The Increasingly Complicated Story of Ehrlichia
The Increasingly Complicated Story of Ehrlichia
The Increasingly Complicated Story of Ehrlichia
4 April 2002
277
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The Increasingly
Complicated Story
of Ehrlichia
KEY FACTS
University of Missouri-Columbia
Ehrlichial infection can result in
a wide range of manifestations
(from inapparent infection to
fatal illness).
Diagnosis can be problematic
because not all species of
Ehrlichia produce cross-reactive
antibody titers and positive titers
may reflect either inactive
infection or past exposure.
Dogs and other domestic species
have the potential to harbor ticks
that can transmit certain types of
ehrlichiosis to humans.
hrlichial infection was first recognized as a cause of canine disease in Algeria circa 1935.1 Veterinarians in the United States did not become familiar
with this disease until the Vietnam War era when military working dogs,
including many that had never left the country, developed what was then known
as tropical pancytopenia caused by Ehrlichia canis.2,3 Since then, other species of
Ehrlichia that cause disease in dogs have been identified. Classification of these
ehrlichial species has been reorganized, diagnostic testing options have increased,
and additional manifestations of ehrlichiosis have been recognized in a wider
geographic area. In the mid-1980s, an ehrlichial species was recognized as a
cause of disease in humans in the United States; since then, various other species
have been found to infect humans as well. Some ehrlichial species that infect
dogs can also infect humans (through tick bites), leading to concerns about the
role of dogs in harboring a disease that may be transmitted to humans. This article addresses these developments and their importance in the understanding,
diagnosis, and treatment of ehrlichiosis primarily in dogs.
CLASSIFICATION
Ehrlichia are gram-negative obligate intracellular bacteria that lack
lipopolysaccharide endotoxins and rely on arthropod vectors for transmission.
For many years, E. canis was the only ehrlichial species known to cause disease in
dogs, and it is by far the best described veterinary ehrlichial pathogen. Several
additional Ehrlichia species that infect dogs as either primary or incidental hosts
are now recognized. Previous classification schemes have made use of the cell
*Dr. Preziosi is currently affiliated with the University of Pennsylvania.
Target Cells
Major Host
Known Vector(s)
Mononuclear cells
Mononuclear cells
Granulocytes
Dogs
Humans
Dogs
Rhipicephalus sanguineus
Amblyomma americanum, Dermacentor variabilis
R. sanguineus, A. americanum, D. variabilis
Granulocytes
Granulocytes
Granulocytes
Ruminants
Equidae
Humans
Ixodes ricinus
I. ricinus, Ixodes pacificus
Ixodes scapularis, I. ricinus, I. pacificus
Platelets
Dogs
R. sanguineus
EPIDEMIOLOGY
Most ehrlichial species rely on arthropod vectors for
transmission, although the specific vectors are not well
described for every species of Ehrlichia. The geographic
distribution pattern of various ehrlichial species is
related to the distribution of the relevant vector(s). The
predominant vector for E. canis is the brown dog tick
(Rhipicephalus sanguineus), which is found worldwide.9,10
Accordingly, E. canis has been reported in dogs from
Africa, Europe, Asia, the Middle East, and the United
States. In contrast to E. canis, E. ewingii is known to use
at least three different vectors. In addition to R. sanguineus, both Dermacentor variabilis (American dog
tick) and Amblyomma americanum (lone star tick) are
capable of transmitting E. ewingii infection.10 The primary distribution of the lone star tick in the midwestern
and southeastern United States may account for the
increased incidence of E. ewingii infection in these
regions.5,6,10 Ehrlichia equi infection, which is transmitted by Ixodes ticks, is most often reported in the upper
Arthropods
Flukes
Ehrlichiosis 279
infected dogs will ever develop clinical illness. In a single study of naturally infected dogs, 53% demonstrated
positive E. canis antibody titers 4 years after the presumed time of infection but remained clinically asymptomatic. Many of these dogs did, however, demonstrate
abnormalities suggestive of ehrlichial disease on complete blood cell counts (e.g., hyperglobulinemia,
thrombocytopenia).29 Although subclinical infection is
well documented for E. canis, it is less clear whether
other Ehrlichia species also induce persistent but subclinical infections. In at least one case,12 E. ewingii
morulae were observed in an asymptomatic dog.
Chronic Stage
The pathogenesis of the chronic stage of E. canis infection is poorly understood because adequate models are
not available. Not all infected animals progress to the
chronic stage, and the factors that influence progression
are still unknown. Persistent E. canis infection results in
persistent antibody formation (both nonspecific and
ehrlichial directed).9,30,31 Unfortunately, humoral immunity to E. canis provides no protection.4,32 In fact, many of
the manifestations of chronic ehrlichial disease may result
from an exuberant but nonprotective humoral immune
response.4,9 As in the acute stage, hemorrhagic tendencies
may be related to either thrombocytopenia or thrombocytopathia. In addition to the mechanisms mentioned
previously, hyperglobulinemia associated with chronic
infection is often more pronounced, and hyperviscosity
syndrome with resultant thrombocytopathy may result.26
Glomerulonephritis may result from the deposit of antigenantibody complexes with resultant inflammatory
damage.23 Bone marrow hypoplasia has been a classic
finding associated with chronic E. canis infection and
may result in pancytopenia.3,22,23 Nonregenerative anemia
commonly associated with chronic E. canis infection may
be caused by either anemia of inflammatory disease or by
pancytopenia due to bone marrow hypoplasia.22,23,33 Concurrent infectious diseases documented in dogs with E.
canis have been attributed to immunosuppressive effects
of chronic infection.23
CLINICAL FINDINGS
Ehrlichia canis
Clinical findings associated with E. canis infection
vary tremendously and are likely influenced by the
strain of organism, host immune status, and breed of
animal.4,34 German shepherds are classically thought to
be more susceptible to infection and to have a more fulminant course of infection than dogs of other
breeds.3436 By definition, no clinical signs are apparent
during the subclinical phase of infection, although
hematologic abnormalities may be identified.29 Often,
Ehrlichia ewingii
E. ewingii is one of two ehrlichial agents known to
result in granulocytic infection in dogs, with the other
agent being E. equi.12 Unfortunately, identification of
granulocytic morulae does not differentiate E. equi infection from E. ewingii infection, which likely predominates in the southern and lower midwestern United
States. Because E. ewingii belongs to the same genogroup
as E. canis, E. canis titers should be positive during infection.12 Many descriptions of granulocytic ehrlichial infection are of dogs with acute-onset polyarthritis, and these
cases have more often than not been ascribed to E.
ewingii infection.5,3941,45 The lameness may involve more
than one leg or appear to shift from limb to limb. Joint
stiffness and occasional joint swelling due to effusion
may be noted, and dogs are often febrile. Splenomegaly
and hepatomegaly have been reported. Bleeding tendencies may be noted, and many infected dogs have mild to
moderate thrombocytopenia.12 Central nervous system
involvement, particularly meningitis, has been
reported.46 Dual infection with both E. canis and E.
ewingii has also been reported in association with profound ataxia and epistaxis.47 Polyarthritis resolves quickly
with appropriate therapy. Fatal granulocytic ehrlichial
infections seem to be extremely rare in dogs.
Ehrlichia equi
As with E. ewingii, the true incidence of E. equi infections in dogs is unknown, but E. equi may account for a
significant proportion of granulocytic ehrlichiosis in the
northeastern and upper midwestern United States and
California, where equine infections are endemic.7,11,12
Experimental infection with E. equi in dogs produced
only mild to inapparent clinical signs, but naturally
infected dogs have presented with nonspecific illness,
including fever, lethargy, and thrombocytopenia.11,48
There are no unique clinical findings attributed to infection with E. equi, but polyarthritis is described less frequently than for E. ewingii.11 Without an index of suspicion, veterinarians may not request the specific diagnostic
testing required to differentiate this ehrlichial infection
from others, and E. canis titers may be negative.11,12
Ehrlichia risticii
E. risticii, the causative agent of Potomac horse fever, can
infect dogs and cats as well as horses. This agent is transmitted not by a tick bite but rather by ingestion of snails,
perhaps explaining why canine infection is not commonly
Ehrlichia chaffeensis
Although E. chaffeensis is primarily notable as a
human pathogen, dogs are also susceptible to infection
with this organism. Experimentally infected dogs seem
to have mild or inapparent disease.49 However, a report
of three dogs infected naturally with E. chaffeensis documented more serious signs, including vomiting, epistaxis, lymphadenopathy, and anterior uveitis.6 Because
E. chaffeensis shares genogrouping with E. canis, routine
titers should prove positive in infected dogs.6
Ehrlichia platys
E. platys is unique among the Ehrlichia species because
of its predisposition for platelets rather than leukocytes.
E. platys does not share serologic cross-reactivity with E.
canis, but co-infections have been documented.8,15,50,51
Although infection with E. platys results in cyclic thrombocytopenia in dogs, it is seldom the cause of clinical
Ehrlichiosis 281
Feline Ehrlichiosis
The topic of feline ehrlichiosis deserves separate mention from canine ehrlichiosis.57 Cats have been experimentally infected with both E. risticii and E. equi, producing either subclinical infection or mild illness.48,58 To
date, experimental infection with E. canis or E. ewingii
has not been attempted. Naturally occurring feline ehrlichiosis has been documented in only 31 cats worldwide.
These cats presented with various clinical signs, including fever, anorexia, arthropathy, gastrointestinal signs,
and general malaise.57,5962 Until a clearer picture of the
importance and clinical presentation of feline ehrlichiosis
is developed, ehrlichiosis should remain a consideration
in cats with various unexplained clinical illnesses. Diagnosis relies on ruling out other causes for the described
clinical illness in combination with either identification
DIAGNOSIS
Ehrlichiosis is usually diagnosed based on clinical
signs, consistent laboratory abnormalities, and
Ehrlichia-specific testing. Although observation of
intracellular morulae is diagnostic, the search for morulae is most often unrewarding.35 The use of concentration techniques, such as buffy coat examination with a
Romanovsky-type stain, maximizes the chance of identifying morulae.3 Morulae may be observed in white
blood cells from peripheral blood or other fluids,
including cerebrospinal and joint fluids.39,40,46,47 In general, morulae are more readily apparent during the
acute phase of monocytic E. canis infection or during
infection with the granulocytic species E. ewingii and
E. equi (Figure 1).5,11,23,35
The most commonly employed diagnostic test for
suspected ehrlichial infection is indirect fluorescent
antibody (IFA) serology. This form of testing does not
detect the actual ehrlichial organism but rather
ehrlichial-reactive antibody in the serum. Veterinarians
employing IFA testing must understand that a positive
titer in a dog from an endemic area does not confirm
that the disease under investigation is caused by
ehrlichial infection. Rather, a positive titer confirms
exposure to the organism but may be observed after
exposure and clearance of the organism, during the
subclinical stage, or after successful treatment, as well as
during active infection. Likewise, a negative titer does
not rule out infection. Moribund animals may cease to
TREATMENT
Tetracycline-related antibiotics have been the treatment of choice for ehrlichial infections for years. 3
Excellent absorption and an infrequent dosing interval
make doxycycline the preferred drug.32,66 Although a 7to 14-day course of doxycycline at 10 mg/kg/day has
been previously recommended,4,6,32 this length of treatment may be inadequate.66,67 In fact, in a study of subclinically infected dogs treated with doxycycline for 6
weeks, ehrlichial organisms could still be identified by
PCR in one of four dogs.67 Although the appropriate
length of treatment has not been clearly determined,
treatment for dogs with chronic infection may be quite
long in duration and titers may remain elevated for
months to years, regardless of the treatment length.
Even long courses of treatment (average, 210 days) did
not produce negative titers in a significant proportion
Ehrlichiosis 283
EVALUATING TREATMENT
Evaluation of treatment remains problematic. Resolution of clinical signs and normalization of platelet
counts are usually noted within days of initiating
proper treatment for acute cases and often for mild
chronic cases as well. 4,23,69 Even after rapid clinical
improvement, studies have found that platelet counts
may again decrease after completion of doxycycline
therapy, titers remain elevated, organisms can still be
cultured, and PCR results remain positive.64,69 Serum
antibody titers can remain elevated for months to years
after appropriate treatment in dogs that remain clinically and hematologically normal.30,31,64,69 These persistently positive titers, which tend to correlate with the
highest initial titers, may indicate continued infection
or re-infection or may be indicative of a past infection
only.23,30 PCR may offer the best option for documenting clearance of the organisms after therapy, but even
PCR evaluation can be problematic. PCR detects bacterial DNA but cannot distinguish between living and
nonliving organisms. However, it is unlikely that killed
ehrlichial organisms would persist in the body for
more than several weeks, rendering a positive PCR
result strongly suggestive of active infection. The
greater problem is related to false-negative results when
sampling tissues that contain low levels of organisms
(e.g., blood, bone marrow).64,65 Practically speaking,
treated dogs for which the clinical and laboratory evidence of disease is resolved need not be further evalu-
CONCLUSION
Ehrlichiosis is a bacterial infection transmitted largely
through the bite of infected ticks. Dogs with ehrlichiosis
can no longer be assumed to have an E. canis infection
alone. Veterinarians should be aware of the similarities
and differences between E. canis and other arthropodborne infections. Dogs with suggestive clinical signs and
laboratory abnormalities may be started on doxycycline
pending specific diagnostic testing. Veterinarians practicing in endemic areas are confronted with the often
difficult task of sorting out ehrlichial infection from
mere exposure. Once a diagnosis is established, treatment should continue for at least 3 weeks. Tick prevention for animals in endemic areas should be maintained
throughout tick season, not only to prevent disease but
Ehrlichiosis 285
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