What do we really know about feline bartonellosis? (Proceedings)

Bartonella infections of domestic cats have only recently been recognized, but likely have existed for thousands of years. Bartonella DNA was recently detected by polymerase chain reaction (PCR) in 800-year-old dental material from cats and in 4000-year-old dental material from a human being. The first report of Bartonella infection of a cat appeared in 1992, and many clinical and experimental studies of feline bartonellosis have followed. Several Bartonellae are zoonotic human pathogens. Zoonotic species include Bartonella henselae, Bartonella vinsonii subsp. berkhoffii, B. vinsonii subsp. arupensis, B. washoensis, B. elizabethae, B. koehlerae, B. clarridgeiae, and B. quintana. Bartonella quintana, a cause of trench fever, endocarditis, bacillary angiomatosis, and other conditions, and B. henselae, a cause of cat scratch disease, bacillary angiomatosis, endocarditis, and other conditions, are the most well known of these zoonotic pathogens. Cat scratch disease has been recognized in human beings as a specific disease entity for over 50 years, and references to similar conditions can be found as far back as the 17th century. Many other manifestations of zoonotic bartonellosis (such as parenchymal bacillary peliosis, relapsing fever with bacteremia, optic neuritis, pulmonary, hepatic, or splenic granulomas, osteomyelitis and others) are reported. Immunocompetent individuals tend to have more localized and self-limiting infections, whereas infections that occur in immunocompromised individuals are more often systemic and can be fatal without treatment. Veterinarians, veterinary staff, groomers, and other individuals with extensive animal contact appear to be at a greater risk for Bartonella infection than others.

Cats are recognized as the primary reservoir and vector for zoonotic B. henselae infections, and have also been implicated as vectors for B. clarridgeiae infection of people. Cats may also be reservoirs and vectors of B. koehlerae and other Bartonella species as well. Transmission of B. henselae from cats to human beings probably occurs through contamination of cat scratches or other wounds, or mucous membranes such as conjunctiva, with flea excrement. Transmission may occur via cat bites if cat blood or flea excrement contaminate the bite site. Bartonella henselae is transmitted among cats by fleas. Viable Bartonella organisms are excreted in flea feces and cats are likely inoculated via contamination of wounds or mucous membranes with infected flea feces. The role of the flea as a vector for transmission to human beings is not clear, but transmission via flea feces is considered likely. Ticks are another possible vector. Viable Bartonella spp. have been detected in questing ticks; also in other arthropod vectors including biting flies and sheep keds.

Cats infected with B. henselae may have relapsing bacteremia for months to years, and relapsing bacteremia is suspected in cats infected with other Bartonella species. Bacteremia appears to be more common in young cats (<2-3 years of age) and older cats are more likely to be seropositive. How long serum antibodies persist following clearance of infection is unknown. Experimental data indicate that serum antibodies persist for months to years following apparent clearance of bacteremia. Bacteremia in cats is more prevalent in regions with warm, humid climates where flea infestations are more common. In some regions, prevalence of serum antibodies to B. henselae in cats is reportedly as high as 75-90%.

Clinical manifestations

Most cats with Bartonella bacteremia appear to be clinically normal. Some cats experimentally infected with B. henselae or B. clarridgeiae exhibited mild and transient clinical signs including fever, lethargy, anorexia, and lymphadenomegaly. Uncommon signs included central nervous system signs (nystagmus, tremors, or possible focal motor seizures), myalgia or reproductive failure. There is great genetic diversity among B. henselae isolates, and clinical signs in experimentally infected cats varied with the isolates used for inoculation. Many tissues of cats experimentally infected with B. henselae and B. clarridgeiae had multiple foci of inflammatory cells. Many naturally infected cats do not exhibit obvious clinical signs, but may have lymphadenomegaly or transient fever. Fatal endocarditis was reported in one cat naturally infected with B. henselae. No clinical signs were reported in cats experimentally or naturally infected with B. koehlerae or B. bovis. Cats infected with B. henselae or B. clarridgeiae have relapsing bacteremia, and relapsing bacteremia is suspected in cats infected with other Bartonella species. It has been suggested that several other conditions of cats, particularly some chronic conditions heretofore considered idiopathic, may be related to Bartonella infection. Although it is possible that Bartonella infections may play a role in development of some of these conditions, there are no published controlled studies verifying a causal association of Bartonella infection with specific disease conditions. Recent studies have failed to demonstrate an association between Bartonella infection in cats and stomatitis, neurologic disease, or uveitis. Because of the high prevalence of Bartonella infection in the domestic cat population, large, appropriately controlled studies are necessary to determine what causal associations may exist between Bartonella infections and clinical conditions of cats.

Diagnosis

Culture of Bartonella from blood or other tissues provides a definitive diagnosis of Bartonella infection in cats, and is the criterion standard against which other means of diagnosis are measured. As a result of relapsing bacteremia, blood culture may yield false negative results in cats infected with Bartonella spp. The Vector Borne Disease Laboratory at North Carolina State University has reported some increased sensitivity using a specialized enrichment medium for Bartonella culture. Amplification of DNA from peripheral blood by standard polymerase chain reaction (PCR) assay may be no more sensitive for detection of Bartonella bacteremia than standard culture if blood is sampled when a cat is temporarily abacteremic or has a very low level of bacteremia. Nested or real-time PCR assays may be more sensitive than standard PCR assays. While polymerase chain reaction assays are very sensitive for detection of bacterial DNA, they do not distinguish between DNA of living and dead organisms. Other pitfalls of PCR assays are that there may be false positive results following contamination of samples, and false negative results due to degradation of nucleic acids related to collection methods, transport, storage, or handling. Benefits of PCR assays are their sensitivity, short turnaround time, and species-specific diagnosis through sequencing of the PCR products. Since cats may be infected with multiple Bartonella species, consideration should be given to including broad range primers or primers for multiple species when performing PCR testing. Laboratories should be contacted for specific instructions for sample collection and shipment for culture or PCR assays. Strict sterile collection technique is required when samples are collected for PCR assay.

There are not clear criteria for establishing a diagnosis of bartonellosis in cats using serological methods. Immunofluorescent antibody (IFA), enzyme immunoassay (EIA), and Western blots are used for detection of anti-Bartonella serum antibodies. Positive predictive values of IFA and EIA techniques for bacteremia are low (~42-46%) but the negative predictive values are higher (~90-93%). Therefore, it has been suggested that serologic testing may be a useful screening tool for identifying a cat that is unlikely to be infected with Bartonella. Approximately 5 - 12% of bacteremic cats were serologically negative with IFA or EIA tests. These cats may have been tested early in infection before serum antibodies developed, or may not have developed detectable serum antibodies to the bacteria. No specific reciprocal titer or range of titers has been reported as having a high predictive value for bacteremia. Predictive values are not well established for Western blot assays. In addition, it is not known how long serum antibody titers persist following clearance of Bartonella infection, and it can be difficult to document clearance of Bartonella infection. Because of the genetic diversity of Bartonella organisms, infections with some strains or species of Bartonella may be missed using any serological method. Seroreactivity may depend on the antigen preparations and detection systems used.

Co-infection with other pathogens

Cats may be co-infected with multiple species of Bartonella and with multiple rRNA types of B. henselae. Cats may also be co-infected with Bartonella spp., other vector-transmitted pathogens, and/or other pathogens such as feline leukemia virus, feline immunodeficiency virus (FIV), or hemotrophic mycoplasmas. Cats seropositive (actual infection status was unknown) for B. henselae and FIV reportedly had more severe lymphadenopathy or gingivitis than cats positive for Bartonella or FIV alone. Co-infection with multiple pathogens makes it difficult to attribute clinical signs of disease to infection with a particular organism, and also confounds interpretation of response to treatment.

Treatment and prevention

The current consensus is that due to the possibility of development of antibiotic resistance (not only among Bartonella isolates, but also among other bacteria) only cats exhibiting clinical signs of Bartonella infection should be treated with antibiotics. Results of several published studies describing the use of antibiotics to treat Bartonella infections in cats demonstrate that true clearance of Bartonella infections is probably difficult to accomplish with any antibiotic treatment, and difficult to document. Prolonged follow up testing of treated cats is needed to verify clearance of infection due to the prolonged, relapsing bacteremias reported, and some published experimental studies had limited follow-up times of 2 weeks to 6 weeks. Antibiotics used in published studies included erythromycin, tetracycline, doxycycline, amoxicillin/clavulanic acid, rifampin, enrofloxacin, and some combinations of these drugs. No single drug or drug combination was shown to routinely clear infection. Currently, azithromycin is often recommended for treatment of infected cats, but there is no published, randomized, controlled study documenting its efficacy. Use of any antibiotic appears to decrease the level of bacteremia in infected cats. When considering treatment, the possibility of co-infection with multiple pathogens should be investigated, and cats treated accordingly. Other possible causes of clinical signs in cats seroreactive to Bartonella antigens should be thoroughly pursued before specific treatment for Bartonella is considered. Because the prevalence of Bartonella seroreactivity is high in domestic cats, clinical conditions may be erroneously attributed to Bartonella infection. If other causes of clinical signs in ill cats are identified, treatment for those entities should be undertaken prior to administering antibiotic treatments for Bartonella. Treatment of healthy cats belonging to immunocompromised clients is sometimes suggested, but until a very effective treatment is demonstrated this is not advised as a routine practice. Cats that are treated for or spontaneously clear Bartonella infection are not necessarily protected from future infections. Vector control remains the best means of preventing Bartonella infections in cats. Therefore precautions such as excellent vector control programs and avoiding scratch or bite wounds must be taken to prevent zoonotic transmission.

Public health

The United States Public Health Service/Infectious Diseases Society of America (USPHS/IDSA) Guidelines for Preventing Opportunistic Infections Among HIV-Infected Persons recommend the following when acquiring a new cat: adopt a cat over 1 year of age that is in good health, avoid rough play with cats, maintain flea control, wash any cat-associated wounds promptly, and do not allow a cat to lick wounds or cuts. There is no direct evidence that declawing cats decreases the probability of transmission of B. henselae from cats to human beings. The USPHS/IDSA Guidelines state that there is no evidence of any benefit to cats or their owners from routine culture or serologic testing of cats for Bartonella infections. However, because the negative predictive value of B. henselae serologic test results for feline bacteremia is very good, serology may in some situations be an appropriate screening test for cats that immunocompromised persons are considering as pets, with the recommendation that only seronegative cats be acquired. Nonetheless, there is still an approximately 10-15% probability that a seronegative cat is infected with Bartonella.

Control of arthropod vectors, and avoidance of animal bites and scratches, are the most important and the most effective preventive measures currently available to avoid transmission of Bartonella infections from animals to human beings.

What do we know?

Bartonellas have been associated with their reservoir hosts for many years

Clinical conditions Bartonella infections caused in cats are not well defined

Diagnosis of Bartonella infection of cats is challenging due to relapsing bacteremia and apparent persistence of serum antibodies– development of diagnostic tests that are both very sensitive and very specific is needed

Cats can be repeatedly infected with Bartonella spp.

Treatment of Bartonella infections of cats is challenging – further controlled studies are needed

Treatment of Bartonella infection is generally not indicated in healthy cats, but rather in ill cats when other causes of clinical conditions are ruled out

Preventing transmission of Bartonella infections of and by cats is best accomplished by vector control, and it is important to implement and maintain excellent vector control programs. Also important in preventing transmission of Bartonella infection from cats to human beings are such common sense precautions as avoiding cat scratches and bites, promptly washing any cat associated injuries, and seeking medical attention when indicated.

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