Treating Subclinical Rickettsial Disease in Dogs

You have asked… How should we manage subclinical dogs that are seropositive for rickettsial diseases?

The expert says… Popular combined screening tests, such as SNAP 4Dx Plus and AccuPlex4, can help identify healthy subclinical (nonclinical) dogs seropositive for rickettsial agents by assaying for heartworm antigen and for antibodies against Lyme disease (Borrelia burgdorferi), anaplasmosis (Anaplasma phagocytophilum), and ehrlichiosis (Ehrlichia canis). In addition, the SNAP 4Dx Plus test identifies antibodies against E chaffeensis, E ewingii, A platys, and a novel E muris-like agent found in dogs.^1,2 Anaplasma and Ehrlichia organisms may also be associated with carrier status both in untreated exposed dogs and in treated dogs. Whether to give antibiotics to dogs with subclinical, nonproteinuric Lyme-seropositivity has been debated^3-6; the consensus appears to be no, although such dogs should be monitored for occult proteinuria. Meanwhile, how should subclinical Anaplasma spp and/or Ehrlichia spp seropositive dogs be clinically managed? Might they still be carriers, and might carriers become clinically ill in the future? Can the carrier state be cleared, and can seropositive dogs be used safely as blood donors? Do these dogs remain potential reservoirs for infection of other animals and humans?

Related Article: A Matter of Opinion: Should We Treat Asymptomatic, Nonproteinuric Lyme-Seropositive Dogs with Antibiotics? Clinical Cues Certain rickettsial organisms parasitize granulocytic (A phagocytophilum, E ewingii) or mononuclear (E canis, E chaffeensis) WBCs or platelets (A platys). Signs in infected dogs vary (see Clinical Signs of Rickettsial Infection below),^7-11 and infection may result in chronic carrier states with no sign of clinical illness.

Diagnostic tests may reveal cytopenias (eg, thrombocytopenia, possible anemia and/or leukopenia), basophilic cytoplasmic inclusion bodies (morulae) in WBCs or platelets (via synovial fluid cytology or peripheral blood or buffy coat smears), renal proteinuria with negative urine culture, hypoalbuminemia, hyperglobulinemia with polyclonal or monoclonal gammopathy, hypercholesterolemia, and possibly elevated liver enzymes.^7-11 To Treat or Not to Treat? For seropositive dogs with illness suggestive of rickettsial disease, treatment with doxycycline at 5 mg/kg q12h or 10 mg/kg q24h for 28 days is recommended; dogs with acute or mild to moderate illness generally respond within 1 or 2 days of antibiotics.^7-11 Quantitative IFA or ELISA testing may be used to assess response to therapy and establish baselines for future comparisons at 0 and 6 to 12 months posttreatment, particularly if signs recur or worsen. Decreased titers or normalization of hematologic/urinalysis abnormalities may indicate organism clearance or decreased antigenic burden. But should we routinely treat subclinical seropositive dogs with doxycycline? The author’s answer is no; however, occult clinicopathologic changes such as cytopenias (eg, anemia, leukopenia, thrombocytopenia), proteinuria, hypoalbuminemia, or hyperglobulinemia should be evaluated (see Management Plan for Subclinical Seropositive Dogs on page 3 of this PDF). Abnormalities necessitate antimicrobial treatment, and further investigation may be indicated to rule out other causes of these changes, including coinfection with other infectious diseases, as seropositivity may be a coincidence or a marker for tick and wildlife exposure. Additional testing for heartworm antigen and antibodies against B burgdorferi, Babesia spp, Bartonella spp, Leptospira spp, Hepatozoon spp, Brucella spp, or Leishmania spp may be indicated.

Related Article: Fever, Lameness, & Heart Murmur in a Coonhound

Why Not? This clinical rationale for management (not treatment) of subclinical seropositive dogs with no clinicopathologic abnormalities is sevenfold: 1. Seropositivity proves exposure only, not necessarily active infection or carrier status. A dog can remain seropositive even after previous treatment or after infection has cleared.7-12 2. Many exposed dogs remain healthy and either do not become ill or have mild disease that does not necessitate treatment.^7-12 In experimental studies, beagle puppies and adults were exposed to Ixodes ticks and observed for over a year.^13-15 Adult dogs showed no signs of illness; however, puppies exposed at 6 to 12 weeks of age showed self-limiting lameness, anorexia, and fever but did not require treatment. These studies were meant to investigate Lyme disease, but 35% to 45% of the dogs were inadvertently coinfected, demonstrating antibodies against both B burgdorferi and A phagocytophilum (some were also seropositive to Babesia microti).^13-15 In an experimental E canis infection model, beagles became chronic carriers but did not show the severe bone marrow hypoplasia demonstrated in German shepherd dogs with breed-associated reduced cellular immune responses.¹⁶ 3. Serosurveys show that a high percentage of clinically healthy dogs have antibodies against Ehrlichia spp.⁷ No differences for seroprevalence against Anaplasma spp were found between healthy and sick dogs in Minnesota¹⁷ or Pennsylvania¹⁸; however, Lyme and Anaplasma spp coinfection appeared to increase risk for illness.¹⁷ 4. Treatment may not clear the carrier state, and organisms can remain despite doxycycline therapy. E canis organisms were found in splenic aspirates after 6 weeks of doxycycline treatment.^7,12 Likewise, doxycycline may not clear all Anaplasma spp carriers¹⁰; A phagocytophilum PCR tests were negative during and after treatment in another study, although lack of clearance was proven when PCR tests became positive again after corticosteroid challenge.^19,20 5. Because immunity to these agents is not long lasting, dogs may be reexposed and become reinfected without proper tick control. Titers may persist or become negative after treatment.^7-12 It is possible that carrier status actually protects dogs from becoming ill from reexposure and acute illness. 6. Abusing or misusing doxycycline, not as inexpensive as it was previously, may have adverse effects to both the individual and environment. Although doxycycline is typically safe, GI signs in up to 18% and elevated liver values in up to 40% of treated dogs have been reported.²¹ Furthermore, veterinarians should not overuse antibiotics, to avoid increasing bacterial resistance and compromise doxycycline efficacy. 7. Depending on the duration and magnitude of rickettsemia, carrier dogs may act as potential reservoirs for infection. Wildlife reservoirs are more important for organisms carried by Ixodes and Amblyomma ticks (eg, A phagocytophilum, E chaffeensis), but as all stages of Rhipicephalus spp ticks feed on dogs, dogs are the main reservoirs for E canis and other organisms carried by these ticks (eg, Babesia spp). As antimicrobials may not clear carriers, tick control remains the most important tool to prevent ticks from picking up infection from carriers and infecting new hosts.

Related article: A Matter of Opinion: Should We Treat Asymptomatic, Nonproteinuric Lyme-Seropositive Dogs with Antibiotics? Why Screen Without Intent to Treat? Seropositive dogs are sentinels and help educate owners about public health issues, tick-borne disease, and whether tick prevention efforts are adequate. Awareness of the background seroprevalence of these infections in a practice’s region can prevent overdiagnosis in these and other cases. Screening for occult changes (eg, proteinuria, cytopenias) in seropositive subclinical dogs allows early intervention when it is likely to be most helpful.

MERYL P. LITTMAN, VMD, DACVIM, is associate professor at University of Pennsylvania. Her interests include protein-losing nephropathy, and she has lectured at various conferences, including the NAVC Conference, on Lyme disease, other tick-borne coinfections, and proteinuria. Dr. Littman completed an internship and residency in small animal internal medicine at University of Pennsylvania.

HOW, WHEN, & WHETHER TO TREAT SUBCLINICAL RICKETTSIAL DISEASE • Meryl P. Littman References 1. Ehrlichia-muris infection in a dog from Minnesota. Hegarty BC, Maggi RG, Koskinen P, et al. JVIM 26:1217-1220, 2012. 2. Diagnosis of rickettsial diseases in dogs and cats. Allison RW, Little SE. Vet Clin Pathol 12040 April 2013; ePub ahead of print. 3. ACVIM small animal consensus statement on lyme disease in dogs: Diagnosis, treatment, and prevention. Littman MP, Goldstein RE, Labato MA, et al. JVIM 20:422-434, 2006. 4. Should we treat asymptomatic, nonproteinuric Lyme-seropositive dogs with antibiotics? No. Littman MP. Clin Brief 9:13-16, 2011. 5. Should we treat asymptomatic, nonproteinuric Lyme-seropositive dogs with antibiotics? It depends. Goldstein RE. Clin Brief 9:13-16, 2011. 6. Treating Lyme-seropositive dogs. Barr SC. Clin Brief 10:8, 2012. 7. Ehrlichia canis infection. Harrus S, Waner T, Neer TM. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 4th ed—St. Louis: Elsevier, 2012, pp 227-238. 8. Ehrlichia chaffeensis infection. Harrus S, Waner T, Neer TM. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 4th ed—St. Louis: Elsevier, 2012, p 238. 9. Ehrlichia ewingii infection. Cocayne CG, Cohn LA. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 4th ed—St. Louis: Elsevier, 2012, pp 241-244. 10. Anaplasma phagocytophilum infection. Diniz PP, Breitschwerdt EB. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 4th ed—St. Louis: Elsevier, 2012, pp 244-254. 11. Anaplasma platys infection. Harvey JW. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 4th ed––St. Louis: Elsevier, 2012, pp 256-259. 12. Consensus statement on ehrlichial disease of small animals from the infectious disease study group of the ACVIM. Neer, TM, Breitschwerdt EB, Greene RT, et al. JVIM 16:309-315, 2002. 13. Borrelia burgdorferi migrates into joint capsules and causes an up-regulation of interleukin-8 in synovial membranes of dogs experimentally infected with ticks. Straubinger RK, Straubinger AF, Härter L, et al. Infect Immun 65:1273-1285, 1997. 14. Experimental induction of chronic borreliosis in adult dogs exposed to Borrelia burgdorferi-infected ticks and treated with dexamethasone. Chang YF, Novosel V, Chang CF, et al. Am J Vet Res 62:1104–1112, 2001. 15. Experimental Lyme disease in dogs produces arthritis and persistent infection. Appel MJG, Allen S, Jacobson RH, et al. J Infect Dis 167:651–664, 1993. 16. Cell-mediated and humoral immune responses of German shepherd dogs and beagles to experimental infection with Ehrlichia canis. Nyindo M, Huxsoll DL, Ristic M, et al. Am J Vet Res 41:250-254, 1980. 17.  Serological and molecular prevalence of Borrelia burgdorferi, Anaplasma phagocytophilum, and Ehrlichia species in dogs from Minnesota. Beall MJ, Chandrashekar R, Eberts MD, et al. Vector Borne Zoonotic Dis 8:455–464, 2008. 18.  Anti-Anaplasma spp. antibody seroprevalence in diseased dogs and healthy blood donor dogs in a veterinary teaching hospital in a Lyme endemic area. Gavin KA, Nolan TJ, Littman MP. JVIM 22:781, 2008. 19.  Experimental inoculation of dogs with a human isolate (NY18) of Anaplasma phagocytophilum and demonstration of persistent infection following doxycycline therapy. Alleman A, Chandrashekar R, Beall M, et al. JVIM 20:763, 2006. 20.  An update on anaplasmosis in dogs. Alleman RA, Wamsley HL. Vet Med (Praha) 103:212-222, 2008. 21.  Investigation of doxycycline-related side effects in dogs. Schulz B, Hupfauer S, Hartmann K. JVIM 23:695, 2009.