Canine Bartonellosis

Definition. Bartonella species are emerging zoonotic bacterial pathogens that are of increasing medical importance in veterinary and human medicine.^1-3 Approximately 11 species have been identified as pathogenic for human disease, and 6 of these have been isolated from pet cats and dogs.¹ Bartonella henselae and Bartonella vinsonii subspecies berkhoffii are the most commonly identified species in sick dogs and have been isolated from the blood of immunocompetent human patients.⁴

Systems. These intraerythrocytic, endotheliotropic bacteria have been associated with a spectrum of disease manifestations involving the lymph nodes, heart (valves and myocardium), vasculature, liver, joints, and central nervous system.⁴

Genetic Implications. As is true of other companion animal infectious diseases, a genetic predisposition may exist. Bartonella species have been found in 18% of healthy golden retrievers; although U.S. data are scarce, some research suggests that overall seroprevalence is less than 5%.^1,5 In 1 study involving 1872 working dogs owned by the U.S. government, German shepherd dogs were significantly less likely to be seropositive for B vinsonii subspecies berkhoffii than other breeds.⁶ Acquired or therapeutically induced immunosuppression enhances disease expression.

Incidence/Prevalence. Cats are the primary reservoir host for B henselae, which is transmitted among cats and potentially dogs by fleas. Canids, including coyotes, dogs, and gray foxes can serve as reservoir hosts for B vinsonii subspecies berkhoffii, and tick transmission of this subspecies is suspected.⁷ In nontropical areas, dogs appear to be accidental hosts for several Bartonella species.¹

Geographic Distribution. The geographic distributions of the various Bartonella species vary greatly (likely reflecting the distribution of their hosts and vectors), but B henselae and B vinsonii subspecies berkhoffii have worldwide distribution. Prevalence is higher in regions where flea and tick infestations are more likely.^1-3,7 On the basis of seroprevalence data, dogs are exposed to B henselae and B vinsonii subspecies berkhoffii throughout the U.S., but some research has demonstrated that B vinsonii seropositivity may be more likely in tropical and coastal areas receiving high levels of precipitation.^1,8,9 (Figures 1 and 2).

Figure 1: Bartonella henselae seroprevalence by state based upon tick-borne disease panel results (9030 samples from sick dogs tested from 2004–2007) from the North Carolina State University College of Veterinary Medicine, Vector-Borne Diseases Diagnostic Laboratory. An antibody titer of 1:64 was considered seroreactive, and individual requests for B henselae serology are not included in the data summary.

Figure 2: Bartonella vinsonii subspecies berkhoffii seroprevalence by state based upon tick-borne disease panel results (9030 samples from sick dogs tested from 2004–2007) from the North Carolina State University Vector-Borne Diseases Diagnostic Laboratory. An antibody titer of 1:64 was considered seroreactive, and individual requests for B vinsonii subspecies berkhoffii serology are not included in the data summary.

Species. B henselae and B vinsonii subspecies berkhoffii have caused endocarditis in dogs and people. To date, 7 Bartonella species have caused endocarditis in dogs.⁴

Breed Predilection. Epidemiologically, B henselae and B vinsonii subspecies berkhoffii seroprevalences correlate with midsize and large-breed dogs that are allowed to roam.^10,11

Age & Range. Exposure is more likely in middle age to older dogs residing in rural environments with frequent flea and tick exposure.

Gender. Female sex predilection is suspected in human patients. No sex predilection has been identified in dogs.

Bartonella species can be transmitted to humans via a bite or scratch (cat, dog, or rabbit scratch disease). Research in cats has shown that claws contaminated with flea feces are the predominant source of infection, whereas reports of B henselae shedding in cat saliva are inconclusive.¹

Less is known about risk factors for canine bartonellosis, but dogs are most likely infected through animal scratches and bites from fleas, ticks, and other arthropod vectors. In particular, there is increasing interest in the role of tick bites in transmitting Bartonella infection because some correlation has been found between high tick burden and B vinsonii subspecies berkhoffi seroreactivity.⁷ Understandably, these bacteria pose an occupational risk for animal health professionals.^12,13

Presumably complex, the pathophysiology of Bartonella species infection is incompletely understood.^3,4 Following transmission, bacteria localize to erythrocytes, endothelial cells, and, based upon in vitro data, macrophages and dendritic, microglial, and CD34 bone marrow progenitor cells. Lymphoid hyperplasia, granulomatous inflammation in a variety of tissues, vasculitis, and vasoproliferative lesions are among the reported pathologic lesions.

History. Due to the highly adaptive nature of these vector-borne bacteria, most dogs experience an acute illness that may or may not be associated with fever or evidence of a systemic inflammatory response, followed by a chronic, insidious course of illness spanning months to years. Lameness, intermittent lethargy or fever, epistaxis, and neurologic abnormalities, including lack of coordination or seizures, can develop progressively in chronically infected dogs.^4,14-16

Physical Examination. Chronically infected dogs may not exhibit clinical signs of illness.¹⁷ Dogs with neutrophilic polyarthritis may exhibit a mild shifting leg lameness or severe debilitating joint pain.

Definitive Diagnosis
As is true for other intracellular pathogens that induce chronic infection in dogs after vector-borne transmission, diagnostic confirmation of active infection with a Bartonella species can be extremely challenging. Due to cost and duration of therapy, the diagnosis of bartonellosis should be confirmed by culturing the organism from blood; cerebrospinal, aqueous, or joint fluids; thoracic, pericardial, or abdominal effusions; or tissue biopsy samples.

PCR Assay
When blood culturing cats, B henselae and B clarridgeae can be readily isolated; however, isolation from dog, horse, or human blood samples using the same approach is very insensitive.¹⁸ Therefore, to increase diagnostic sensitivity, we combined enrichment culture in a specialized growth medium (designated Bartonella alpha-Proteobacteria growth medium or BAPGM) with a highly sensitive polymerase chain reaction (PCR) assay. Currently, BAPGM (galaxydx.com) provides the most sensitive (98% at 1 bacterium/mcL) modality to confirm active infection with a Bartonella species in companion animal or human patient samples (Figure 3).

Figure 3: A diagram depicting the steps involved in the BAPGM platform. PCR is performed following extraction of DNA from the original patient sample, enrichment incubation in BAPGM, and subculture onto a blood agar plate. BAPGM is a patented insect cell culture-based liquid growth medium that was optimized to facilitate the growth of Bartonella species and other fastidious bacteria.¹⁸ The enrichment process increases the quantity of Bartonella species DNA so as to enhance the sensitivity of the PCR assay. All PCR-positive samples are sequenced to determine the Bartonella species and strain.

Figure 4: An example of Bartonella vinsonii subspecies berkhoffii immunofluorescent organisms (serum antibody titer of 1:2048) using the IFA serologic assay in the North Carolina State University Vector-Borne Diseases Diagnostic Laboratory. The test serum was from a military working dog with B vinsonii subspecies berkhoffii genotype III endocarditis. Bacteremia was confirmed using the BAPGM platform.⁴

Alternatively, PCR can be used to amplify bartonella DNA from paraffin-embedded lymph nodes, heart valves, or other tissues, but PCR with preenrichment culture is reportedly 2 to 3 times more sensitive than direct PCR alone.^19,20 Immunosuppressive drugs appear to increase the quantity of Bartonella in blood, whereas administration of antibiotics prior to obtaining samples for BAPGM culture will decrease detection.

IFA Testing
By indirect immunofluorescent antibody (IFA) testing, antibody reactivity to the Bartonella species antigens is detected in only 50% of dogs and humans in which active infection with B vinsonii subspecies berkhoffii and B henselae can be documented (Figure 4). Therefore, antibody testing in dogs and human patients is insensitive, and, if detected, the presence of antibodies can only be used to infer prior exposure.⁴

Differential Diagnosis
As intravascular, endotheliotropic bacteria, Bartonella species can localize to numerous tissue locations within the body. Bartonellosis would be a differential diagnosis for dogs with endocarditis, myocarditis, polyarthritis, meningoencephalitis, granulomatous inflammatory disease, lymphoid hyperplasia, hypersplenism, epistaxis, idiopathic cavitary effusions, vasculitis, fever of unknown origin, and vasoproliferative lesions. Each of these conditions can be caused by numerous infectious, neoplastic, and autoimmune conditions. Due to the presence of antinuclear antibodies in dogs with bartonellosis, infection with these bacteria should be ruled out in dogs with suspected systemic lupus erythematosus.

Laboratory Findings
Most dogs chronically infected with a Bartonella species have no laboratory abnormalities until fulminate clinical signs develop. Then, laboratory abnormalities are nonspecific.^19-22 These bacteria have been isolated from the blood, cerebrospinal fluid, and joint effusion samples from dogs with immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, neutropenia, neutrophilia with a mild left shift, eosinophilia, unexplained hypoalbumenemia, mild hyperglobulinemia, mild to moderate elevations in liver enzyme activities, and hematuria.
 

Postmortem Findings
Due to the chronic nature of Bartonella species infections, causation has not been clearly established for many pathologic lesions found in culture or PCR-positive dogs. Multiple Bartonella species have been associated with endocarditis in dogs. Other pathologic lesions for which these bacteria should be considered include granulomatous lesions of undetermined cause, lymphoid hyperplasia, hypersplenism, peliosis hepatis, and bacillary angiomatosis.^4,23

Inpatient or Outpatient
Following diagnostic confirmation of active infection, most dogs can be treated as outpatients. Dogs with severe life-threatening illness, such as endocarditis, myocarditis, encephalitis, immune-mediated hemolytic anemia, or idiopathic thrombocytopenic purpura require intravenous antibiotics in conjunction with intensive monitoring and critical care; temporary immunosuppressive drugs may also be needed to suppress immune destruction of platelets or erythrocytes.

Medical
Antibiotic therapy is needed to eliminate the source of infection; pain management may also be needed. Additional medications are discussed in the following section.

Surgical
Surgery may be required in selected cases to obtain tissue biopsies for histopathology, BAPGM enrichment culture, and PCR.

Activity
Moderate exercise restriction would only be applicable for dogs with endocarditis, myocarditis, or severe debilitating polyarthritis.

Nutritional Concerns
Substantial, unexplained weight loss has occurred in a small subset of dogs in which Bartonella bacteremia was confirmed. Feeding a high-quality, high-quantity protein diet should enhance immune function and facilitate antibiotic elimination of infection.

Alternative Therapy
Due to the protracted course of antibiotic therapy that is currently recommended for treatment of bartonellosis in dogs, obtaining a definitive diagnosis is highly recommended. Alternative therapies have not eliminated this infection in dogs, and no alternative therapy has been shown to produce adjunctive affects.

Client Education
Clients should avoid bites, scratches, or contact with saliva from infected dogs. In conjunction with directed medical therapy, clients should apply acaricides to prevent future vector transmission by fleas or ticks.^5,7,10,11

Drugs
Antibiotics are currently the mainstay of treatment. Because these bacteria can induce intracellular as well as intravascular infection, antibiotics should be dosed to achieve therapeutic drug concentrations within cells and within plasma.

-On the basis of findings from in vitro antimicrobial testing, azithromycin, doxycycline, enrofloxacin, and rifampin are effective antibiotics.²⁴ Due to recently documented treatment failures and evidence supporting rapid development of resistance, azithromycin should be used with caution.^20,25

-Simultaneous administration of more than 1 antibiotic is necessary to eliminate infection in some dogs. Doxycycline, as a sole therapy, can induce clinical or hematologic improvement but does not eliminate the infection.

Contraindications
Caution should be exercised if there is a history of allergic response to a specific class of antibiotics.

Precautions
Antibiotics used to treat bartonellosis can induce anorexia, vomiting, diarrhea, and increased liver enzyme activities.

Interactions
Many dogs become lethargic and inappetent 3 to 6 days after initiation of antibiotics. Although the cause of this phenomenon is not known, it is presumably due to bacterial death and cytokine release.

Patient Monitoring
A complete blood count and serum biochemical profile should be performed 2 weeks following initiation of antibiotic therapy, or sooner if the dog experiences progressive clinical signs of illness.

Complications
Treatment failures are a major complication.

Course
Dogs are treated with antibiotics for 6 weeks; in some dogs, a combination of 2 antibiotics may be necessary to achieve a cure.

Future Follow-Up
To confirm therapeutic elimination of the infection, a BAPGM platform culture/PCR assay should be performed 2 weeks following completion of antibiotic therapy. If the dog is Bartonella seroreactive, antibody titers drop rapidly. Most successfully treated dogs will become seronegative within 3 to 6 months.

Relative Cost
Diagnostic evaluation, effective treatment, and recommended follow-up to prove therapeutic elimination make this an expensive disease to manage ($$$$).

Prevention
All known Bartonella species are transmitted by a spectrum of arthropod vectors, by animal bites or scratches, by blood transfusion from an infected donor, or mechanically by needle sticks.^1-4,7

Prognosis
Prognosis varies from grave to good, depending upon the disease manifestations and response to antibiotics.

Future Considerations
Since Bartonella is a recently discovered genus of bacteria, considerable research is required to define optimal treatment and prevention strategies.

See Aids & Resources for references and suggested reading.