinary b For more information on the treatment of cats with Pathobiology at Oklahoma State University and Leo FUO, please refer to the treatment section in the “Ty” McSherry, DVM, DACVP, clinical pathologist article starting on page 14. Many of the treatments at Antech Diagnostics in Irvine, California, for the cytology images. used in dogs can also be used in cats.

References 1. Miller JB. Hyperthermia and fever of unknown origin. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 1. 6th ed. St. Louis: Elsevier Saunders; 2005:9-13. 2. Lunn KF. Fever of unknown origin: a systematic approach to diagnosis. Compend Contin Educ Pract Vet 2001;23(11):976-992. 3. Johannes DM, Cohn LA. A clinical approach to patients with fever of unknown origin. Vet Med 2000;95(8):633-642. 4. Couto CG. Fever of undetermined origin. In: Nelson RW, Couto CG, eds. Small Animal Internal Medicine. 4th ed. St. Louis: Elsevier; 2009:1274-1277.

5. Lappin MR. Fever of unknown origin I and II. Proc Western Vet Conf 2003. 6. Wolfe AM. Fever of undetermined origin in the cat. Proc Atl Coast Vet Conf 2002. 7. Feldman BF. Fever of undetermined origin. Compend Contin Educ Pract Vet 1980;2(12):970-977. 8. Dunn JK, Gorman NT. Fever of unknown origin in dogs and cats. J Small Anim Pract 1987;28:167-181. 9. Roth AR, Basello GM. Approach to the adult patient with fever of unknown origin. Am Fam Phys 2003;68:2223-2228.

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The Diagnostic Approach to FUO in Cats CE 10. Mourad O, Palda V, Detsky AS. A comprehensive evidencebased approach to fever of unknown origin. Arch Intern Med 2003;163:545-551. 11. Johnson DH, Cunha BA. Drug fever. Infect Dis Clin North Am 1996;10:85-91. 12. Greene CE, Schultz RD. Immunoprophylaxis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:1069-1119. 13. Hartmann K. Feline leukemia virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:105-131. 14. Sellon RK, Hartmann K. Feline immunodeﬁciency virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:131-143. 15. Dow SW, Jones RL, Henik RA, et al. Clinical features of salmonellosis in cats: six cases (1981–1986). JAVMA 1989;194(10):1464-1466. 16. Rossi M, Hanninen ML, Revez J, et al. Occurrence and species level diagnostics of Campylobacter spp., enteric Helicobacter spp. and Anaerobiospirillum spp. in healthy and diarrheic dogs and cats. Vet Microbiol 2008;129(3-4):304-314. 17. Fox JG. Enteric bacterial infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:339-369. 18. Wess G, Unterer S, Haller M, et al. Recurrent fever as the only or predominant clinical sign in four dogs and one cat with congenital portosystemic vascular anomalies. Schweiz Arch Tierheilkd 2003;145(8):363-368. 19. Dubey JP, Lappin MR. Toxoplasmosis and neosporosis. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:754-775.

20. Greene CE. Feline foamy (syncytium-forming) virus infection. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:154-155. 21. Calvert CA, Wall M. Cardiovascular infections. In: Greene CE, ed. Infectious Diseases of the Dog and Cat. 3rd ed. St. Louis: Elsevier Saunders; 2006:841-865. 22. Malik R, Barrs VR, Church DB, et al. Vegetative endocarditis in six cats. J Feline Med Surg 1999;1(3):171-180. 23. Greiner M, Wolf G, Hartmann K. Bacteraemia in 66 cats and antimicrobial susceptibility of the isolates (1995–2004). J Feline Med Surg 2007;9(5):404-410. 24. Dawson S, Bennett D, Carter SD, et al. Acute arthritis of cats associated with feline calicivirus infection. Res Vet Sci 1994;56(2):133-143. 25. Liehmann L, Degasperi B, Spergser J, et al. Mycoplasma felis arthritis in two cats. J Small Anim Pract 2006;47(8):476-479. 26. Carro T, Pedersen NC, Beaman BL, et al. Subcutaneous abscesses and arthritis caused by a probable bacterial L-form in cats. JAVMA 1989;194(11):1583-1588. 27. Pedersen NC, Pool RR, O’Brien T. Feline chronic progressive polyarthritis. Am J Vet Res 1980;41(4):522-535. 28. Bennett D. Immune-mediated and infective arthritis. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. Vol 2. 6th ed. St. Louis: Elsevier Saunders; 2005:1958-1965. 29. Battersby IA, Murphy KF, Tasker S, et al. Retrospective study of fever in dogs: laboratory testing, diagnoses and inﬂuence prior to treatment. J Small Anim Pract 2006;47:370-376. 30. Hanna FY. Disease modifying treatment for feline rheumatoid arthritis. Vet Comp Orthop Traumatol 2005;18(2):94-99. 31. Klein NC, Cunha BA. Treatment of fever. Infect Dis Clin North Am 1996;10(1)211-216.

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 elevated body temperature a. secondary to heatstroke. b. associated with a drug reaction. c. secondary to a prolonged seizure. d. secondary to malignant hyperthermia. 2. Stage 1 diagnostic testing for cats with FUO should include a. urinalysis. b. ultrasonography. c. arthrocentesis. d. biopsy. 3. __________ examination should be conducted repeatedly in cats with an FUO. a. Physical c. Neurologic b. Fundic d. all of the above 4. Which is not known to be associated with polyarthritis in cats? a. feline infectious peritonitis b. mycoplasma c. calicivirus d. L-form bacterial infection

5. The underlying predisposing causes of bacteremia in cats include a. pneumonia. b. pyelonephritis. c. gastrointestinal tract disease. d. all of the above 6. The most common cause of FUO in cats is a. neoplasia. b. infectious disease. c. immune-mediated disease. d. none of the above 7. __________ has been reported to cause FUO in cats. a. A portosystemic shunt c. Lymphadenitis b. Polyarthritis d. all of the above 8. Thoracic radiography should be conducted a. in all cats with FUO. b. if ultrasonography results indicate respiratory disease. c. if the minimum database does not reveal the cause of the FUO. d. only in cats with clinical signs of respiratory disease.

9. Which statement regarding fever in cats is true? a. Cats with true fevers typically have body temperatures greater than 106°F. b. Cats are not affected by stress hyperthermia; therefore, a thorough diagnostic evaluation should immediately be conducted on every febrile cat. c. A subtle subcutaneous swelling on the limb of a febrile cat can be ignored because it is an unlikely cause of fever. d. About 50% of FUOs in cats remain undiagnosed despite thorough diagnostic evaluation. 10. Which statement regarding testing in cats with FUO is true? a. FeLV and FIV tests do not need to be conducted in cats previously tested for these diseases. b. A serum bile acids assay is never indicated in a cat with FUO. c. A blood smear should be evaluated along with the CBC for every cat with an FUO. d. Bone marrow aspiration is indicated only when the CBC is abnormal.

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CE Article 3

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Immunosuppressive Therapy for Canine Immune-Mediated Hemolytic Anemia ❯❯ Suliman Al-Ghazlat, BVSc, DACVIMa NYC Veterinary Specialists Forest Hills, New York

At a Glance Treatment Options Page 33

Suggested Immunosuppressive Protocol Page 35

Management of Relapse Page 40

Abstract: The mortality for dogs with severe immune-mediated hemolytic anemia (IMHA) is unacceptably high, and better immunosuppressive regimens are needed to increase survival. Understanding the basic immunology of the disease and the mechanisms of action of the available immunosuppressive 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.

he pathogenesis of canine immunemediated hemolytic anemia (IMHA) involves the production of immunoglobulin (Ig) that recognizes either a self (autoimmune) antigen or a foreign (immunemediated) antigen associated with red blood cells (RBCs). This results in sensitization or opsonization of the RBCs and their subsequent destruction by the complement system, the mononuclear phagocyte system, or both.1–3 The interaction of RBC surface-bound Ig with protein crystallizable fragment receptors (FcRs) on different cells in the immune system leads to a wide range of immune responses, including antibody-dependent cellular cytotoxicity, phagocytosis, complement activation, mast cell degranulation, lymphocyte proliferation, antibody secretion, and enhancement of antigen presentation. These responses also promote phagocytosis and clearance of opsonized RBCs by the mononuclear phagocyte system cells and lead to intravascular hemolysis by full activation of complement.1,2,4,5 In severe cases, clinical signs of anemia progress rapidly, and animals may present in shock. Most dogs that succumb to IMHA do so within the ﬁrst 2 weeks after onset (acute phase).3,6–11 A retrospective study of 60 dogs with IMHA showed a mortality of 52%, with a good long-term outcome in dogs that survived the ﬁrst 2 weeks of the disease.11

Treatment Options Current immunosuppressive therapies for IMHA act by a variety of mechanisms, but ultimately they all suppress antibody production by lymphocytes and/or inhibit the clearance of opsonized RBCs by macrophages or lysis by the complement system.5,12–14 Because the half-life of IgG (the antibody class involved in most cases of canine IMHA) in dogs is approximately 1 week, therapies directed only at suppression of antibody production are unlikely to affect the outcome in the acute phase of the disease.13,14 Over the past 25 years, great advances have been made in the field of immunology, especially in the development of new immunosuppressive agents (e.g., cyclosporine, leflunomide, mycophenolate mofetil) that are more potent, more selective, and less toxic than glucocorticoids.5,14,15 The wide array of new drugs offers the opportunity to use combinations that block different pathways of immune activation while selecting agents with nonoverlapping toxicity proﬁles. Nonetheless, IMHA mortality remains high, ranging from 22% to 80%.2,3,6–11,16–18 Moreover, multiple retrospective studies have shown that the addition of cyclosporine, azathioprine, or cyclophosphamide to glucocorticoids

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did not improve mortality.8,11 IMHA and its therapy can be divided into three phases: induction of remission, maintenance of remission and prevention of relapse, and management of relapse. The causes of death in dogs that die during the acute phase of IMHA are not well documented, but in addition to lack of response to immunosuppressive agents, they include thromboembolic disease, sepsis, and other side effects of therapy, as well as reactions to antithrombotic therapy and blood transfusions.8,9,18 One way to improve outcomes in the acute phase of IMHA is to focus the induction of immunosuppression on manipulating FcR/Ig interactions, reducing phagocytosis, and inhibiting complement. The causes of death during the maintenance phase of IMHA therapy are also unclear, but they may be related to disease recurrences or side effects of immunosuppression. To improve outcomes and minimize relapses in this phase, maintenance immunosuppressive therapy should be potent, speciﬁc, and associated with few or no side effects.

Glucocorticoids

QuickNotes The mortality for dogs with severe IMHA is high, with most deaths occurring within the ﬁrst 2 weeks of clinical disease.

Glucocorticoids remain the mainstay of immunosuppressive therapy for canine IMHA. Their activity is largely derived from their ability to repress the transcription of many genes responsible for encoding proinflammatory cytokines and adhesion molecules that influence immune cell trafficking and cellular interactions. The molecular basis of glucocorticoid action lies in the capacity to diffuse through the cell membrane and bind to cytosolic steroid receptors, which subsequently undergo nuclear translocation and modulate transcriptional activation.5,12,19,20 The main effect of glucocorticoids in the treatment of IMHA is to suppress complement and phagocytosis of opsonized RBCs by interfering with the expression and function of macrophage FcRs, which is an immediate effect.5,20 Prednisone (2 mg/kg bid) is commonly used to induce remission in IMHA, and a variety of dosages and protocols have been advocated.1–3,5–11,16–18 There have been no studies to evaluate the effect of different prednisone dosages on short- or long-term outcomes. Factors that may influence dosing include patient size, body condition, breed, disease severity, concurrent illnesses, and the presence of

gastrointestinal (GI) signs at presentation. For induction, the recommended dose is 2 mg/kg bid for dogs weighing less than 6 kg and 1.1 mg/kg or 30 mg/m2 bid for those weighing more than 30 kg.2,17 Remission is signaled by a stable or rising packed cell volume (PCV) with no clinical signs of decreased oxygen-carrying capacity over a period of 7 to 14 days. At this time, the dose may be decreased by 25% to 50% (depending on the severity of side effects) and then by 25% every 2 weeks thereafter.2 Once a dose of 0.5 mg/kg sid is reached, the patient can be switched to alternate-day prednisone therapy. As the side effects of prednisone at this point are typically mild, decreasing the dose by 25% every 4 to 6 weeks rather than every 2 weeks is generally advisable. Prednisone administration can be completely discontinued if there are no signs of relapse while the patient is receiving 0.25 mg/kg every other day for 4 to 6 weeks (TABLE 1). A complete blood count (CBC) should be obtained before any decrease in the dose of immunosuppressive agents. A less aggressive tapering protocol may be advised when glucocorticoids are used as the sole immunosuppressive agent. Although most dogs can be completely weaned from glucocorticoids, a few patients may require lifelong, low-dose therapy to maintain remission.2,11 This prednisone protocol is based solely on my clinical experience, and there are no published studies establishing its superiority. Adverse effects of glucocorticoids include iatrogenic hyperadrenocorticism, GI ulceration and perforation, recurrent infections, sepsis, and thromboembolic disease.21–23 Glucocorticoids may also predispose patients to pancreatitis, although this has not been proven.24 Based on clinical experience, largeand giant-breed dogs are especially sensitive to adverse effects of glucocorticoids. In contrast, most dogs weighing less than 6 kg generally experience only mild adverse effects. Dexamethasone is considered by some clinicians to be superior to prednisone in inducing IMHA remission, but there are no studies to support this opinion, and (anecdotally) GI ulceration and pancreatitis are more common with dexamethasone than with prednisone.13,14 In addition, due to its longer duration of effect in suppressing the hypothalamic–pituitary– adrenal axis, dexamethasone is not appropri-

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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 are no signs of GI disturbance

Discharge the patient from the hospital and continue the same medications

Day 14 PCV is rising but subnormal, with no signs of

Obtain a CBC and chemistry proﬁle Maintain prednisone at 30 mg bid Decrease azathioprine to 50 mg q48h

myelotoxicity/hepatotoxicity or serious glucocorticoid side effects

Day 21 PCV is normal, with no signs of myelotoxicity or serious glucocorticoid side effects

Day 28 (week 4) PCV is normal, with no signs of myelotoxicity or serious glucocorticoid side effects

Obtain a CBC Decrease prednisone to 20 mg bid Maintain azathioprine at 50 mg q48h Obtain a CBC 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®

FREE FREE CE Immunosuppressive Therapy for Canine IMHA CE

ate for alternate-day therapy. Because the main effect of glucocorticoids in treating IMHA is to suppress complement and FcR-mediated clearance of opsonized RBCs, glucocorticoids are the drugs of choice in the induction phase of treatment. However, as glucocorticoids can have severe side effects when used chronically at high doses, they are not ideal for maintaining remission and preventing relapse.

Human Intravenous Immunoglobulin

QuickNotes Glucocorticoids are the mainstay of immunosuppressive therapy for canine IMHA, but they can cause serious side effects.

Danazol Danazol is an androgen derivative used in the early 1990s as an adjunctive treatment for canine immune-mediated thrombocytopenia.33,34 Similar to glucocorticoids, danazol (10 to 15 mg/kg sid) may inhibit binding of the Fc portion of immunoglobulin to FcRs and hence prevent phagocytosis of opsonized RBCs.33,35 However, in one preliminary report of a small, prospective study in dogs with IMHA, adding danazol did not show any signiﬁcant beneﬁcial effects compared with prednisone alone.35 Danazol is an anabolic steroid and can cause dramatic weight gain in a short time, especially when used in combination with prednisone. Furthermore, danazol is expensive and may be hepatotoxic.36 Due to these side effects of chronic use, danazol is not recommended to maintain remission.

Human IV immunoglobulin (hIVIG) is a sterile, purified IgG preparation manufactured from pooled human plasma that typically contains more than 95% unmodified IgG, which has intact Fc-dependent effector functions, and only trace amounts of IgA and IgM. Several mechanisms of action have been proposed, including antiidiotypic activity, inhibition 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 therphagocytosis 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 sequesphagocytosis.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 splenecwith 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 secutive days over a period of 6 to 12 hours as an adjunctive therapy is superior to medical has been beneficial in some refractory cases therapy alone in reducing mortality and shortof canine nonregenerative IMHA.31 No signifi- ening the interval to normal PCVs in dogs with cant side effects were reported in these lim- severe IMHA.37 In fact, splenectomy may be effective for both remission induction and mainited samples.31,32 Due to its rapid onset of action and poten- tenance therapy for severe IMHA. It may also 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 mediof 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 No large-scale studies have evaluated the repeated infusions could induce acute anaphylaxis. 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 recombottle), 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 predecreases hospitalization time and transfusion liminary data, further studies to evaluate the requirements. Repeated maintenance infusions safety and efficacy of splenectomy in the treatment of canine IMHA are warranted. are currently not recommended.

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Immunosuppressive Therapy for Canine IMHA CE CE Plasmapheresis Plasmapheresis is a process whereby the components in plasma believed to cause or exacerbate disease are removed. The remaining blood components are then combined with replacement plasma or an inert substitute and returned to the patient.39,40 The clinical effectiveness of plasmapheresis in the treatment of autoimmune disease may be due to the partial removal of autoantibodies, immune complexes, complement components, proinﬂammatory agents, and soluble adhesion molecules.39 Plasmapheresis is most useful for rapidly reducing plasma concentrations of autoantibodies or immune complexes while other immunosuppressive measures are applied to prolong the effect.39 One study reported encouraging results for plasmapheresis in dogs with systemic immune-mediated diseases.40 The study suggested that any dog with an acute immune-mediated disease refractory to conventional immunosuppressive therapy can be considered for plasmapheresis.40 Although there are no reported clinical trials of plasmapheresis for IMHA, it may be helpful in acute, refractory cases or cases complicated by concurrent systemic infection.41 However, availability of plasmapheresis is limited in veterinary medicine, and experience with its use for treating animals with immune-mediated diseases is minimal.

on reducing levels of circulating antierythrocyte antibodies. As such, it is probably ineffective for remission induction during the acute phase of IMHA. One retrospective study showed no beneficial effect of adding cyclophosphamide to prednisone in 60 dogs with IMHA,11 and another study showed higher mortality in dogs so treated compared with dogs that received prednisone alone.8 Interpretation of these studies is complicated by their retrospective nature, and it is likely that cyclophosphamide was used only in the more severe cases. However, a small, randomized, prospective trial found no beneficial effects from adding cyclophosphamide to prednisone in the management of acute IMHA and even suggested that cyclophosphamide may adversely affect outcome.10 Indeed, several in vitro and in vivo experimental studies suggest that cyclophosphamide may paradoxically augment immune responses through a toxic effect on T regulatory cells.43 Cyclophosphamide also has serious adverse effects, including gastroenteritis, myelosuppression, sterile hemorrhagic cystitis, and secondary neoplasia.5,44,45 Based on this evidence, cyclophosphamide is not recommended for induction of remission in dogs with IMHA, and the risk–benefit profile should be considered carefully before it is used for maintenance therapy.

Cyclophosphamide

Azathioprine

Cyclophosphamide is a cytotoxic, myelosup- Azathioprine is a cy totoxic antimetabopressive alkylating agent. It cross-links DNA lite that is conver ted to 6 -mercaptopuhelixes to prevent their separation, thus pre- rine in the liver. It is a purine analogue venting the formation of a DNA template.5,42 that functions as a competitive purine Cyclophosphamide is toxic to both resting antagonist, thereby inhibiting cellular proand dividing cells, particularly proliferating liferation.5,12,46 Azathioprine is less toxic to 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 procytic 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 antigenwith fulminant IMHA. Several authors have specific tolerance and decrease the risk of recommended using cyclophosphamide in relapse.47 Azathioprine also suppresses maccases in which intravascular hemolysis or rophage function, which reduces inflammaautoagglutination 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 azathioysis.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.

QuickNotes Due to its rapid onset of action, human intravenous immunoglobulin may be a good choice in the initial management of severe IMHA.

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QuickNotes Cyclophosphamide is not recommended for induction of remission in dogs with IMHA.

Several studies have suggested a beneficial effect of azathioprine in the treatment of canine IMHA.6,11,17 However, as these studies are retrospective and lack data on azathioprine timing and dosing and because multiple concurrent immunosuppressive and antithrombotic agents were used, it is difficult to attribute the improved survival directly to use of azathioprine. A large, retrospective study showed that in dogs treated for IMHA with the combination of prednisone, azathioprine, and ultralow-dose aspirin (0.5 mg/kg sid), the survival rates at discharge, 1 month, and 1 year were 88%, 82%, and 69%, respectively, which compared favorably with rates in previously reported studies (57%, 58%, 34%).17 Due to azathioprine’s slow onset of action, it is unlikely to play any role in improving shortterm survival. The recommended canine loading dose is 2 mg/kg sid for 5 to 7 days, followed by 2 mg/kg every other day for maintenance.17 I generally continue azathioprine maintenance until the patient has been weaned off prednisone for 4 weeks. There is no well-established dose-tapering protocol for azathioprine, but I taper the dose gradually over 2 to 3 months by extending the period of time between doses by 1 day every 4 weeks (TABLE 1). The most common adverse effects of azathioprine therapy are GI disturbances and myelosuppression, particularly in large dogs.46,48,49 Acute pancreatitis and cholestatic hepatopathy have been anecdotally reported in dogs receiving azathioprine.48,50,51 The prognosis for azathioprine-induced bone marrow toxicity is good if the drug is discontinued before severe myelofibrosis occurs.49 Therefore, a CBC should be obtained every week for the first month of azathioprine therapy and every 4 weeks for the duration of therapy, and the drug should be discontinued immediately if the neutrophil count declines significantly. Due to its slow onset of immunosuppressive action, azathioprine is not a drug of choice for induction of remission. Conversely, due to its selective immunosuppressive effects, few side effects, availability, and relatively low cost, it is a good choice for maintenance therapy.

Cyclosporine A Cyclosporine A (CsA) is a cyclic polypeptide metabolite of the fungus Tolypocladium inﬂatum. It has potent immunosuppressive

properties through its blockage of transcription of cytokine genes in activated T cells. CsA inhibits the phosphatase activity of calcineurin, thereby preventing activation of the nuclear factor of activated T cells (NFAT).5,12,52 NFAT activation and nuclear translocation are required for the transcription of many cytokines, particularly interleukin-2 (IL-2), which is necessary for the proliferation and maturation of T cells.5,52,53 CsA also enhances expression of transforming growth factor-β (TGF-β), which is a potent inhibitor of IL-2–stimulated T cell proliferation and generation of antigenspecific cytotoxic lymphocytes.5,52 Studies indicate that CsA blocks the activation of C-Jun N terminal kinases and p38 signaling pathways triggered by antigen recognition, making CsA a highly specific inhibitor of T cell activation.12 In addition, by suppressing the production of interferon γ, CsA may inhibit the phagocytic capabilities of macrophages.5,53 The efficacy of CsA has been demonstrated in cats and dogs undergoing renal transplantation and in dogs with immune-mediated disorders.54 One retrospective study showed improved outcome in dogs with IMHA that received CsA and glucocorticoids compared with glucocorticoids alone, but the difference did not reach statistical significance.8 This finding suggests that CsA may be superior to glucocorticoids alone, as CsA was likely added only in the more severe cases. Preliminary results from a prospective study showed no beneficial effect from combining CsA with prednisone on the survival of dogs with IMHA in the first 28 days after onset.55 However, four of the 19 dogs in the prednisone-only group experienced relapses compared with none in the combination group. This study has not yet been published, and the number of subjects was small. In addition, a relatively small dose of CsA was used (4 mg/kg sid), and there was no mention of monitoring drug levels. Generally, a dosing regimen of 5 to 10 mg/kg sid is recommended for dogs, and plasma concentrations should be periodically monitored to achieve an effective but safe trough level (400 to 500 ng/mL); an optimal level has not been established.5 The most common side effects of CsA in dogs include GI irritation, gingival hyperplasia, antibiotic-responsive dermatitis, and papillomatosis.5,54,56 Malignancies, including

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Immunosuppressive Therapy for Canine IMHA CE lymphoma and squamous cell carcinoma, have been noted as well.57,58 In addition, anaphylaxis has been reported in people and dogs receiving IV CsA.59 CsA-associated nephrotoxicosis is a well known complication in people but appears to be rare in dogs and cats whose serum CsA levels are maintained within the therapeutic range (400 to 500 ng/mL).54 CsA is expensive and requires blood level monitoring, which usually makes it cost-prohibitive for large dogs. However, due to its potent and speciﬁc suppressive effects on lymphocyte proliferation and autoantibody production and tolerable side effects even when used chronically, it may be a good choice for maintenance. In addition, due to its suppression of phagocytosis, it may be beneﬁcial during the induction phase of therapy. 5,53

Mycophenolate Mofetil Mycophenolate mofetil (MMF) is a fermentation product of several Penicillium spp that is metabolized completely in the plasma and liver into its active metabolite, mycophenolic acid (MPA).60–62 MPA is an effective, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), which is a key enzyme in de novo purine biosynthesis.12,52,60–62 Most other cell lines can maintain their function through the salvage pathway of purine biosynthesis alone, but proliferating lymphocytes depend on both the salvage pathway and the de novo pathway. Due to the high speciﬁcity of MPA for IMPDH, MPA is a very selective lymphocyte inhibitor.60,61,63 Blockade of IMPDH by MPA was shown to deplete the guanosine pool in lymphocytes and to inhibit T- and B-cell proliferation, differentiation of alloreactive cytotoxic T cells, and antibody responses.60–62 Other mechanisms that may contribute to the immunosuppressive effects of MPA include induction of apoptosis of activated T cells and impairment of the maturation of dendritic cells.64 MMF has been shown to be safe and effective in prolonging the survival of canine experimental renal allografts and, anecdotally, has been used successfully in several cases of canine immune-mediated disease.61,62 The recommended starting MMF dose for dogs is 20 to 40 mg/kg/day PO divided into two or three doses.62 Experimental studies showed that

dogs are especially sensitive to the adverse GI effects (e.g., diarrhea, vomiting) of this drug.61 There are no reports on the use of MMF to manage canine IMHA, but based on its mechanism of immunosuppressive action, it should be investigated for maintenance of remission.

Leflunomide Leflunomide is a synthetic isoxazole derivative that is metabolized in the gut and liver.60 The active metabolite of leflunomide, A77 1726, reversibly inhibits dihydro-orotate dehydrogenase, the rate-limiting enzyme in the de novo synthesis of pyrimidines.12,52,60,65–67 Again, lymphocytes need both the salvage and the de novo pathways of pyrimidine synthesis to meet the high demand for pyrimidines during lymphocyte activation and proliferation. Leflunomide specifically suppresses activated T and B cells while other cells maintain their basal cell division. Experimental transplantation studies showed that A77 1726 prevents antibody production.60 Leflunomide also inhibits the production of proinflammatory cytokines (e.g., IL-1, tumor necrosis factor α) and augments the production of the antiinflammatory cytokine TGF-β, culminating in significant antiinflammatory effects.43,52,61,65 One study reported promising results of the use of leflunomide for treatment of immunemediated and inflammatory diseases in dogs refractory to conventional therapy.65 In this study, 26 dogs with different immune-mediated diseases were treated with leflunomide, including six dogs with IMHA. Five of these six dogs responded well to leflunomide therapy, and the one dog that died had severe myelofibrosis that was probably related to the primary disease. The initial dose of leflunomide was 4 mg/kg/day, but the dose was adjusted to obtain a target trough A77 1726 plasma level of 20 μg/mL.67 Most of the dogs had mild to moderate disease or partial response to conventional therapy, affording sufficient time for leflunomide to exert its immunosuppressive effects. Leflunomide is not commonly used in veterinary medicine, so adverse effects are not well documented. Adverse effects reported in a small number of dogs were rare and mild, including decreased appetite, lethargy, mild anemia, and self-limiting GI signs.65 However, most of the dogs in the study were

QuickNotes An immunosuppressive regimen is only one part of a comprehensive therapeutic approach to improve the outcome of dogs with IMHA.

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concurrently receiving other immunosuppressive agents that may have contributed to these effects. Based on this single study of dogs with IMHA, it seems that leﬂunomide may be an effective immunosuppressive drug with minimal side effects and should be investigated for maintenance of remission of canine IMHA.

Mizoribine Mizoribine is an imidazole nucleoside, and its active metabolite (mizoribine monophosphate) is a potent inhibitor of IMPDH.52,68 Therefore, like MMF, it blocks purine biosynthesis in B and T cells and inhibits their proliferation. The antiproliferative effect of mizoribine is linked to a decrease in guanine ribonucleotide pools. Mizoribine has been approved in Japan for renal transplant recipients and is currently undergoing clinical testing in Europe as a substitute for azathioprine in human renal transplant recipients. It appears to be safe and (unlike azathioprine) to have minimal myelotoxicity or hepatotoxicity. The availability of this drug is very limited, and little is known about its safety and efﬁcacy in veterinary medicine, but theoretically, it could be employed for the maintenance of IMHA remission.

Management of Relapse The relapse rate for canine IMHA is not well documented, but retrospective studies suggest that it is relatively high (13% to 20%).8,9,11,16,17 Clinicians must monitor patients for relapse (Table 1), make a prompt diagnosis, assess the severity and the acuteness of the relapse, and institute an appropriate immunosuppressive protocol. The choice of regimen depends on the severity of the relapse. A patient with an acute relapse (e.g., drop in PCV from normal to 25% or lower) should be hospitalized for supportive care and aggressively treated to reinduce remission. Immunosuppressive doses of glucocorticoids are the mainstay of therapy for relapse; adjunctive induction therapies for severe, refractory cases include hIVIG, splenectomy, and plasmapheresis. On the other hand, a patient with a mild relapse while being weaned off immunosuppressive therapy can be managed less aggressively. For example, a dog in which the PCV drops from 40% to 35% after the prednisone dose is decreased from 1.5 to 1 mg/kg/day

can be managed by increasing the dose to the previous level. This dog can be managed as an outpatient if it is asymptomatic for anemia, but its CBC should be reevaluated in 1 week to assess the efﬁcacy of therapy. Importantly, a drop in PCV for a dog with IMHA does not always signal a relapse. Other causes of a decreased PCV in dogs receiving immunosuppressive therapy for IMHA include sepsis and GI hemorrhage. Failure to identify patients with these complications can be detrimental and potentially fatal.

Conclusion Canine patients with severe IMHA have a guarded prognosis. Despite the introduction of several new immunosuppressive agents, mortality remains high.2,3,5–7,12–16 Glucocorticoids are the mainstay of IMHA therapy for induction of remission, but the addition of more potent immunosuppressive agents to prednisone therapy may be warranted in severe cases and in patients with major adverse glucocorticoid effects. Because azathioprine, CsA, leflunomide, and MMF are unlikely to have immediate beneficial effects in dogs with IMHA but may have immediate adverse reactions, I generally wait to add one of these agents to glucocorticoid therapy until the PCV is stable and the dog exhibits no GI disturbances. At my institution, the most common immunosuppressive agents used in combination with prednisone for severe IMHA are CsA and azathioprine. CsA is faster acting and has fewer side effects than azathioprine, but it can be cost prohibitive in large dogs. Preliminary results seem promising for leflunomide and discouraging for cyclophosphamide, but there are few published prospective, randomized trials evaluating the use of various immunosuppressive agents used in combination with prednisone versus prednisone alone. Immunosuppressive therapy is only one part of a comprehensive approach to improving the outcome of IMHA. Other therapies being studied include antithrombotic agents; one large, retrospective study showed improved survival in dogs with IMHA that were treated with ultralow-dose aspirin to prevent thromboembolic complications.17 The timing, volume, and type of oxygen-carrying support provided by blood products or blood substitutes is another area that requires further investigation.

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Immunosuppressive Therapy for Canine IMHA CE References 1. Baker RN. Anemia associated with immune responses. In: Feldman BF, Zinkl JG, Jain NC, et al, eds. Schalm’s Veterinary Hematology. Baltimore: Lippincott Williams & Wilkins; 2000:169-175. 2. McCullough S. Immune-mediated hemolytic anemia: understanding the nemesis. Vet Clin Small Anim 2003;33:1295-1315. 3. Klag AR, Giger U, Shofer FS. Idiopathic immune-mediated hemolytic anemia in dogs: 42 cases (1986–1990). JAVMA 1993;202:783-788. 4. Heyman B. Regulation of antibody responses via antibodies, complement and Fc receptors. Ann Rev Immunol 2000;18:709-737. 5. Gregory CR. Immunosuppressive agents. In: Kirk RW, Bonagura JD, eds. Kirk’s Current Veterinary Therapy XIII. Philadelphia: Saunders; 2000:509-513. 6. Reimer ME, Troy GC, Warnick LD. Immune-mediated hemolytic anemia: 70 cases (1988–1996). JAAHA 1999;35:384-391. 7. Duval D, Giger U. Vaccine-associated immune-mediated hemolytic anemia in the dog. J Vet Intern Med 1996;10:290-295. 8. Grundy SA, Barton C. Influence of drug treatment on survival of dogs with immune-mediated hemolytic anemia: 88 cases (1989– 1999). JAVMA 2001;218:543-546. 9. Carr AP, Panciera DL, Kidd L. Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: a retrospective study of 72 dogs. J Vet Intern Med 2002;16:504-506. 10. Mason N, Duval D, Shofer FS, et al. Cyclophosphamide exerts no beneficial effect over prednisone alone in the initial treatment of acute immune-mediated hemolytic anemia in dogs: a randomized controlled clinical trial. J Vet Intern Med 2003;17:206-212. 11. Burgess K, Moore A, Rand W, Cotter SM. Treatment of immunemediated hemolytic anemia in dogs with cyclophosphamide. J Vet Intern Med 2000;14:456-462. 12. Allison AC. Immunosuppressive drugs: the first 50 years and a glance forward. Immunopharmacology 2000;47(2-3):63-83. 13. Couto CG. Use and misuse of immunosuppressants. Proc 20th ACVIM Forum 2002;16:599. 14. Cohn L. Immune mediated blood dyscrasias: therapeutic opinions. Proc 22nd Annu Forum Am Coll Vet Intern Med 2004:326-327. 15. Braun F, Lorf T, Ringe B. Update of current immunosuppressive drugs used in clinical organ transplantation. Transpl Int 1988;11(2):77-81. 16. Jackson ML, Kruth SA. Immune-mediated hemolytic anemia and thrombocytopenia in the dog: a retrospective study of 55 cases diagnosed from 1969 through 1983 at the Western College of Veterinary Medicine. Can Vet J 1985;26:245-250. 17. Weinkle TK, Center SA, Randolph JF, et al. Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993–2002). JAVMA 2005;226(11):1869-1880. 18. Scott-Moncrieff JC, Treadwell NG, McCullough SM, et al. Hemostatic abnormalities in dogs with primary immune-mediated hemolytic anemia. JAVMA 2001;37:220-227. 19. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids— new mechanisms for old drugs. N Engl J Med 2005;353(16):1711-1723. 20. Ruiz P, Gomez F, King M, et al. In vivo glucocorticoid modulation of guinea-pig splenic macrophage Fc-receptors. J Clin Invest 1991;88:149-157. 21. Cosenza SF. Drug-induced gastroduodenal ulceration in dogs. Mod Vet Pract 1984;12:923-925. 22. Toombs JP, Collins LG, Graves GM, et al. Colonic perforation in steroid-treated dogs. JAVMA 1986;188:145-150. 23. Casonato A, Pontara E, Boscar M, et al. Abnormalities of von Willebrand factor are also part of the prothrombotic state of Cushing’s syndrome. Blood Coagul Fibrinolysis 1999;10:145-151. 24. Moriello KA, Bowen D, Meyer DJ. Acute pancreatitis in two dogs given azathioprine and prednisone. JAVMA 1987;191(6):695-696. 25. Knezevic-Maramica I, Kruskall MS. Intravenous immune globulins: an update for clinicians. Transfusion 2003;43:1460-1480. 26. Reagan WJ, Scott-Moncrieff JC, Christian J, et al. Effects of human intravenous immunoglobulin on canine monocytes and lymphocytes. Am J Vet Res 1998;213(59):1568-1574. 27. Rahilly LJ, Keating JH, O’Toole TE. The use of intravenous human immunoglobulin in treatment of severe pemphigus foliaceus in a dog. J Vet Intern Med 2006;20:1483-1486. 28. Trotman TK, Phillips FH, King LG, et al. Treatment of severe adverse cutaneous drug reactions with human intravenous immunoglobulin in two dogs. JAAHA 2006;42:312-320.

29. Byrne KP, Giger U. Use of human immunoglobulin for the treatment of severe erythema multiforme in a cat. JAVMA 2002;220:197-201. 30. Nuttall TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug induced Stevens-Johnson syndrome in a dog. J Small Anim Pract 2004;45:357-361. 31. Scott-Moncrieff JCR, Reagan WJ, Glickman LT, et al. Treatment of nonregenerative anemia with human gamma globulin in dogs. JAVMA 1995;206:1895-1900. 32. Kellerman DL, Bruyette DS. Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med 1997;11:327-332. 33. Jans HE, Armstrong PJ, Price GS. Therapy of immune-mediated thrombocytopenia: a retrospective study of 15 dogs. J Vet Intern Med 1990;4:4-7. 34. Bloom JC, Meunier LD, Thiem PA, Sellers TS. Use of danazol for treatment of corticosteroid-resistant immune-mediated thrombocytopenia in a dog. JAVMA 1989;194(1):76-78. 35. Miller E. Danazol therapy for the treatment of immune-mediated hemolytic anemia in dogs (abstract). J Vet Intern Med 1997;11(2):130. 36. Welder AA, Robertson JW, Melchert RB. Toxic effects of anabolic-androgenic steroids in primary rat hepatic cell cultures. J Pharmacol Toxicol Methods 1995;33:187-195. 37. Toll J, Aronsohn M. Prospective evaluation of medical therapy with or without early splenectomy for treatment of severe immunemediated hemolytic anemia in the dog (abstract). J Vet Intern Med 2003;17(3):383. 38. Yan J, Vetvicka V, Xia Y, et al. Critical role of Kupffer cell CR3 (CD11b/CD18) in the clearance of IgM-opsonized erythrocytes or soluble beta-glucan. Immunopharmacology 2000;46(1):39-54. 39. Bartges JW. Therapeutic plasmapheresis. Semin Vet Med Surg 1997;12(3):170-177. 40. Matus RE, Gordon BR, Leifer CE, et al. Plasmapheresis in ﬁve dogs with systemic immune-mediated disease. JAVMA 1985;187(6):595-599. 41. Creager AJ, Brecher ME, Bandarenko N. Thrombotic thrombocytopenic purpura that is refractory to therapeutic plasma exchange in two patients with occult infection. Transfusion Pract 1998;38:419-423. 42. Stanton M, Legendre A. Effects of cyclophosphamide in dogs and cats. JAVMA 1986;188:1319-1322. 43. Su Y, Rolph M, Cooley M, Sewell W. Cyclophosphamide augments inﬂammation by reducing immunosuppression in a mouse model of allergic airway disease. J Allergy Clin Immunol 2006;117(3):635-641. 44. Marin MP, Samson RJ, Jackson ER. Hemorrhagic cystitis in a dog. Can Vet J 1996;37(4):240. 45. Ruther U, Nunnensiek C, Schmoll HJ. Secondary neoplasias following chemotherapy, radiotherapy and immunosuppression. Contrib Oncol 2000;55:36-61. 46. Beale KM. Azathioprine for treatment of immune-mediated disease of dogs and cats. JAAHA 1988;192:1316-1318. 47. Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human Cd4+ T lymphocytes. J Clin Invest 2003;111(8):1133-1145. 48. Houston DM, Taylor JA. Acute pancreatitis and bone marrow suppression in a dog given azathioprine. Can Vet J 1991;32(8):496-497. 49. Rinkardt NE, Kruth SA. Azathioprine-induced bone marrow toxicity in four dogs. Can Vet J 1996;37:612-613. 50. Perini GP, Bonadiman C, Fraccaroli GP, Vantini I. Azathioprinerelated cholestatic jaundice in heart transplant patients. J Heart Transplant 1990;9(5):577-578. 51. King PD, Perry MC. Hepatotoxicity of chemotherapy. Oncologist 2001;6:162-176. 52. Halloran PF. Molecular mechanisms of new immunosuppressants. Clin Transplant 1996;10:118-123. 53. Salom RN, Maquire JA, Hancock WW. Mechanism of a clinically relevant protocol to induce tolerance of cardiac allografts. Perioperative donor spleen cells plus cyclosporine suppress IL-2 and interferon-gamma production. Transplantation 1993;56(6):1309-1314. 54. Robson D. Review of the pharmacokinetics, interactions and adverse reaction of cyclosporine in people, dogs and cats. Vet Rec 2003;152:739-748. 55. Husbands B, Polzin D, Armstrong PJ, et al. Prednisone and cyclosporine vs prednisone alone for treatment of canine immune-mediated hemolytic anemia (IMHA) (abstract). J Vet Intern Med 2004;18:389.

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Quick Course Factors to Consider When Choosing Kitten Vaccines At no time are cats at greater risk for disease than in the first few months of life.1 That’s why it’s important to vaccinate kittens early to induce immunity before they are exposed to pathogens. “Maternal antibodies can block the kitten’s ability to respond to a vaccine,”2 according to Alice Wolf, DVM, DACVIM, DABVP, emeritus/adjunct professor at Texas A&M University College of Veterinary Medicine and chief medical consultant for the Veterinary Information Network. “Every kitten has a different level of maternal antibodies— even kittens from the same litter—and these antibodies can persist for different periods of time.” Some kittens have very low or no maternal antibodies at 6 weeks

of age.3 Studies have also shown that maternal antibody interference may persist beyond 14 weeks of age.2–4 To compensate for variations in maternal immunity, initial kitten vaccinations should begin at 6 to 8 weeks of age and continue at 3- to 4week intervals until the kitten is at least 16 weeks of age.5 Practitioners are encouraged to consult the 2006 American Association of Feline Practitioners (AAFP) feline vaccination guidelines for complete vaccine recommendations.

for adult cats, the AAFP strongly recommends vaccinating kittens against this disease. In an experimental study, susceptibility to FeLV decreased with age, but young kittens were most vulnerable.6 Persistent viremia occurred with 100% of cats infected with FeLV as newborns, 85% of cats exposed between 2 weeks and 2 months of age, and 15% of cats infected at 4 months to 1 year of age.6 Even though owners may claim a kitten is a strictly indoor pet, kittens can escape or owners may eventually allow them outdoors.

The Case for FeLV Vaccination Although vaccination for feline leukemia virus (FeLV) is considered noncore

Choosing the Right Vaccines Some vaccine components, such as preservatives, adjuvants, or pH, can contribute to local inflammation.2 Chronic inflammation has been implicated as a potential factor in the development of vaccine-associated sarcomas (VAS).7 Although the precise cause of VAS is not known, the AAFP Feline Vaccine Advisory Panel suggests using less inflammatory products whenever possible.5 Most products today are killed, modified-live virus (MLV), or recombinant canarypox-vectored vaccines. Killed virus vaccines generally require an adjuvant to bolster the immune response. Most MLV and recombinant feline vaccines, on the other hand, are capable of stimulating an effective immune response without

POSTINJECTION LUMPS: THE 3-2-1 RULE Most postvaccination lumps usually resolve within a few weeks. However, lumps that persist for more than 3 months after the injection, are larger than 2 cm in diameter, or continue to increase in size 1 month after injection should be investigated.5 In these cases, a biopsy and chest radiographs can help determine the diagnosis and prognosis. Cats with vaccine-associated sarcomas require aggressive treatment, and, if possible, injectable vaccines should be discontinued in the future in these cats.5

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Primary Kitten Vaccine Series5 Initial Dosea

Booster Intervals

Feline panleukopenia virus (FPV)

As early as 6 weeks of age

Every 3 to 4 weeks

Feline herpesvirus-1 (FHV-1)

As early as 6 weeks of age

Every 3 to 4 weeks

Feline calicivirus (FCV)

As early as 6 weeks of age

Every 3 to 4 weeks

Rabies

As early as 8 weeks of age or 12 to 16 weeks of age

Vaccine

Considerations

Core Vaccines

Single dose in the first year; follow state or local statutes

Recommended Vaccine Feline leukemia virus (FeLV) aDepends

As early as 8 weeks of age

One booster 3 to 4 weeks later

Kittens should test negative for FeLV before vaccination

on the vaccine.

adjuvants. The canarypox-vectored recombinant vaccines, for example, stimulate protective immunity and reduce the potential risks associated with an adjuvant. Another way to potentially reduce inflammation at the injection site is with the needle-free VET JET® transdermal delivery system. Compared with conventional needles and syringes, this system disperses a smaller volume of vaccine (0.25 ml) into the tissue through a tiny orifice (about the diameter of a 36gauge needle). Discussing Vaccine Issues with Clients Owners should be instructed to monitor their kittens for signs of possible vaccine reactions. “The most common reaction is a mild malaise or fever that may last for 24 hours,” explains Dr. Wolf. “That’s simply the immune system responding to the vaccine.” Mild swelling at the vaccine site may also occur and generally resolves within

a few weeks. However, a lump that persists or grows can be a sign of VAS. Although the risk of VAS is relatively low (approximately one to two cases per 10,000 vaccinated cats 8,9), the probability that a kitten will be exposed to a potentially fatal disease is considerably higher.10 Still, vaccines are important, even for indoor kittens. “It’s possible for owners to track the panleukopenia virus into the house,” according to Dr. Wolf, “and while less likely, owners can bring respiratory viruses home on their clothing.”11 Kittens may also be exposed to sick cats through porch screens or when boarded, groomed, or traveling with their owners. “Certainly, all kittens need to receive their core vaccines,” says Dr. Wolf. REFERENCES 1. Richards J, Rodan I: Feline vaccination guidelines. Vet Clin North Am Small Anim Pract (31)3:455−472, 2001. 2. Greene CE, Schultz RD: Immunophylaxis, in Greene CE (ed): Infectious Diseases of the Dog and Cat, ed. 3. St. Louis, Saunders Elsevier,

2006, pp. 1069–1119. 3. Dawson S, Willoughby K, Gaskell R, et al: A field trial to assess the effect of vaccination against feline herpesvirus, feline calicivirus and feline panleukopenia virus in 6-week-old kittens. J Feline Med Surg 3:17–21, 2001. 4. Reese MJ, Patterson EV, Tucker SJ, et al: The effect of anesthesia and surgery on serological responses to vaccination in kittens. JAVMA 233(1):116–121, 2008. 5. AAFP Advisory Panel: The 2006 American Association of Feline Practitioners Feline Vaccine Advisory Panel Report. JAVMA 9(1):1405–1441, 2006. 6. Hoover EA, Olsen RG, Hardy WD Jr, et al: Feline leukemia virus infection: Age-related variation in response of cats to experimental infection. J Natl Cancer Inst 57:365–369, 1976. 7. Macy DW, Hendrick MJ: The potential role of inflammation in the development of postvaccinal sarcomas in cats. Vet Clin North Am 26(1): 103–108, 1996. 8. Kass PH, Barnes WG Jr, Spangler WL, et al: Epidemiologic evidence for a causal relation between fibrosarcoma and tumorgenesis in cats. JAVMA 203:396–405, 1993. 9. Esplin DG, McGill LD, Meininger AC, et al: Postvaccination sarcomas in cats. JAVMA 202:1245–1247, 1993. 10. Tizard IR: The uses of vaccines, in Veterinary Immunology: An Introduction, St. Louis, Saunders Elsevier, 2009, pp. 270−285. 11. Gaskell RM, Dawson S, Radford A: Feline respiratory disease, in Greene CE (ed): Infectious Diseases of the Dog and Cat, ed. 3. St. Louis, 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. In: White CE, White DJG, eds. Cyclosporin A. Amsterdam: Elsevier Biomedical Press; 2003:45-75. 57. Blackwood L, German AJ, Stell AJ, O’Neil T. Multicentric lymphoma in a dog after cyclosporine therapy. J Small Anim Pract 2004;45:259-262. 58. Callan MB, Preziosi D, Mauldin E. Multiple papillomavirus-associated epidermal hamartomas and squamous cell carcinoma in situ in a dog following chronic treatment with prednisone and cyclosporine. Vet Derm 2005;16:338-345. 59. Kuiper RAJ, Malingre MM, Beijnen JH, et al. Cyclosporine-induced anaphylaxis. Ann Pharmacother 2000;34:858-861. 60. Gummert JF, Ikonen T, Morris RE. Newer immunosuppressive drugs: a review. J Am Soc Nephrol 1999;10:1366-1380. 61. Platz KP, Sollinger HW, Hullett DA, et al. RS-61443—a new, potent immunosuppressive agent. Transplantation 1991;51:27-31. 62. Dewey CW, Boothe DM, Rinn KL, et al. Treatment of a myasthenic dog with mycophenolate mofetil. J Vet Emerg Crit Care 2000;10:177-187. 63. Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate mofetil for the treatment of refractory autoimmune haemolytic

anaemia and auto-immune thrombocytopenia purpura. Br J Haematol 2002;117:712-715. 64. Mehling A, Grabbe S, Voskort M, et al. Mycophenolate mofetil impairs the maturation and function of murine dendritic cells. J Immunol 2000;165:2374-3281. 65. Gregory CR, Stewart A, Sturges B, et al. Leflunomide effectively treats naturally occurring immune-mediated and inflammatory diseases of the dog that are unresponsive to conventional therapy. Transplant Proc 1998;30:4143-4148. 66. Cohen S, Cannon GW, Schiff M, et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Arthritis Rheum 2001;44:1984-1992. 67. Gregory CR, Silva HT, Patz JD, Morris RE. Comparative effects of malononitriloamide analogs of leflunomide on whole blood lymphocyte stimulation in humans, rhesus macaques, cats, dogs, and rats. Transplantation Proc 1998;30:1047-1048. 68. Yokota S. Mizoribine: mode of action and effects in clinical use. 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 IMHA is correct? a. Most dogs die during the maintenance phase of disease management. b. All dogs can be successfully weaned off immunosuppressive therapy. c. Dogs that survive the first 2 weeks of the disease generally have a good longterm prognosis. d. To avoid relapses, dogs should never be weaned off immunosuppressive medications. 2. Which statement regarding glucocorticoid therapy for treating IMHA is correct? a. Prednisone at 2 mg/kg bid is a good dose for large- and giant-breed dogs, whereas small-breed dogs should not receive more than 1.2 mg/kg bid. b. It has been proven that dexamethasone is superior to prednisone for inducing remission. c. Dexamethasone is not appropriate for alternate-day therapy. d. Prednisone at doses higher than 2 mg/kg bid is associated with better outcomes. 3. Which statement regarding immunosuppressive agents used to treat canine IMHA is correct? a. Azathioprine is a good drug to induce remission, but it can cause bone marrow suppression. b. Hepatotoxicity is a common side effect

of cyclophosphamide. c. Secondary malignancies have been reported in dogs receiving cyclosporine. d. Cyclosporine is a potent cytotoxic immunosuppressive drug. 4. Which statement regarding the mechanism of action of immunosuppressive agents is incorrect? a. Azathioprine is a competitive purine antagonist. b. Mizoribine blocks the purine biosynthetic pathway. c. Leﬂunomide blocks the biosynthesis of pyrimidine. d. Cyclosporine works by blocking the biosynthesis of pyrimidine. 5. Which is not a reported side effect of cyclosporine therapy in dogs? a. GI disturbances b. infection c. development of secondary neoplasia d. aplastic anemia 6. Which is not a side effect of azathioprine therapy in dogs? a. pancreatitis b. bone marrow toxicity c. gingival hyperplasia d. GI disturbances 7. Which is not a side effect of glucocorticoids? a. GI ulceration and perforation

Compendium: Continuing Education for Veterinarians® | January 2009 | CompendiumVet.com

b. increased risk of infection c. bone marrow suppression d. increased risk of thromboembolic disease 8. Which patient is the most suitable candidate for hIVIG treatment? a. a dog with a 3-day history of mild weakness, a PCV of 26%, total bilirubin of 1.5 mg/dL, and 2+ spherocytes b. a dog experiencing an IMHA relapse with PCV of 24% and a history of receiving an hIVIG dose 1 month earlier c. a dog that has been hospitalized for IMHA for 3 days and received prednisone 2 mg/kg bid and three blood transfusions d. a dog presenting with acute IMHA, a PCV of 20%, and a history of congestive heart failure 9. Which immunosuppressive therapy is unlikely to be effective in the ﬁrst 2 weeks of treating IMHA? a. glucocorticoids c. azathioprine b. splenectomy d. hIVIG 10. In dogs with IMHA, administration of which immunosuppressive drug has been associated with a worse outcome in retrospective studies? a. cyclosporine b. leﬂunomide c. cyclophosphamide d. mycophenolate mofetil

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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 Name: __________________________________ Age: ________ Species: _____________________ Breed: ___________________ Gender: ❏ Male ❏ Female

Neutered/spayed: ❏ Yes ❏ No

Is food left out for your pet during the day?

❏ Yes

❏ No

Does your pet have access to other, unmonitored food sources (e.g., treats fed by neighbor, food left for outdoor cats)?

Current weight: _____________ Usual weight: _____________

❏ Yes

Body condition score (1–9): _____

If yes, please describe:________________________________

Evidence of muscle wasting

❏ None

❏ Mild

❏ Severe

❏ No

____________________________________________________ ____________________________________________________

Reason for Visit

____________________________________________________

If you have more than one pet, do they have access to each other’s

____________________________________________________

How many adults are in your household? ___________________ How many children are in your household, and how old are they? ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Do you have other pets?

❏ Yes

❏ No

If yes, please describe:

____________________________________________________

Household Demographics

Where is your pet housed?

food?

❏ Indoors ❏ Yes

❏ Outdoors

❏ Both

❏ No If so, please list species

and specify if they live indoors or outdoors. ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Feeding Management Who typically feeds your pet? ____________________________ ____________________________________________________

____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ How do you store your pet’s food? ________________________ ____________________________________________________ ____________________________________________________ ____________________________________________________ Activity How active is your pet? ❏ Hyperactive ❏ Not very active

❏ Very active

❏ Average

❏ Hardly moves

How often is your pet walked? ❏ At least 3 times/day ❏ Seldom

❏ 1-2 times/day

❏ Once a day

❏ 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

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:

Nausea/salivation

❏ 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

____________________________________________________

❏ Yes

❏ No

____________________________________________________

Have there been any changes in urination? Diet

For each of the following categories, list the brand names (if applicable) and amounts of all foods your pet eats daily, as well as how often each food is fed (e.g., twice a day).

❏ Yes

❏ No

____________________________________________________ Are you open to making a change in your pet’s diet? ❏ Yes

❏ No

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?

____________________________________________________

If so, which foods? ____________________________________

____________________________________________________

❏ Yes

❏ No

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

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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.

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• 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