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J Vet Intern Med 2002;16:309–315 Consensus Statement on Ehrlichial Disease of Small Animals from
the Infectious Disease Study Group of the ACVIM*
T. Mark Neer, Edward B. Breitschwerdt, Russell T. Greene, and Michael R. Lappin The Infectious Disease Study Group of the American were subclinically infected13; 2 of 6 cats given E risticii–
College of Veterinary Internal Medicine (ACVIM) infected pony blood IV developed fever, anorexia, and di- held a Special Interest Group meeting at the 18th Annual arrhea.22 On the basis of a few seroprevalence studies uti- ACVIM Forum in Seattle, WA,a to discuss controversies in lizing primarily E canis and E risticii antigens, exposure the diagnosis and therapy of ehrlichiosis in dogs and cats.
appears to be common in the natural setting. Precise spe- The Study Group chose this topic because of the large ciation (eg, canis versus risticii) cannot be determined de- amount of new information generated in the last 10 years.
finitively because of serologic cross-reactivity among some One of the goals of this meeting was to develop a Consen- ehrlichial species.23,24 Ehrlichial DNA has been amplified sus Statement that would represent the most current under- from the blood of cats utilizing polymerase chain reaction standing of this disease in both dogs and cats. Consensus (PCR). On the basis of sequencing results, E equi (Sweden, was difficult to achieve on some issues, but the Study Denmark, Ireland/United Kingdom, and Massachusetts) and Group did identify 20 issues on which there was general E canis (Canada and North Carolina) appear to infect nat- uniformity of opinion. The issues developed for this Con- sensus Statement were formulated by the members of the 3. What Is the Geographic Distribution of the Different
Study Group and were intended to reflect controversies in Ehrlichial Species?29 Ehrlichial species infect animals of
the veterinary literature. This document was reviewed and most regions of the world. For some, geographic distribu- approved by the membership of the Infectious Disease tion has not been totally determined (see Table 1).
4. Are There Different Tick Vectors for the Ehrlichia
1. What Ehrlichia spp. Infect Dogs? Ehrlichia canis
spp. that Infect Dogs and Cats? Geographic distribution
was the 1st species found to infect dogs.1,2 E canis infection of ehrlichial species is likely related, at least in part, to the results in a variety of acute and chronic clinical syndromes current distribution of vectors for these agents. As a general but also can be subclinical. Ehrlichia platys also has been rule, Ixodes ticks are more likely to be vectors for the gran- recognized as a pathogen of dogs for over 20 years; infec- ulocytic forms of Ehrlichia, and the monocytic Ehrlichia tion results in thrombocytopenia but usually causes minimal spp. are more likely to be transmitted by Rhipicephalus, clinical illness.3 Since infection with these 2 Ehrlichia spp.
Amblyomma, or Dermacentor ticks. Several ticks are was described, several other species have been shown to known, or at least strongly suspected, to be vectors for the cause natural disease in the dog. These include Ehrlichia transmission of specific ehrlichial infections in dogs (see risticii var. atypicalis,4,5 Ehrlichia ewingii,6,7 Ehrlichia chaf- feensis,8,9 Ehrlichia phagocytophila,10,11 Ehrlichia equi,12,13 In addition, in the horse, E risticii has been transmitted and human granulocytic Ehrlichia (HGE).14 The latter 3 by the ingestion of trematode stages that are found in in- species are most likely the same organism because they termediate hosts such as aquatic insects and snails. The have been found to be closely related by DNA sequencing Ehrlichia-infected metacercariae in these insects are trans- techniques.15,16 The prevalence of infection with specific mitted after the ingestion of the insect and serve as efficient ehrlichial species varies substantially among geographic re- 5. What Are the Most Common Clinical Manifestations
2. What Ehrlichia spp. Infect Cats? Ehrlichia-like bod-
of Ehrlichiosis? Canine ehrlichiosis is a multisystemic dis-
ies or morulae have been detected in neutrophils, eosino- order that now is known to be caused by a variety of ehr- phils, and mononuclear cells of naturally exposed cats.17–21 lichial species. The classic presentation is characterized by Cats can be experimentally infected with E equi13 and E depression, lethargy, mild weight loss, and anorexia, with risticii22 after IV inoculation. Ehrlichia equi–infected cats or without hemorrhagic tendencies.29,33 If present, bleedingusually is manifested by dermal petechiae, ecchymoses, or From Louisiana State University, Baton Rouge, LA (Neer); North both. Although bleeding can occur from any mucosal sur- Carolina State University, Raleigh, NC (Breitschwerdt); Phoenix Vet- face, epistaxis is most frequent. Hemorrhagic tendencies are erinary Internal Medicine Services, Phoenix, AZ (Greene); and Col-orado State University, Ft Collins, CO (Lappin). most commonly associated with thrombocytopenia and Reprint requests: Dr Mike Lappin, Department of Clinical Sciences, thrombocytopathia.29 In addition to this classic presentation, Colorado State University, 300 W Drake Road, Ft Collins, CO 80523. uveitis,29 polymyositis,34 polyarthritis,35,36 and central ner-vous system signs including seizures, ataxia, vestibular def- * This position paper has been approved by the Board of Re-
icits, and cerebellar dysfunction37,38 have been attributed to gents of the American College of Veterinary Internal Medicine.
infection with Ehrlichia spp. As a general rule, the granu- This paper has not been peer reviewed.
Copyright ᭧ 2002 by the American College of Veterinary Internal locytic species of Ehrlichia (E ewingii, E equi, E phago- cytophila, and HGE) have been associated with polyarthritis more often than have the other species of Ehrlichia. In hu- Geographic distribution of Ehrlichia spp.
Ticks known, or at least strongly suspected, to be vectors for the transmission of specific ehrlichial infec- Worldwide; primarily tropical and temperate climates. Because of chronic infection, dis- ease manifestations may develop years af- ter tick transmission and after the dog has the disease might not be considered.
United States, primarily the southern region E risticii subsp. atyp- United States United States, primarily the southern and United States, primarily the West Coast (Cali- fornia), Wisconsin, Minnesota, and thenortheast and north-central regions indirect fluorescent antibody (IFA) test. In dogs experimen- tally infected with E canis, this test detects serum antibod- United Kingdom, Africa, Asia, Europe (Swe- ies as early as 7 days after initial infection, but some dogs may not become seropositive until 28 days after infection.
Southeastern United States, southern Europe Clinical signs of disease can occur before the development (Greece, Italy, Israel, France), South Amer- of serum antibodies, and IFA test results can be negative in acutely infected dogs. If ehrlichiosis is strongly suspectedin a seronegative dog, serologic testing should be repeated a May all be geographic variants of the same species.
in 2–3 weeks to assess for seroconversion. There is variableserologic cross-reactivity among E canis and E risticii, Eplatys, and granulocytic Ehrlichia spp., and dogs infected mans, both adult respiratory distress syndrome and acute with other species may be seronegative when assessed by renal failure have been reported with monocytic and gran- IFA with E canis morulae. For example, over 100 dogs with ulocytic Ehrlichia spp.; these syndromes also may occur in clinical ehrlichiosis due to E risticii were seronegative to E dogs.39–41 Apparently, many dogs are exposed and serocon- vert but never show clinical signs (see question 17). It is Most laboratories report serum titers to reflect the quan- unknown why some animals harbor the agent for months tity of antibodies present in a serum sample. However, titers to years without developing clinical signs. Breed predis- do not correlate with the duration of infection or the se- positions to clinical disease have been reported; German verity of disease. Some laboratories use different ‘‘cut-off’’ Shepherd Dogs, for example, may have increased suscep- values to differentiate positive and negative results. Be- tibility. The evolving importance of coinfection with other cause of differences in reporting among laboratories, the tickborne diseases can make it difficult to attribute clinical most appropriate cut-off titer is unknown at this time. It is signs to a single specific agent. Most clinical manifestations the consensus of this group that titers Ͻ1 : 80 should be attributed to canine ehrlichiosis also have been described in deemed suspect and that repeated serologic testing within 2–3 weeks, PCR confirmation, or Western immunoblotting 6. What Clinicopathologic Findings Should Alert the
should be considered. A recently marketed, point-of-care E Clinician to the Possibility that an Animal May Have an
canis antibody screening testb is calibrated to be positive at Ehrlichial Infection? With canine ehrlichiosis, the most
a titer of approximately 1 : 100 or greater. Clinical disease consistent CBC abnormalities are thrombocytopenia and can be detected in some dogs before seroconversion, and mild nonregenerative anemia.33 However, infected dogs failure to detect ehrlichial antibodies in acutely ill dogs does may have normal platelet counts. Pancytopenia may be seen in the severe chronic phase of the disease and usually is When clinical signs or clinicopathologic abnormalities the result of hypoplasia of all bone marrow precursor consistent with ehrlichiosis are found in conjunction with cells.33 Granular lymphocytosis, which may be confused positive ehrlichial serology, a clinical diagnosis of ehrlich- with well-differentiated lymphocytic leukemia, also has iosis should be made and treatment instituted. However, been reported.42 Nonregenerative anemia and thrombocy- because of latent infection, a positive antibody titer does topenia are the most common hematologic abnormalities in not necessarily mean that the clinical manifestations are due cats. Hyperproteinemia has been reported in approximately to ehrlichiosis at the time of presentation. This is especially 33% of affected dogs. Polyclonal gammopathy is most true in endemic areas where many healthy dogs have pos- common, but monoclonal gammopathies have been report- itive serum titers to E canis.44 An unknown number of dogs may spontaneously resolve Ehrlichia spp. infection but re- 7. How Should Serology Be Used for the Diagnosis of
main seropositive (see question 15). Additionally, E canis Canine Ehrlichiosis? A diagnosis of ehrlichiosis usually is
antibodies cross-react with E ewingii,45 E chaffeensis,8 Neo- based on the detection of serum antibodies by use of the rickettsia helminthoeca,46 and Cowdria ruminantium.47 Therefore, in regions where other rickettsial agents are en- unknown whether blood, bone marrow cells, or cells col- demic, a positive E canis titer should be considered evi- lected by splenic aspirate are optimal for testing. Perfor- dence of infection with one or more of these other ehrlichial mance of PCR assays on joint fluid, cerebrospinal fluid, and species or simply cross-reactivity with another rickettsial aqueous humor ultimately may prove beneficial in some agent, as opposed to active disease due to E canis. cases. It is our consensus at this time that PCR should be In some cases, serologic confirmation by Western im- used in conjunction with serology, not instead of it, for the munoblotting may be indicated, but this test is not routinely initial diagnosis of ehrlichiosis in untreated animals. See available.48,49 Western immunoblotting can be helpful in dis- question 14 for recommendations on the use of PCR in tinguishing between infection with Ehrlichia spp. that dis- play serologic cross-reactivity in IFA such as E canis and 10. What Are the Most Effective Treatments for Ehr-
E ewingii and E canis and E chaffeensis.45 lichiosis? Drugs that have been successful in the treatment
If a dog does not respond to treatment for ehrlichiosis in of ehrlichiosis include tetracycline, chloramphenicol, imi- the anticipated time frame, then another cause of the clin- docarb dipropionate, and amicarbalide.29 Tetracycline and ical abnormalities should be considered. Also, concurrent oxytetracycline have been considered the initial drugs of infections with other tick-transmitted agents may occur choice in the past2 and still are effective, but doxycycline more frequently than we have realized in the past.50 There- and minocycline now are used more frequently. Several dif- fore, testing for other tickborne agents such as Babesia can- ferent protocols have been used.55–57 The consensus rec- is, Bartonella vinsonii, or Rickettsia rickettsii may be in- ommendation of the Study Group is to prescribe doxycy- cline at a dosage of 10 mg/kg PO q24h for 28 days. Dra- 8. How Should Serology Be Used for the Diagnosis of
matic clinical improvement generally occurs within 24–48 Feline Ehrlichiosis? Definitive statements cannot be made
hours after the initiation of tetracycline therapy in dogs with at this time. Information on the Ehrlichia spp. infecting cats acute-phase or mild chronic-phase disease. Platelet counts is not available, data from experimentally infected cats are correspondingly increase during this time and usually are lacking, and there is no standardization among laboratories normal within 14 days of treatment. Tetracycline and doxy- currently providing Ehrlichia spp. serologic tests for use cycline also have been used successfully in cats with pre- with cat sera. Most cats with suspected ehrlichiosis tested sumed ehrlichiosis.17–21,23–26 Although there is minimal in- to date have been assessed by IFA utilizing E canis and E formation available at this time concerning the treatment of risticii morulae.23,24 We recommend that cats with clinical cats, the consensus recommendation of the Study Group is findings referable to ehrlichiosis and seroreactivity with to prescribe doxycycline at a dosage of 10 mg/kg PO q24h ehrlichial antigens be treated with anti-ehrlichial drugs (see question 10). Some cats with ehrlichiosis may have low or Enrofloxacin has been shown effective for the treatment negative titers; 3 cats with E canis DNA were seronegative of another rickettsial disease, Rocky Mountain spotted fe- ver,58 but it is ineffective against experimentally induced E 9. How Should Blood Culture and PCR Be Used in the
canis infection.57 For over 20 years, imidocarb dipropionate Diagnosis of Ehrlichiosis? Blood cultures may take up to
also has been shown to be an effective treatment of canine 8 weeks to become positive, are expensive, and are not ehrlichiosis when administered at a dosage of 5 mg/kg IM routinely available. For this reason, blood culture currently twice, 2–3 weeks apart.59 A recent evaluation of imidocarb dipropionate suggested that 2 doses of 5 mg/kg IM given PCR is a sensitive method for the detection of acute E 15 days apart were as effective as doxycycline in resolving canis and granulocytic ehrlichial infection in dogs.51,52 PCR clinical signs, but platelet counts were slower to normalize and DNA sequencing have been used to identify new spe- when compared to dogs treated with doxycycline.60 Appar- cies or to show that some Ehrlichia spp. such as HGE, E ently, imidocarb also was effective in treating several cats phagocytophila and E equi are closely related.15,16 Primers can be designed to detect all sequenced Ehrlichia spp. or 11. Is There a Difference in Response to Treatment
can be used to identify individual species.
among Different Ehrlichia spp.? To date, most studies
There currently are several potential limitations to the use have reported that doxycycline is effective against all ehr- of PCR in the diagnosis of ehrlichiosis in clinical practice.
lichial species. Even the more recently recognized granu- Samples for testing must be sent to commercial laborato- locytic species appear to be susceptible to the doxycycline ries, and current commercially available PCR assays are regimen usually prescribed for the treatment of E canis.61 relatively expensive. Insufficient quality control can result The efficacy of newer antibiotics against ehrlichial infec- in both false-positive and false-negative results. Whereas tions still is compared to doxycycline as the standard ther- the specificity of PCR can be considerable on the basis of apy. There is some variability in the reported efficacy of primer design, there currently is no standardization among imidocarb. In one report, the authors speculated that E chaf- laboratories, and comparison of results is difficult. PCR feensis infection of dogs may be more resistant to doxy- tests may yield positive results within 4–10 days of expo- cycline therapy than E canis infection.9 However, it is pos- sure to E canis in experimental studies.53,54 Whereas PCR sible that the treated dogs did not have persistent immunity, can become positive in experimentally infected dogs before were reexposed to Amblyomma ticks, or became rapidly seroconversion, sensitivity in naturally infected animals reinfected, rather than failing to respond to doxycycline.
currently is unknown. In untreated animals, positive PCR Unlike Rhipicephalus sanguineus, which transmits E canis results confirm infection by an ehrlichial species, whereas and generally is found in kennels or structures that house positive serologic test results only confirm exposure. It is numerous dogs, Amblyomma americanum is a field tick found in extremely high concentrations in areas with large apeutic elimination is likely. However, the organism may deer populations. No immunity occurs after infection with be sequestered in other tissues, such as the spleen (see ques- E canis or E chaffeensis, and dogs reintroduced to tick- infested environments can become reinfected. Clinically, 15. Can Dogs with Ehrlichiosis Truly Be Cured or
the efficacy of acaricides to control tick infestations in these Cleared of the Infection? This is one of the more difficult
2 settings can differ substantially.
questions to address because the ‘‘gold standard’’ to assess 12. What Clinicopathologic Parameters Should Be
for organism clearance has not yet been determined in the Monitored during the Treatment of Canine Ehrlichiosis?
dog. Experimental studies have shown that blood cultures Thrombocytopenia occurs in approximately 82% of E can- and PCR of blood samples become negative with the res- is–infected dogs,62 and the resolution of thrombocytopenia olution of clinical signs or thrombocytopenia, suggesting usually is indicative of a good response to therapy.29 After that the organism is cleared from the body.55,57 However, in treatment, platelet counts begin to increase within 24–48 a recent study of 6 E canis experimentally infected dogs, 4 hours and are usually normal within 14 days.55,56 If platelet of 6 dogs were PCR positive on splenic aspirates 34 months counts do not increase within 7 days of therapy, another after infection.66 Of these 4 dogs, 2 were negative on PCR mechanism for thrombocytopenia could be present, such as of blood samples. The other 2 dogs were PCR negative on immune-mediated destruction or coinfection with Babesia all tissues. It is possible that the spleen is the last organ to or Bartonella.29 Ineffective or incomplete responses with harbor E canis during recovery or that the organism is se- drugs like enrofloxacin have been reported (ie, an initial questered in splenic macrophages to avoid immune elimi- increase in the platelet count but recurrence of thrombo- nation. However, it is also possible that ehrlichial DNA cytopenia 14 days after treatment because of failure to elim- detected in the spleen could persist from dead organisms inate the infection).57 If platelet counts are used as a marker and does not represent active infection. It is our consensus for improvement or cure, they should be reevaluated at least that treated dogs have eliminated the organism if hyper- 4–8 weeks posttherapy. Gradual resolution of hyperglobu- globulinemia and other clinical and laboratory abnormali- linemia over 6–9 months also suggests therapeutic elimi- ties resolve progressively, even if a positive serum titer re- 13. How Should Serology Be Used for the Monitoring
16. Can Dogs with Ehrlichiosis Be Reinfected? Dogs
of Effective Treatment? After successful treatment in most
can become reinfected with E canis after a previously ef- dogs, antibody titers decline and generally become negative fective treatment, and recovery does not necessarily equate within 6–9 months of therapy. The duration of positive ti- with permanent immunity.56,67 Experimentally, dogs can be ters is in part dependent on how high the titers were at the reinfected with homologous or heterologous strains of E beginning of treatment; higher titers usually take longer to canis. Reinfection is likely in environments with high tick become negative than low titers. Some laboratories (and the density, and rigorous tick control measures or the prophy- new point-of-care antibody screening test) provide only a lactic use of doxycycline (as used in military working dogs positive or negative serum antibody result, and actual serum in tick-infested regions)68 are important management con- titers are unknown or unreported in these animals. If the laboratory reported the titer to a very high endpoint, the 17. Should Healthy Dogs Be Assessed Serologically for
monitoring for a fall in titer from a very high concentration Ehrlichial Antibodies? Arguments for serologic screening
could be misleading, because there is a decreased accuracy in healthy dogs include the following: (1) the testing of with dilutions at high concentrations. Some dogs have a large numbers of dogs over a wide geographic area would resolution of clinical and clinicopathologic abnormalities give more information concerning seroprevalence and iden- yet retain high titers to E canis for years.63,64 It cannot al- tify endemic areas of ehrlichiosis; (2) seroprevalence stud- ways be determined in these dogs whether there is contin- ies would allow the dog to be used as a sentinel for ehr- ued infection or merely persistence of antibodies. Thus, an- lichiosis in humans in the same geographic areas; (3) in tibody detection by any methodology, including IFA, en- multidog environments such as kennels and breeding op- zyme-linked immunosorbent assay, or Western immuno- erations, the testing of all dogs, especially new additions, blotting, probably is not a very effective means of assessing might minimize the potential for development of the disease within the kennel or breeding operation; (4) the detection 14. How Should PCR Be Used for the Monitoring of
of subclinically infected dogs could promote more effective Effective Treatment? PCR may ultimately prove useful in
therapy, thereby reducing the chronic phase of illness; and distinguishing successfully treated animals with persistently (5) the testing and treating of subclinically infected dogs high IFA titers from unsuccessfully treated animals with could reduce the reservoir of ehrlichial species in the en- persistent E canis infection.53,66 It is the consensus of the group that if PCR is used to monitor treatment, the PCR Arguments against serologic screening in healthy dogs assay should be repeated after antimicrobial therapy has include the following: (1) healthy dogs presumably are a been discontinued for 2 weeks. If PCR results are positive, low incidence group, and false-positive test results in low an additional 4 weeks of treatment should be given with incidence groups could result in the unnecessary treatment the PCR assay repeated after antimicrobial therapy has been of uninfected dogs; (2) it is likely that most serologic discontinued for 2 weeks. If PCR results are positive after screening of healthy dogs will be performed by the cur- 2 treatment cycles, the use of an alternate anti-ehrlichial rently available point-of-care test,a which uses E canis an- drug should be considered. If PCR results are negative, the tigen and will consistently detect infection with this species test should be rechecked in 2 months; if still negative, ther- but will not detect other ehrlichial species that infect dogs; (3) it is unclear whether treatment prevents the development Wildlife hosts such as rodents probably are the mainte- of the chronic phase of infection (see question 14); (4) some nance reservoirs for E chaffeensis and E equi, with imma- immunocompetent dogs may be able to eliminate E canis ture tick stages serving as vectors. Deer may become in- infection without therapy67; (5) it is unknown how many fected or involved in vector maintenance in the natural set- dogs eliminate ehrlichial infection naturally; (6) it is im- ting. Ticks should be removed with care and destroyed. In possible to determine which dogs will go on to develop addition to tick exposure, some individuals may become chronic disease manifestations; (7) some dogs eliminate in- infected by handling deer carcasses and contacting associ- fection without treatment and, hence, the presence of serum ated engorged ticks or infected blood.71,72 antibodies only denotes exposure to an ehrlichial speciesand does not document current infection; (8) the treatment of healthy dogs is likely of minimal benefit because in- Within the past several decades, the number of Ehrlichia fected, treated dogs do not develop permanent immunity, spp. recognized to infect cats, dogs, and human beings has and infected dogs generally are reexposed in their endemic expanded substantially. The recent application of advanced environment; (9) other canid reservoir hosts exist in the techniques in molecular biology has changed how ehrlich- environment, and the treatment of positive pet dogs is un- iosis is diagnosed and has provided new tools for the as- likely to have an impact on the prevalence of the organism sessment of treatment. As these techniques are applied, the in the environment; (10) although not proven at this time, numerous questions that relate to the management of dogs the treatment of all seropositive dogs may increase the risk and cats with ehrlichiosis ultimately will be answered. We for the development of doxycycline resistance69; and (11) hope this consensus statement will assist veterinarians in all drugs currently used for the treatment of ehrlichiosis have potential adverse effects and, if used extensively inanimals that may never become clinically ill with ehrlich-iosis, treatment may result in more problems than it pre-vents.
Footnotes
Because of the lack of data concerning the appropriate- a ACVIM Forum, Seattle Convention Center, Seattle, WA, May 26, ness of treating healthy animals, we currently recommend that, if a seropositive healthy animal is detected, the pros b SNAP 3 Dx Assay, IDEXX Laboratories, Inc, One IDEXX Drive, and cons of treatment (outlined above) be discussed with the owner and a decision made about which managementcourse is best for the dog in question.
18. What Preventive Measures Should Be Used to De-
Acknowledgments
crease Infection with Ehrlichial Organisms? Prevention
The authors would like to thank the Infectious Disease in endemic areas can be accomplished by maintaining strict Study Group members who gave oral input concerning this tick control programs for dogs and premises. If a kennel topic at the Study Group meeting held at 18th Annual currently is known to be Ehrlichia negative, new additions ACVIM Forum in Seattle, WA, and to the following mem- to the kennel should be tested by IFA serology and, if pos- bers who provided written review: Drs Helio Autran de itive, treated with a course of doxycycline before being Morais, Julie Levy, Meryl Littman, and Dennis Macy.
housed with the other dogs. Additionally, a thorough checkfor the presence of ticks should be performed, and the dogs References
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