EHRLICHIOSIS CANINA Y FELINA

8/16/2019 EHRLICHIOSIS CANINA Y FELINA

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Seasonality: Dogs infected with A. phagocytophilum

or Ehrlichia ewingii more often present in the springthrough early summer when the Ixodes scapularis– and

Amblyomma americanum–vector ticks are mostactively feeding. Dogs infected with E. canis presentany time of year because of the chronic nature of theinfection.

Owner Observations:• Acute phase: Typically lethargy, anorexia, weight

loss, and depression.

• Chronic phase: Same as acute phase but with thepotential addition of signs of bleeding tendencies

(epistaxis, dermal petechiae, hyphema), central nerv-ous system involvement (seizures, vestibular signs,cervical pain), ocular disease (eye color change dueto corneal edema, hyphema, uveitis), or lameness.

Other Historical Considerations/Predispositions:With E. canis, the disease is divided into three phases(acute, subclinical, chronic). These phases are notknown to occur with the other Ehrlichia or Anaplasmaspp. The acute phase occurs 1 to 3 weeks after the ani-mal is bitten by an infected tick. Signs are generallymild and spontaneously resolve after 2 to 4 weeks. The

animal may then clear the infection or go into a sub-clinical phase that can last weeks to years, duringwhich time the animal is asymptomatic. Most animalsare presented during the chronic phase, with clinicalsigns ranging from mild to very severe. Dogs and catscan be co-infected with other tick-borne pathogens.This may cause immunosuppression, making the ani-mal more susceptible to severe disease.

Physical Examination Findings• Fever.

• Depression, lethargy.

• Weight loss.

• Signs indicative of bleeding tendencies (epistaxis,melena, petechial or ecchymotic hemorrhages,hyphema, retinal hemorrhage, hematuria) occur in25% to 60% of dogs.

• Splenomegaly (25%).

• Generalized lymphadenopathy (20%).

• Central nervous system signs (hyperesthesia, stupor,ataxia, paresis, seizures, head tilt, cerebellar dys-function, vestibular signs, nystagmus, or other cra-nial nerve deficits).

hrlichiosis was first recognized as a disease of dogs

in Algeria in 1935 but did not gain prominenceuntil the 1960s when a number of military work-

ing dogs stationed in Vietnam contracted a highly fatalhemorrhagic disease. Termed tropical canine pancy-topenia, the disease was caused by Ehrlichia canis, anorganism found to be transmitted by the brown dogtick, Rhipicephalus sanguineus. Canine ehrlichiosis wasfound to exist virtually anywhere this tick species wasfound and has been reported in most tropical and sub-tropical regions of the world, including the UnitedStates. Subsequently, other Anaplasma and Ehrlichiaspp were found to infect dogs, horses, and ruminants.

Ehrlichia spp are gram-negative, pleomorphic, obligateintracellular cocci related to Rickettsia.

In the late 1980s, ehrlichiosis was identified as apotentially fatal disease of humans. That spurred alarge interest in researching Ehrlichia organisms. Inrecent years, genetic studies resulted in the discoveryof additional organisms and a taxonomic reclassifica-tion of some species. The genus Ehrlichia is now cate-gorized within the family Anaplasmataceae, alongwith three other genera: Anaplasma, Neorickettsia,and Wolbachia. Some of the important veterinarypathogens from this family are listed in Table 1; each

species listed has been reported to cause illness indogs. Ehrlichiosis has also been reported in a smallnumber of cats; the causative organisms resemble E.canis, Neorickettsia risticii , and Anaplasma phagocy-tophilum. For ease of discussion, the term ehrlichiosisas used in this article refers to the group of diseasescaused by any of the organisms in Table 1.

DIAGNOSTIC CRITERIA

Historical InformationGender Predisposition: None.

Age Predisposition: None.

Breed Predisposition: All breeds are susceptible, butGerman shepherds seem to elicit a poorer cell-medi-ated response and are predisposed to developing bonemarrow suppression that is more severe and lessresponsive to treatment.

C ANINE AND FELINE EHRLICHIOSIS*Nancy A. Vincent-Johnson, DVM, MS, DACVIM (Small Animal, Internal Medicine), DACVPMLieutenant Colonel, United States Army Veterinary CorpsCommander, National Capital District Veterinary CommandFort Belvoir, VA

*The views expressed in this article are those of the authorand do not reflect the official policy or position of theDepartment of the Army, the Department of Defense, or theUS Government.

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• Intracytoplasmic inclusion bodies (morulae) mayoccasionally be seen during the acute phase inmonocytes (E. canis), granulocytes (E. ewingii , A.

phagocytophilum), or platelets ( Anaplasma platys).

• Coagulation panel (activated partial thromboplastintime [aPTT], prothrombin time [PT], fibrin degrada-tion products) is typically normal, but mucosalbleeding time may be prolonged.

• Concurrent infections are common (e.g., protozoan,bacterial, urinary tract infection).

Other Diagnostic Findings• Radiographic or ultrasonographic examination may

reveal splenomegaly, hepatomegaly.

• Ophthalmic examination may reveal anterioruveitis, hyphema, conjunctivitis, conjunctival oriridial petechiations, corneal opacity, photophobia,papilledema, retinal hemorrhages, retinal detach-ment, or retinal vascular engorgement and tortuos-ity with circular to horseshoe-shaped perivascularlesions.

• Serology. $

— Immunofluorescent antibody (IFA): Dogsinfected with E. canis typically have positiveIFA titers at the time of presentation; however,clinical signs may occur before the develop-ment of antibodies. Titers do not necessarilycorrelate with the severity or duration of infec-tion. Many healthy dogs are seropositivebecause of exposure and thus care must betaken in interpreting antibody tests. Suspectcases with negative or low titers should beretested in 2 to 4 weeks to look for a rise in titer,which would indicate recent exposure.

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• Lameness, joint pain or swelling (more commonlyseen with E. ewingii ).

• Polymyositis.

• Other: Pale mucous membranes, ocular and nasaldischarge, dyspnea, limb or scrotal edema, uveitis,and/or abdominal tenderness. Dogs may also showclinical signs attributable to acute respiratory dis-tress syndrome, glomerulonephritis, acute renal fail-ure, or hyperviscosity syndrome.

Laboratory Findings• Thrombocytopenia (82%).

• Mild to moderate anemia (82%; usually nonregen-erative; may be Coombs’ positive).

• Hyperproteinemia (33% to 75%), hyperglobuline-mia (occasionally extreme).

• Hypoalbuminemia.

• Leukopenia, leukocytosis, or normal leukocyte count.

• Lymphocytosis or lymphopenia, monocytosis.

• Proteinuria.

• Increases in alanine aminotransferase, alkaline phos-

phatase, amylase, blood urea nitrogen, creatinine.• Polyclonal or (rarely) monoclonal gammopathy on

protein electrophoresis.

• Bone marrow aspirate:

— Acute phase: Hyperplasia, especially of mega-karyocytes.

— Chronic phase: Hypoplasia of all three celllines, plasmacytosis.

• Pancytopenia may be seen in chronic, severe cases(less than 25%); occurs more often in German shep-herds.

Pathogen Associated Disease Vector

Ehrlichia canis Canine monocytic ehrlichiosis Rhipicephalus sanguineus

Ehrlichia ewingii Canine granulocytic ehrlichiosis Amblyomma americanum

Ehrlichia chaffeensis Human monocytic ehrlichiosis A. americanum

Anaplasma phagocytophilum2 Human anaplasmosis,3 equine ehrlichiosis Ixodes spp

Anaplasma platys4 Canine cyclic thrombocytopenia R. sanguineus?

Neorickettsia helminthoeca Salmon poisoning of dogs Nanophyetus salmincola(nematode)

Neorickettsia risticii Potomac horse fever Trematode cercariae foundin snails and aquatic insects

1The presence of a morula in a monocyte or granulocyte is not necessarily specific for the organism listed; the terms monocytic and granulocytic ehrlichiosis reflect historical designations.2Formerly Ehrlichia equi, Ehrlichia phagocytophilum.3Formerly human granulocytic ehrlichiosis.4Formerly Ehrlichia platys.

T A B L E 1S o m e I m p o r t a n t Ve t e r i n a r y P a t h o g e n s o f t h e F a m i l y

A n a p l a s m a t a c e a e 1


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— ELISA: An in-house combination test for E.canis, Borrelia burgdorferi , and heartworm isavailable in the United States (SNAP 3Dx,IDEXX Laboratories, Inc., Westbrook, ME). Thetest is highly sensitive (95%) and specific(99%). A positive ELISA result corresponds withan IFA titer of 1:100 or higher for E. canis butnot related pathogens.

— Cross-reactivity exists between species but ishighest among species of the same genus.Therefore, infection with various ehrlichialspecies may yield a positive result on an IFA forE. canis. Western immunoblotting or poly-merase chain reaction (PCR) can be used to dis-tinguish between them. Despite cross-reactivity,only about 50% of dogs with E. ewingii test pos-itive on E. canis tests. This percentage would beexpected to be much lower in dogs infectedwith A. phagocytophilum, A. platys, and N. ris-ticii; thus titers to those species should be

requested when indicated.— Infected cats may have low or negative titers.

• PCR assays. $

— PCR is used to confirm infection by amplifyingand subsequently detecting DNA of the infec-tious organism in the sample. Generic primersare used to screen for organisms in relatedgenus groups; specific primers are used to iden-tify a particular species. It is important to use alaboratory with excellent quality control asboth false-positive and false-negative results

can occur when quality control is lacking.Whole blood in EDTA is typically used for sub-mission. Although it is a fairly sensitive test,false-negative results can occur when there is alack of organisms in the blood because of sequestration in tissue reticuloendothelial cells.

— PCR should always be used in conjunction withserology.

— PCR has identified an E. canis–like organismpresent in three cats that were serologicallynegative.

• Blood culture is not recommended outside aresearch setting: It is expensive and not widelyavailable, and positive results may take up to 8weeks to develop.

Summary of Diagnostic Criteria• Clinical signs vary from vague (anorexia, weight

loss, lethargy) to more specific. A high index of sus-picion is warranted in patients with bleeding ten-dencies (epistaxis, petechiae, ecchymosis) orextreme hyperglobulinemia.

• Thrombocytopenia: The majority of affected dogs

will have thrombocytopenia; however, do not ruleout ehrlichiosis when platelet counts are normal.

• Serology: A positive result with concurrent clinical

signs strongly supports but does not confirm thediagnosis because many healthy animals in anendemic area will be positive. Serology may benegative early in the course of infection or if theinfecting species is not the exact species tested for.

• PCR: A positive result confirms an infection. PCRmay be falsely negative if the organism issequestered in tissue outside of blood.

• Morulae: Although morulae are not frequently seen,their presence in monocytes, granulocytes, orplatelets on a blood smear confirms the diagnosis.

Differential DiagnosisBecause ehrlichiosis can mimic so many different dis-eases, it is important to test for Ehrlichia and relatedspecies when the following diseases are suspected:

• Immune-mediated thrombocytopenia—Animalswith thrombocytopenia should be thoroughlyscreened for other causes before presuming it isidiopathic. Testing should be done to check forehrlichiosis and other infectious causes. No specifictest exists for diagnosing immune-mediated throm-bocytopenia. In fact, dogs with ehrlichiosis can

STANDARDS of CARE: E M E R G E N C Y A N D C R I T I C A L C A R E M E D I C I N E9

C H E C K P O I N T S

—Although screening of healthy dogs for E.canis antibody is controversial among theexperts, it has become a reality with theintroduction of the SNAP 3Dx in-housecombination test. Many apparently healthydogs test positive for E. canis. The bigquestion is what to do with these dogs.

The ACVIM Consensus Statementrecommendation is to discuss the pros andcons of treatment with the owner to comeup with the best management plan for thedog in question.

—Two alternative recommendations are:

—Perform a complete blood count (CBC) toevaluate the dog for evidence of anemiaand/or thrombocytopenia. If either ispresent, treat the dog with a course of doxycycline. If the CBC is normal, thedog can be either treated empiricallywith doxycycline or simply monitoredfor overt clinical signs over the next fewmonths.

OR

—Perform PCR testing. If Ehrlichia spp DNAis detected, treatment is indicated.


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O N T H E N E W S F R O N T

— The etiologic agent of human monocyticehrlichiosis is E. chaffeensis, whereasthat of human anaplasmosis (previouslyhuman granulocytic ehrlichiosis) is A.

phagocytophilum. Severe illness and deathhave been associated with ehrlichiosis inhumans. Animals may act as sentinels for

human infection.

A P R I L 2 0 0 4 V O L U M E 6 . 310

develop antiplatelet antibodies, which would yielda positive result if using an antiplatelet antibody testto confirm immune-mediated thrombocytopenia.

• Pancytopenia—Testing should be done to checkfor ehrlichiosis. If negative, a bone marrow aspirateshould be performed to look for other causes.

• Rodenticide toxicity—The bleeding disorder thatoccurs in animals with anticoagulant rodenticide

toxicity is due to inhibition of vitamin K1, the resultbeing a reduction in activity of the coagulation fac-tors II, VII, IX, and X. A coagulation profile wouldshow prolonged activated clotting time, PT, and/oraPTT. The bleeding tendencies that occur withehrlichiosis are caused by platelet dysfunction anda decrease in platelet numbers. A coagulation pro-file is usually normal in animals with ehrlichiosis.

• Multiple myeloma—Ehrlichiosis can cause a mon-oclonal gammopathy, Bence Jones proteinuria, andplasmacytosis of bone marrow that mimics multiplemyeloma. Dogs with these signs should be tested

for ehrlichiosis. Dogs with multiple myeloma fre-quently have radiographic evidence of osteolyticbone lesions that would be absent in dogs withehrlichiosis.

• Lymphocytic leukemia—Dogs with ehrlichiosismay exhibit granular lymphocytosis. The increasedlymphocyte numbers in conjunction with increasedgranularity of the cytoplasm may be difficult to dif-ferentiate from chronic lymphocytic leukemia, par-ticularly if there is monoclonal gammopathy andBence Jones proteinuria. Dogs with these findingsshould be tested for ehrlichiosis before presuming a

diagnosis of leukemia.

• Polyarthritis—Animals with clinical signs of jointpain or swelling should be tested for ehrlichiosis(particularly E. ewingii and A. phagocytophilum).Morulae may be seen within cells from joint fluid;their presence is diagnostic for infection.

• Polymyositis.

• Meningitis.

• Glomerulonephritis—Ehrlichiosis can induce pro-teinuria and/or glomerulonephritis.

TREATMENTRECOMMENDATIONS

Initial Treatment • Dogs suspected of having ehrlichiosis should be

started on specific treatment immediately ratherthan waiting for positive test results. Dramaticimprovement usually occurs within 24 to 48 hoursof initiating therapy. Dogs with chronic manifesta-tions, including pancytopenia, glomerulonephritis,and hyperviscosity syndrome, respond more slowlyand may have irreversible changes.

• Doxycycline (dogs and cats): 10 mg/kg PO q24h for28 days. In cats, the capsule or liquid form of doxy-cycline is preferable to the pill form, which has ahigher risk of causing esophagitis and strictures. Thecapsules can be coated in butter, and at least 6 mlof water should be given after a capsule is adminis-tered to help get it into the stomach. $

• One report suggests that E. chaffeensis in dogs maybe more resistant than E. canis to doxycycline ther-apy. However, it is likely that the dogs cited in thereport were reinfected via continued exposure toticks. Humans infected with E. chaffeensis do notexhibit resistance to doxycycline.

Alternative/OptionalTreatments/Therapy• Imidocarb dipropionate (5 mg/kg IM or SC followed

by a second injection 2 weeks later) is an alternativetreatment, but some variability in its efficacy isreported. It can be used in animals whose owners

are unable to administer daily oral doxycycline orfor those animals that cannot tolerate doxycycline.The most common adverse effects of imidocarbinjection are pain at the injection site and mildcholinergic signs (salivation, nasal drip, vomiting).Pretreatment with atropine at 0.022 mg/kg IM or SC20 minutes before the imidocarb injection can pre-vent cholinergic effects.

• Enrofloxacin and other quinolones are not effectivein treating ehrlichiosis.

Supportive Treatment • Depending on the severity and type of clinical

signs, supportive treatment consisting of nutritionalsupplementation, anabolic steroids, fluid therapy,and/or blood transfusions may be necessary insome animals.

• Short-term immunosuppressive glucocorticoid ther-apy may be needed to treat severe, life-threateningthrombocytopenia. Glucocorticoids are often admin-istered initially while awaiting test results because of the difficulty distinguishing between ehrlichiosis andimmune-mediated thrombocytopenia.


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Patient Monitoring• Platelet counts begin to improve within 24 to 48

hours of initiating therapy and are usually normalwithin 14 days. To monitor efficacy, platelet countsshould be rechecked 48 to 72 hours after initiatingtherapy and again at 7 and 14 days. Platelet countsshould be checked 4 to 8 weeks after therapy toensure that a relapse of thrombocytopenia has notoccurred.

• Most dogs undergo a decline in antibody titer fol-lowing treatment and become antibody negativeover a course of 6 to 9 months. Some treated dogsmaintain high titers for years yet appear clinicallyhealthy. It is not known whether this is because of continued infection, reinfection, or simply persis-tence of antibodies. Therefore, titers are not the bestmethod to assess treatment efficacy. The antibodiesare not protective against reinfection.

• PCR may prove to be useful in distinguishing clini-cally cured animals that retain high posttreatment

IFA titers from unsuccessfully treated animals withpersistent infection. If PCR is used, testing shouldtake place 2 weeks after discontinuing antibiotictreatment. If PCR is positive, the animal should bere-treated for an additional 4 weeks and retestedafter discontinuing the antibiotic for 2 weeks. If theresults are positive after these two treatment cycles,the alternative drug, imidocarb dipropionate,should be given. If PCR results are negative, the testshould be repeated in 2 months. If still negative,treatment was likely successful.

• The organism may be sequestered in the spleen,

even in animals that are clinically cured and testnegative on PCR or blood culture. One studyshowed that of four dogs subclinically infected withE. canis, one remained PCR positive following a 42-day course of doxycycline at 10 mg/kg PO q24h.

Home Management • Because of the marked improvement following initi-

ation of doxycycline, no special home managementis normally needed other than routine observation.

• Prior infection does not infer immunity following

doxycycline treatment; thus tick control is impor-tant to prevent reinfection. In addition to environ-mental control, the use of amitraz-impregnatedcollars, fipronil, or permethrin products is recom-mended for dogs.

• In highly endemic areas during tick season, dogscan be maintained on 3 mg/kg doxycycline POq24h to prevent infection.

Milestones/RecoveryTime Frames• Marked clinical improvement within 24 to 48 hours

of initiating specific therapy. The diagnosis shouldbe reconsidered if there is a lack of significantimprovement in clinical signs and hematologicabnormalities after 1 to 2 weeks of initiating treat-ment. Failure to improve may be indicative of co-infection with another organism or concurrentnoninfectious disease.

• In cases of severe bone marrow suppression, regen-eration may require several months if it occurs atall.

• Gammopathies generally resolve within 3 to 9months but may take up to 15 months to normalizein some cases.

Treatment ContraindicationsAlthough immunosuppressive doses of glucocorticoidsare sometimes indicated to treat severe thrombocy-topenia or other complications of ehrlichiosis, theyshould not be given without concurrently initiatingspecific treatment with doxycycline or imidocarbdipropionate. When used, corticosteroids should be

tapered rapidly while sequentially monitoring plateletcounts. Doxycycline should be administered for a full4 weeks following corticosteroid administration.

PROGNOSIS

Favorable Criteria• Clinical improvement shortly after initiating therapy.

• Normalization of serum protein levels and hemato-logic parameters, resolution of proteinuria.

Unfavorable Criteria

• Lack of significant clinical and hematologic im-provement within 48 hours.

• Severe pancytopenia and bone marrow suppression(may be irreversible).

• Irreversible renal damage and proteinuria.

RECOMMENDED READING

Breitschwerdt EB: Ehrlichiosis: A new zoonosis? Compend ContinEduc Pract Vet 24(suppl 1A):10–14, 2002.

Cohn LA: Ehrlichiosis and related infections. Vet Clin North AmSmall Anim Clin 33(4):863–884, 2003.

STANDARDS of CARE: E M E R G E N C Y A N D C R I T I C A L C A R E M E D I C I N E11

RESOURCE LIST

• ELISA—In-house combination test for E. canis,Borrelia burgdorferi , and heartworm: SNAP 3Dx,IDEXX Laboratories, Inc., Westbrook, ME. $

• PCR and serology are available through the NorthCarolina State University College of VeterinaryMedicine Tick Borne Disease Laboratory. Phone:919-513-6357; Web: www.cvm.ncsu.edu/docs/ tickbornediseaselab.html. $


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Greig B: Granulocytic ehrlichioses, in Bonagura JD (ed): Kirk’sCurrent Veterinary Therapy XIII Small Animal Practice.Philadelphia, WB Saunders, 2000, pp 298–300.

Harrus S, Waner T, Aizenberg I, Bark H: Therapeutic effect of doxycycline in experimental subclinical canine monocyticehrlichiosis: Evaluation of a 6-week course. J Clin Microbiol 36(7):2140–2142, 1998.

Kidd L, Breitschwerdt EB: Transmission times and prevention of tick-borne diseases in dogs. Compend Contin Educ Pract Vet 25(10):742–751, 2003.

McQuiston JH, McCall CL, Nicholson WL: Ehrlichiosis andrelated infections. JAVMA 223(12):1750–1756, 2003.

Neer TM: Ehrlichia canis: A clinical approach to diagnosis andtreatment. Compend Contin Educ Pract Vet 24(suppl1A):15–18, 2002.

Neer TM, Breitschwerdt EB, Greene RT, Lappin MR: Consensusstatement on ehrlichial disease of small animals from theinfectious disease study group of the ACVIM. J Vet Intern Med 16(3):309–315, 2002.

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EHRLICHIOSIS CANINA Y FELINA