Bartonellosis: A hidden epidemic

Edward B. Breitschwerdt, DVM, DACVIM
Center for Comparative Medicine and Translational Research and the Department of Clinical Sciences
College of Veterinary Medicine
North Carolina State University
Raleigh, N.C.

Introduction

Bartonella species are fastidious gram-negative bacteria that are highly adapted to a mammalian reservoir host, within which the bacteria usually cause a long-lasting intra-erythrocytic bacteremia.1-3 These facts are of particular importance to veterinarians and physicians as an increasing number of animal reservoir hosts have been identified for various Bartonella species, including many "pocket-pet" rodents.2 Before 1990 there were only two named Bartonella species; now there are at least 26 named and numerous unnamed or candidatus species.

Fleas play an important role in the transmission of B. henselae, B. clarridgeae, and most likely B. koehlerae among cats.1 In addition to fleas, an increasing number of arthropod vectors, including biting flies, keds, lice, sandflies, and ticks have been implicated in the transmission of Bartonella. Considering the diversity of species and subspecies, the large number of reservoir hosts, and the spectrum of arthropod vectors, the clinical and diagnostic challenges posed by Bartonella may be much more complex than currently appreciated in human and veterinary medicine.

In the natural reservoir host, such as a cat or rodent, chronic bacteremia with a Bartonella species can frequently be detected by blood culture or PCR in outwardly healthy animals.1-3 In contrast, the diagnostic detection of a Bartonella spp. in a nonreservoir-adapted host, such as a dog, horse, or human, can be extremely difficult.2,4 Most—but not all—diseases caused by Bartonella spp. occur in accidental hosts, and these organisms are being increasingly implicated as a cause of zoonotic infections.

Feline bartonellosis

Bartonella henselae bacteremia has been documented in 25% to 41% of healthy cats in different regions throughout the world. A self-limiting febrile illness with a mild to moderate transient anemia and transient neurologic dysfunction can occur in B. henselae bacteremic cats following minor surgical procedures, presumably because of stress. Fever has also been reported in cats experimentally infected with B. henselae by blood transfusion. Furthermore, immunosupression associated with FeLV or FIV appears to increase the pathogenicity of B. henselae infection. In experimentally infected cats, histopathological lesions include: peripheral lymph node hyperplasia; splenic follicular hyperplasia; lymphocytic cholangitis/pericholangitis; lymphocytic hepatitis; lymphoplasmacytic myocarditis; and interstitial lymphocytic nephritis. These findings indicate that antibiotic treatment should be considered in seroreactive or bacteremic cats with these disease manifestations.

Cat scratch disease (CSD) in people

For over a century, regional lymphadenopathy has been associated with cat scratches.1 Several studies have identified seroreactivity to B. henselae antigens and Bartonella DNA (amplified using PCR) in people with suspected CSD.2 Subsequently, Bartonella species have been cultured from all but two cats owned by a group of 14 patients with cat scratch disease, indicating that bacteremia is a frequent occurrence in cats that transmit B. henselae to people.2

With the advent of specific diagnostic techniques, such as culture, serology, and PCR, there has been a dramatic increase in reports describing patients with "atypical" manifestations of CSD. Osteomyelitis, granulomatous hepatitis, and granulomatous splenitis have been increasingly recognized in children infected with B. henselae who frequently lack the classical lymphadenopathy of CSD. As evidenced by reports over the past four years, the spectrum of human disease associated with the genus Bartonella continues to expand, requiring periodic reassessment as new information becomes available.4-8

Some patients deny the possibility of a cat scratch or bite wound, or indicate no contact with cats. Transmission from environmental sources, arthropod vectors, perinatally, by blood transfusion, needle stick, or other animal hosts is probable in these cases.

Canine bartonellosis

As recognition that dogs can be infected with B. vinsonii (berkhoffii), B. henselae, and potentially other Bartonella spp. is relatively recent, seroprevalence data are limited. Based on research out of North Carolina, risk factors that may be associated with B. vinsonii (berkhoffii) seroreactivity in sick dogs include: heavy tick exposure; cattle exposure; rural environments; and heavy flea exposure. Thirty-six percent of serum samples derived from dogs naturally infected with Ehrlichia canis were reportedly reactive to B. vinsonii antigens, further supporting ticks as possible vectors.

The spectrum of disease associated with Bartonella infection in cats, dogs, and most other animal species remains poorly characterized. Stress, hard work, parturition, or concurrent infection with other organisms may contribute to the development of pathology. Infection with B. vinsonii (berkhoffii) might induce a degree of chronic immunosuppression that could predispose dogs to other infectious agents, resulting in a wide array of clinical manifestations in naturally infected dogs. Endocarditis associated with B. vinsonii (berkhoffii) occurs in large-breed dogs with a potential predisposition for aortic valve involvement.2 Based on recently obtained serologic evidence in dogs, B. vinsonii (berkhoffii) or closely related Bartonella species appear to contribute to the development of dermatologic lesions indicative of a cutaneous vasculitis, anterior uveitis, polyarthritis, meningoencephalitis, or immune-mediated hemolytic anemia.2

Bartonellosis diagnosis

In dogs, thrombocytopenia, anemia (frequently immune-mediated), and neutropenia or neutrophilic leukocytosis are the most commonly detected hematological abnormalities associated with Bartonella infection. Eosinophilia is also found in approximately one third of infected dogs. Hemoglobinuria, generally unaccompanied by hematuria, is another frequent finding, particularly in dogs with immune-mediated hemolytic anemia. In B. vinsonii-infected dogs, particularly those with endocarditis, monocytosis can also occur. Serum biochemical abnormalities are usually very mild or nonexistent.

B. vinsonii (berkhoffii) antibodies are infrequently detected in sick (< 4%) or in healthy (< 1%) dogs; therefore, detection of B. vinsonii (berkhoffii) antibodies in a sick dog provides strong clinical evidence for prior exposure and potentially active infection. For this reason, treatment is recommended for B. vinsonii (berkhoffii) seroreactive dogs or dogs from which any Bartonella spp. DNA is detected in blood or tissue samples. However, approximately 50% of dogs infected with B. vinsonii (berkhoffii) or B. henselae lack a detectable antibody response. The recent development of a more sensitive isolation approach using Bartonella alpha Proteobacteria Growth Medium (BAPGM) followed by PCR has greatly facilitated the molecular detection or isolation of Bartonella species from the blood of animals and people. Recent BAPGM culture/PCR results indicate that B. henselae is the most common species infecting dogs, not B. vinsonii (berkhoffii) as previously thought. Diagnostic testing for Bartonella species (e.g., serology, PCR, and BAPGM Blood Culture/PCR combination testing) is available through Galaxy Diagnostics, Inc.

Therapy

To date, an optimal protocol has not been established for the treatment of Bartonella infections in cats, dogs, or people.2 Regardless of the antibiotic used for treatment, a long duration of antibiotic administration (e.g., six weeks) may be necessary to eliminate the infection. Fluoroquinolones alone or in combination with amoxicillin have elicited a positive therapeutic response in dogs, which is accompanied by a progressive decrease in B. vinsonii antibody titers. Newer macrolides, or semi-synthetic derivatives of erythromycin, obtain high intracellular concentrations. However, B. henselae rapidly develops resistance to azithromycin, so these antibiotics should not be used as a sole treatment.2 Doxycycline alone may or may not be effective for treatment of B. vinsonii subsp. berkhoffii, and data from cats experimentally or naturally infected with B. henselae or B. clarridgeae indicate that a high dose of doxycycline (10 mg/kg every 12 hours) for four to six weeks may be necessary to eliminate Bartonella infection in dogs, cats, or other animal species.2 With treatment, serum antibody titers decrease rapidly (three to six months) and are generally no longer detectable in dogs that recover following antimicrobial therapy. Therefore, if antibodies are detectable pre-treatment, post-treatment serology may be a useful adjunct to BAPGM/PCR to determine if therapeutic elimination of Bartonella infections has been achieved.

Prevention and public health considerations

Increasingly, veterinarians play an important role in advising the public as to the epidemiological and zoonotic implications associated with vector-borne pathogens. Minimizing or eliminating flea and tick exposure is perhaps of greater veterinary and public health importance today than during any time in history. When rigorous flea and tick control measures are instituted, it is highly probable that transmission of Bartonella species will be greatly reduced or eliminated.

Veterinary professionals appear to have an occupational risk of infection because of extensive contact with a spectrum of animal species and frequent exposure to Bartonella spp. Therefore, these individuals should exercise increased precautions to avoid arthropod bites, arthropod feces (i.e., fleas and lice), animal bites or scratches, and direct contact with bodily fluids from sick animals. A substantial number of diagnostic biological samples collected on a daily basis in veterinary practices could contain viable bacteria.2,4-8 The increasing number of defined Bartonella spp. in conjunction with the high level of bacteremia found in reservoir-adapted hosts, which represent the veterinary patient population, ensures that all veterinary professionals will experience frequent and repeated exposure to animals harboring these bacteria. Consequently, personal protective equipment, frequent hand washing, and avoiding cuts and needle sticks have become more important as our knowledge of this genus has improved and various modes of transmission have been defined.

Physicians should be educated as to the large number of Bartonella spp. in nature, the extensive spectrum of animal reservoir hosts, the diversity of confirmed and potential arthropod vectors, current limitations associated with diagnosis and treatment efficacy, and the ecological and evolving medical complexity of these highly evolved bacteria.

References

1. Chomel BB, Boulouis HJ, Breitschwerdt EB, et al. Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors. Vet Res 2009;40:29.

2. Breitschwerdt EB, RG Maggi, BB Chomel, et al. Bartonellosis: An emerging infectious disease of zoonotic importance to animals and human beings. J Vet Emerg Crit Care (San Antonio) 2010;20:8-30.

3. Chomel BB, Kasten RW, Williams C, et al. Bartonella endocarditis: a pathology shared by animal reservoirs and patients. Ann N Y Acad Sci 2009;1166:120-126.

4. Breitschwerdt EB, Maggi RG, Nicholson WL, et al. Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. J Clin Microbiol 2008;46:2856-2861.

5. Breitschwerdt EB, Maggi RG, Lantos PM, et al. Bartonella vinsonii subsp. berkhoffii and Bartonella henselae bacteremia in a father and daughter with neurological disease. Parasit Vectors 2010;3:29.

6. Breitschwerdt EB, Maggi RG, Farmer P, et al. Molecular evidence of perinatal transmission of Bartonella vinsonii subsp. berkhoffii and Bartonella henselae to a child. J Clin Microbiol 2010;48:2289-2293.

7. Breitschwerdt EB, Maggi RG, Mozayeni BR, Bradley JM, Hegarty BC, Mascarelli PE. Isolation or PCR amplification of Bartonella koehlerae from human blood. Parasit Vectors 2010; 3: 76.

8. Oliveira AM, RG Maggi, CW Woods, et al. Putative needle stick transmission of Bartonella vinsonii subsp. berkhoffii to a veterinarian. J Vet Intern Med: 2010; 24:1229-1232.