Tick-borne disease: Ecrlichiosis, Lyme borreliosis and anaplasmosis (Proceedings)

In just the past 3 to 5 years, advanced diagnostic capabilities have enhanced our ability to detect infectious pathogens in the dog and have given credence to the term "emerging" infections. However, the ever-expanding list of "emerging infectious diseases", in fact, may not be emerging at all...as it appears; many of these infections have, quite likely, existed in dogs for several years. It's the emerging technology that has enabled our ability to detect these infections.

AND...it's MUCH more than Blue Dots! As we move from the 3Dx test to the 4Dx testing platform, veterinarians now have the ability to test for Anaplasma phagocytophilum antibody, in addition to Borrelia burgdorferi C6 antibody, Ehrlichia canis antibody, and canine heartworm antigen. Specifically, the introduction of the 4Dx SANP Test emphasizes the importance of understanding not only the indications for performing the test, but, most importantly, the implications of a POSITIVE vs. NEGATIVE test result in the sick, versus healthy, patient.

The following highlights some of the key issues behind diagnosis, treatment, and prevention of the most common tick-borne diseases seen in dogs.

Canine Ehrlichiosis

      1. There are many Ehrlichiae capable of infecting dogs...but we currently only test for one (E. canis)...which infections are most significant for dogs?

E. canis (officially called 'canine monocytotropic ehrlichiosis') is probably the most important. It's certainly the most common infection in dogs in the US. However, infections with E. chaffeensis, E. ewingi (canine granulocytotropic ehrlichiosis), and E. equi are also known to infect dogs living in the US.

What compounds conventional diagnostic strategies is the fact commercial tests are simply not available (yet) for many of these infections. Furthermore, it's becoming more apparent that individual dogs can be (and are) infected with multiple tick-borne pathogens simultaneously...such as Anaplasma spp and Neorickettsia.

      2. What is the spectrum of clinical signs associated with ehrlichiosis?

The standard answer goes like this: Incubation is 8 to 20 days.

      ACUTE PHASE (2-4 weeks): signs may be mild to absent (at least to the owner) or may include lethargy, anorexia and possibly epistaxis. IF...the owner seeks medical attention, fever may be detected evidence of spontaneous bleeding. A laboratory profile may reveal thrombocytopenia, low albumin with elevated globulin (total protein may be elevated). THEN...they get better...whether or not they receive treatment.

      SUB-CLINICAL PHASE (months to years): any clinical signs that manifested in the ACUTE STAGE resolve...this is analogous to a "latent infection". Any treatment administered will appear to have worked well...THEN...months to more than a year later, clinical signs associated with infection may redevelop...(we don't know why some dogs never progress into the chronic stage of ehrlichiosis.

      CHRONIC PHASE (months): This is where infections become complicated. Serious clinical signs may develop months to years following exposure and infection. Signs are highly variable. Usually, weight loss, decreased appetite, petechiation or ecchymoses, and epistaxis may develop. Peripheral edema (hypo-albuminemia) and even neurological signs (head tilt, paresis, seizures) may develop.

      LABORATORY CHANGES: Thrombocytopenia and/or anemia appear in about 80% of dogs with ehrlichiosis. NOTE: platelet counts are only modestly reduced (ranges of 150,000 to 50,000 cells/µL are typical)l and distinct from dogs with immune-mediated platelet destruction (3,000 to 5,000 cells/µL).

Hyperglobulinemia/hypoalbuminemia may be present (hence the peripheral edema). Granular lymphocytosis (counts between 5,000 and 17,000 lymphocytes/µL). Pancytopenia seems less common today. Less common are a variety of multisystemic signs, including peripheral limb edema, vasculitis (generalized), neurological signs ranging from head tilt (vestibular) to disorientation to meningitis and seizures. Hyperviscosity syndrome, retinal detachment, and a host of immune-complex disorders affecting joints and kidney may develop. Death is possible...despite aggressive treatment.

BUT...the variation in physical signs and laboratory values is significant. For example...the absence of thrombocytopenia does NOT exclude a diagnosis of ehrlichiosis. As such, it is not feasible to rely exclusively on clinical or laboratory findings to establish a diagnosis. Testing is important. The message here is not to limit testing to only those patients that have obvious physical signs that are distinctively associated with ehrlichiosis..."test outside the box"!

      3. Is co-infection with other tick-borne agents significant with ehrlichiosis?

With increasing significance...YES. The more we look, the more we discover oc-infected dogs...and this is true in humans who are infected with tick-borne disease. AND...it's the co-infected patient that makes it difficult to establish a diagnosis on the basis of clinical signs.

What's still needed in veterinary medicine is a testing platform that will allow screening of individual patients for multiple tick-borne pathogens, simultaneously! And work is currently underway to achieve that.

      4. How long does a tick have to feed in order to transmit the infection?

Interestingly...that is still not known! It's an important fact since newly infected larval and nymph ticks can transmit the infection for 155 days, reservoir ticks can "overwinter" with their ehrlichia...becoming an early spring threat. Since most topical tick preventatives can take from 2 to 3 days to effective kill ticks, the time required to effectively transmit the organism is important!

      5. How should the Snap Test for E. canis be interpreted in a sick patient vs. a healthy patient?

The SICK dog with a POSITIVE E. canis antibody test (blue-dot on the Snap 3Dx or 4Dx) should be treated (see below). NOTE: "SICK" is defined by either physical abnormalities or laboratory abnormalities consistent with ehrlichiosis. Following treatment, clinical and laboratory assessments need to made as necessary to document resolution of the clinical illness. NOTE: in dogs with ehrlichiosis, antibody concentrations do not fall subsequent to treatment...the SNAP test is not expected to revert to a negative status for several months (years?) following treatment.

NOTE: the Snap 3Dx or 4Dx do have an important role in assessment of the 'healthy' patient. Veterinarians are encouraged to utilize such 'panels' in conventional wellness programs. The HEALTHY "appearing" dog that has a POSITIVE E. canis antibody Snap Test result (Surveillance Testing) should be evaluated further: a thorough physical examination + a laboratory profile (CBC and Biochemistry profile at a minimum). Interpretation: Dogs with a POS test result that do NOT have physical or laboratory abnormalities...have been exposed to Ehrlichia canis; a POS test result alone does not define infection. Although treatment is not indicated and these dogs may never become ill, they have been exposed to ticks...NOTE: a positive test result in a healthy dog does define tick exposure and justifies reviewing the client on correct use/application of topical tick preventatives. Poor (or no) application technique/compliance when using tick preventatives is the most common reason tick infestations; not 'resistance' to the topical product.

Dogs with a NEGATIVE E. canis antibody test have not been exposed to the organism... a NEGATIVE dog, with clinical or laboratory signs, does not have E. canis exposure. However, it could be infected with a different type of tick-borne pathogen.

The dog with a NEGATIVE test result, in the absence of clinical or laboratory changes...is considered to be "not infected".

      6. Will the E. canis antibody test (3Dx Snap Test) become negative following treatment?

This is important...NO...not for several weeks or even months. Unlike post-treatment testing patients for the Lyme C6 antibody, the titer of E. canis antibody does not fall following treatment. THEREFORE...the 3Dx test result can remain positive for extended periods following treatment for ehrlichiosis.

Canine Lyme Borreliosis (Lyme Disease)

      1. Recent studies show a dramatic increase in human Lyme disease...has the geographic distribution of Canine Lyme disease changed?)

Typically, canine Lyme disease occurs with the highest prevalence in the same locations that human Lyme disease is most likely to be diagnosed...the Northeastern United States and the upper Midwest. Increased numbers of positive tests in dogs living in Texas suggest that risk of exposure may be significant, particularly around major metropolitan areas. What this author finds interesting are (unpublished) reports from veterinarians regarding the change in Lyme 'positivity' in geographic areas of the US that are clearly outside conventional regions of prevalence. For example: Western PA, Northern IL and Indiana, Southern Lower Michigan, Northern California (esp around Santa Rosa) and Eastern VA and NC. Furthermore, clinical cases being reported from these areas include dogs that have never lived or traveled outside of the community. Lyme disease does appear to be spreading...

      2. What clinical signs are characteristically associated with an active infection?

Experimentally, the time between infection and development of clinical signs ranges from 2 to 5 months following infection...but, signs are only expected to develop in 5%-10% of dogs infected. (much less in cats).

Systemic signs include fever, shifting leg lameness, joint swelling, enlarged lymph nodes, anorexia and lethargy....all of which are rapidly responsive to antimicrobial therapy.

Arthritis. Non-erosive polyarthritis is still reported as the MOST common clinical sign. Synovial fluid demonstrates suppurative polyarthritis (leukocytes: 2000 to 100,000 µL)

Actue Renal Failure, aka "Lyme Nephropathy" (technically it's not "Nephritis"). Although uncommonly diagnosed, this acute, and frequently fatal, complication associated with B. burgdorferi infection is being reported with increasing frequency in dogs from Lyme endemic states...particularly the Northeastern US and, more recently, Northern California. Occasional cases are reported by veterinarians practicing in the upper Midwestern States...Minnesota and Wisconsin. Infections are most often reported in Labradors (Black?) and golden retrievers. The cause is still unknown.

Routine Hematology/Biochemistry: test results are typically normal. Proteinuria in dogs with protein-losing glomerular disease.

      3. How should the SNAP Test for C6 antibody (canine Lyme disease) be interpreted in a sick patient vs. a healthy patient?

The C6 antibody test is an important and significant technological advancement in Lyme diagnosis in dogs...( the C6 antibody assay has been approved for use in humans and does correlate with infection in patients with an EM lesion).

In dogs, there is a strong correlation between infection and POSITIVE antibody test result (test specificity is 96%); a positive test generally denotes infection...it does NOT predict impending clinical disease. Test results may be positive as early as 2 weeks post infection.

A POSITIVE test result in a dog with compatible clinical signs obviously justifies immediate treatment (see below). NONE of the available Lyme disease vaccines will cause a FALSE POSITIVE test on the 3Dx or 4Dx SNAP testing platform.

A POSITIVE test result in a healthy appearing dog should be interpreted as an exposed and infected dog...a positive test result is NOT predictive of impending clinical disease. Despite confirmed infection, most dogs will never develop clinical signs. That said, discussions with veterinarians practicing in the Northeastern US suggest that most practices recommend treating a healthy dog with a POSITIVE C6 Ab test. Outside of Lyme endemic areas, there is a significantly greater tendency NOT to treat the healthy, POSITIVE dog. Instead, clients are informed of the 'exposure/infection' and advised that if lameness or myalgia develops, treatment should be initiated. NOTE: I have also had many comments from practitioners who indicate that treating the "happy and healthy" POSITIVE dog resulted in a "happier and healthier" dog... There are NO reliable laboratory changes (as seen on routine CBC and biochemistry profile) supporting a diagnosis of Lyme disease in the healthy appearing dog with a POSITIVE test result.

A NEGATIVE test result indicates the patient is not infected at that time.

      4. What's does the "Quantitative C6 Antibody" test bring to the table and what are the indications for testing a patient?

The Quantitative C6 Antibody test is a 'send-out' test available only through IDEXX Laboratories. The test can offer the clinician an opportunity to monitor a decline in antibody response 4 to 6 months post- treatment. A high C6 titer appears not to be predictive of impending clinical signs.

      5. Will the Lyme C6 antibody test (3Dx Snap Test) become negative following treatment?

It might... With treatment, the infected dog will experience a decline in the number of spirochetes...which, in turn results in a decline in measurable antibody concentration (C6)...which, in turn is associated with resolution of physical signs. While most dogs will experience a significant decrease in antibody concentration with treatment (may take up to 6 months), only the occasional patient will see a decline in the antibody concentration such that the SNAP Test becomes NEGATIVE.

      6. Which vaccine is best: the recombinant or the killed, whole-cell (spirochete) vaccine?

Comparative studies have not been published. At this writing, one company sells a recombinant Lyme disease vaccine (Merial); 2 companies sell a killed, whole-cell Lyme vaccine (Pfizer and BI). Recently, another killed Lyme vaccine (Intervet-Schering Plough) was licensed and claims in vitro borreliacidal activity against both OspA (expressed by spirochetes inside the tick) and OspC (expressed by spirochetes in the dog). In vivo efficacy of OspC antibody has not been established at this time. Both types of vaccine (recombinant and killed) induce an immune response to the outer surface protein A (OspA) of Borrelia burgdorferi.

The process whereby a recombinant vaccine is manufactured is significantly different than that of the killed, whole-cell vaccines. The recombinant vaccines contain OspA antigen only. The killed vaccines contain millions of dead spirochetes per dose (~50 million) and all of the associated, non-immunogenic proteins on the surface of the spirochete...some of which may be immuno-reactive in dogs.

Natural immunity associated with Lyme disease is attributed to antibody produced against the up-regulated outer surface protein C (OspC) on spriochetes that enter the patient during feeding. Natural immunity is very short-lived (days) and considered to be insignificant.

Vaccination is NOT part of the treatment for Lyme disease. Vaccination is recommended only to prevent re-infection and, then, only after antibiotic treatment has been completed.

Canine Anaplasmosis

      Anaplasma Phagocytophilum Infection

(or...more properly: canine granulocytotropic anaplasmosis, CGA)

(Granulocytic Anaplasmosis, or GA, is also used)

      1. What is it?

It's a tick-borne disease...recently recognized in the Northeast and upper Midwestern US (especially Minnesota and Wisconsin) in dogs that presented with clinical signs consistent with E. canis. Fever, lethargy, and loss of appetite are predominantly reported clinical findings. Thromboocytopenia is the most common laboratory change reported. Although these dogs appear similar to those infected with E. canis, patients are expected to be NEGATIVE for E. canis antibody. In fact, what we once thought was...Ehrlichia equi, is A. phagocytophilum.

      2. Why the emphasis on this organism and the infection it causes?

Two reasons: first, it ranks among the most common tick-borne infections in dogs in the US...with E. canis and Lyme disease. Second, it's carried by the same Ixodes scapularis known to transmit canine Lyme disease. Where there is Lyme disease, there is (typically) anaplasmosis.

      3. How is the infection characterized?

Very much like E. canis...although there is no known sex predilection, a breed predisposition has been suggested (large breeds [Labradors and golden retrievers] may dogs have greater risk. Physical signs include fever, lethargy, and anorexia. Muscle pain is described in over half of the affected dogs. Muscle pain and weakness are described. Joint pain is uncommon. Although mild to moderate thrombocytopenia occurs in 80% of affected dogs, spontaneous bleeding disorders are not described. Lameness is also reported. Laboratory changes look like ehrlichiosis. Thrombocytopenia and lymphopenia predominate (80% of cases). Hypoalbuminemia (and hyperglobulinemia) are relatively common. Dogs may have a mild anemia.

In the few clinical studies that are published, affected dogs had a well-defined history of spending considerable time outdoors (especially camping trips, hiking, hunting) with the owner).

      4. What does a "BLUE DOT" for A. phagocytophilum mean?

The IDEXX SNAP 4Dx test is the only rapid assay for A. phagocytophilum exposure on the market. The test platform should be assessed much in the same way that the E. canis antibody test is interpreted...ie, it does NOTconfirm active infection...it denotes exposure.

This is an excellent example of how the SNAP test platform can be incorporated into a patient's 'wellness profile'. IF...the test result is NEGATIVE, exposure is very unlikely, the patient is not infected, and the client is likely to be providing adequate tick (and flea) control measures.

IF, on the other hand, the healthy-appearing patient has a POSITIVE test result, this denotes prior exposure, justifies the need to perform additional diagnostic (laboratory testing-especially hematology and platelet count) and clearly indicates that the client's efforts in tick-control have been inadequate. Hence, the need to discuss what they are using and how they using it.

Dogs having any physical or laboratory abnormalities, should be treated for at least 2 weeks.

      5. How is anaplasmosis treated?

Doxycycline is the recommended treatment (5 mg/kg, orally, q12h, for at least 2 weeks...it's common to treat for 28 days). Alternatively, 10 mg/kg of doxycycline can be administered orally ONCE daily as long as the patient is able to tolerate that dosing schedule. Resolution of the clinical signs and thrombocytopenia are expected quickly (as soon as 1 day, as long as 3 weeks). Also, rifampin and levofloxacin are reported to be effective. Chloramphenicol can be used in puppies to avoid the risk of doxycycline 'labeling' of enamel.I did find any reference to the use of imidocarb dipropionate to treat canine anaplasmosis.

Although experimental studies have suggested that treatment can be curative, clinical studies suggest this is not the case. Current publications suggest that a 'carrier state' is likely to develop following infection and treatment.

NOTE: there is a common theme here regarding treatment of these 3 tick-borne pathogens. That is, treatment is not likely to cure the patient. Obviously, tick-borne diseases are best PREVENTED... than TREATED.

      6. How is anaplasmosis prevented?

There is currently no vaccine available for the prevention of canine anaplasmosis. AND...none is on the horizon. Today, proper use of a topical tick preventative is still the primary barrier to infection.

REF: Granick JL et al: Anaplasmosis phagocytophilum infection in dogs: 34 cases (2000-2007), JAVMA, 234:1559-1565, 2009.