Bartonellosis Raises Hemangiosarcoma Risk in Dogs

Dog breeders and owners have likely had a dog or know someone with a dog affected by the highly malignant cancer hemangiosarcoma (HSA). They are less likely to know that the vector-borne bacterial pathogen Bartonella may contribute to HSA.

“Bartonella may be the most important bacteria that most of the world has never heard of,” says Edward B. Breitschwerdt, DVM, DACVIM, the Melanie S. Steele Distinguished Professor of Medicine and Infectious Diseases and co-director of the Vector Borne Disease Diagnostic Laboratory at North Carolina State University. “Bartonellosis is one of the most important emerging infectious diseases in humans and dogs.”

A lead investigator of a $4.8 million four-year study funded in 2021 by the Steven & Alexandra Cohen Foundation, Dr. Breitschwerdt is part of a multidisciplinary Bartonella Research Consortium developing new treatments for animals and people affected by the bacterial pathogen. Although combinations of antibiotics are used to treat Bartonella-related conditions, successful outcomes are dimmed by the bacterium’s ability to penetrate almost any cell in the body.

The first incidence of Bartonella infection in a dog was discovered in 1993 in Dr. Breitschwerdt’s laboratory. Tumbleweed, a 3-year-old female yellow Labrador Retriever, had been unsuccessfully treated for nine months when she arrived at the North Carolina State Veterinary Hospital extremely ill with endocarditis, an inflammation of the inner lining of the heart chambers and valves.

The infectious diseases team isolated a new Bartonella subspecies responsible for Tumbleweed’s condition. In collaboration with researchers at the Centers for Disease Control and Prevention, they named the bacterium Bartonella vinsonni subsp. berkhoffii. The risk factors for bartonellosis fit Tumbleweed’s lifestyle: heavy flea and tick exposure and a rural home environment. Additionally, endocarditis is associated with B. vinsonii subsp. berkhoffii occurs in large-breed dogs, such as retrievers, that have a predisposition for aortic valve disease.

“I wanted to know how we had missed the diagnosis of bartonellosis in the past,” Dr. Breitschwerdt says.

New Study Combats Bartonellosis

Bartonellosis is a zoonotic disease in which contact with an infected animal can make people sick. This worries Dr. Breitschwerdt. “Owners of infected dogs, veterinarians and veterinary technicians are particularly at risk of getting sick,” he says. “Direct contact with body fluids, a needle stick, scratch, or bite from an infected animal puts a person at risk.”

In both species, three organ systems are vulnerable to acute or chronic clinical manifestations, and more than one system may be affected. Cardiovascular disease may manifest as endocarditis, as with Tumbleweed, or myocarditis, inflammation of the heart muscle. Neurological effects include seizures or paralysis, and rheumatologic signs occur in joints and surrounding tendinous structures.

Complex to diagnose, Bartonella infection has a stealthy nature in which the bacterium invades, thrives and hides inside cells of blood vessel walls throughout the body. Blood smear tests do not detect the pathogen. Eluding the immune system, Bartonella may trigger an infectious state that leads to hemangiosarcoma.

Like Bartonella, HSA is a stealthy canine cancer that often goes undetected as it develops silently and painlessly. Originating in bone marrow cells, HSA settles in the thin layer of cells lining the interior of blood vessels giving tumor cells access to the blood supply and allowing them to metastasize to virtually any organ in the body. Tumor cells take hold and grow in a vascular web that may contain Bartonella infection. 

About 50 percent of HSA cancer cases occur in the spleen, an organ responsible for eliminating vector-borne pathogens such as Bartonella from the circulatory system. Although cardiac HSA is less common, it is the most common heart tumour in dogs. Less frequently, HSA occurs in the liver, lungs, kidneys, and skin.

Most dogs have an advanced form of HSA when it is discovered. Tumour masses cause few signs other than lethargy and pale mucous membranes due to anemia from small bleeds. Dogs often die before treatment can begin. Standard of care treatment involves surgical removal of the tumour, depending on its location, and/or chemotherapy. Intended to prevent fatal blood loss, treatment is seldom curative as tumour metastasis often has occurred.

“Persistent infection or inflammation caused by Bartonella may increase the risk for HSA later in life,” Dr. Breitschwerdt says. “We suspect pathogenic bacteria, such as Bartonella, play a role in different cancers.”

The effect of Bartonella in dogs and the potential link to hemangiosarcoma is disconcerting to experts like Dr. Breitschwerdt. “In our experience, some breeds may not handle Bartonella well, though bartonellosis occurs in all breeds and in dogs worldwide. Large-breed and mixed-breed dogs are particularly affected,” he says.

The good news is that dogs diagnosed early with bartonellosis and treated with antibiotics typically fully recover. “Most dogs require more than one antibiotic that is given over six weeks,” says Dr. Breitschwerdt. “As with Tumbleweed, treatment can be complicated, and a dog can be sick for months before being diagnosed.”

Having studied Bartonella for 30 years, Dr. Breitschwerdt is excited about the Cohen Foundation funding that involves a team of experts. The largest single grant devoted to combating Bartonella and Bartonellosis is funded by the organization’s Cohen Lyme & Tickborne Disease Initiative which began in 2015 to raise awareness, advance research and find cures for tickborne diseases.

Working with Dr. Breitschwerdt at North Carolina State University on this study is Dr. Ricardo G. Maggi, research professor of internal medicine in the Vector Borne Disease Diagnostic Laboratory. Dr. Timothy Haystead, professor of pharmacology and cancer biology at Duke University, and Dr. Monica Embers, associate professor of immunology at Tulane University, complete the team.

The research pipeline starts with the development of potential Bartonella antibiotic therapies by Dr. Haystead and his laboratory. The North Carolina State researchers are testing the therapies, and those that appear promising are sent to Dr. Embers and her group to review their effectiveness. “The goal is to get down to the heart of the Bartonella DNA and pick up molecular candidates that can be worked into effective therapies,” Dr. Breitschwerdt says.

Dr. Breitschwerdt is quick to give credit to advances made from his five-year study of the prevalence of bartonellosis in dogs with splenic and cardiac HSA funded by the AKC Canine Health Foundation through its Hemangiosarcoma Research Initiative. Since 1995, the Foundation and its donors have invested over $4.8 million in 33 grants to understand the mechanisms and causes, new targets for treatment and early diagnostics for HSA. Versatility in Poodles, a worldwide community of enthusiasts helping to advance breed health and promote breed versatility, is helping to sponsor this research that goes through January 2023.

An early report of this research was published in PLOS ONE in January 2020. Using polymerase chain reaction (PCR) testing, the research team studied fresh frozen HSA tissue, fresh frozen non-tumour tissue, and whole blood and serum from 110 dogs representing 39 breeds and mixed breeds looking for Bartonella, Babesia parasites and Hemotropic Mycoplasma bacteria.  

“While 73 percent of all tissue samples from these dogs were positive for Bartonella DNA, none of the blood samples were, which indicates that whole blood samples do not reflect this pathogen,” Dr. Breitschwerdt says. “The presence of Bartonella DNA in 57 percent of cardiac HSA tumours and in 93 percent of non-tumor cardiac tissue is an important finding.”

Knowing that Bartonella species, B. hensalae specifically, is well-established as a promoter of tumour-cell proliferation and chronic inflammation, the team speculated that B. hensalae is a likely cofactor in the development of HSA in dogs. “Because dogs with HSA have increased amounts of plasma vascular endothelial growth factor (VEGF) compared to healthy dogs and because VEGF is present in tumours, this implicates B. hensalae as a possible cause of HSA,” Dr. Breitschwerdt explains.

“In laboratory cultures, we have seen how B. hensalae induces angiogenesis, the formation of new blood vessels from existing blood vessels, and proliferation of endothelial cells by stimulating the production of VEGF.”

Challenges Diagnosing Bartonellosis

More than 44 Bartonella species and subspecies are recognized today, about half of which are associated with disease symptoms. Although the Bartonella pathogen has existed and evolved for millions of years, only two species, Bartonella bacilliformis and Bartonella quintana, were identified worldwide before 1990. The bacterium is carried primarily by vectors such as fleas, ticks, sand flies, and lice, though spiders, bed bugs and deer keds (deer flies) can carry Bartonella as well.

Numerous species of Bartonella are reported in dog infections, yet the most common ones found in North America are B. hensalae, B. vinsonii subsp. berkhoffii and B. koehlerae — all of which have been detected in dogs diagnosed with endocarditis. Notably, B. hensalae is a pathogen that is transmitted to cats via fleas and can cause cat scratch disease in humans when an infected cat licks, bites or scratches open skin. 

A challenge in treating dogs with bartonellosis is diagnosing the illness. “There is no diagnostic gold standard for Bartonella infection in dogs,” says Dr. Breitschwerdt. “Diagnosis relies on a combination of culture, blood and molecular tests with poor, variable or undetermined sensitivity. Epidemiological studies are based on indirect fluorescent antibody and blood PCR assays, but the lack of sensitivity of these tests should be considered by researchers trying to define Bartonella disease, transmission and zoonotic risks.”

In a retrospective study of 90 dogs diagnosed with HSA published in June 2021 in Pathogens, the research team at North Carolina State University evaluated six assays and found Bartonella DNA or antibodies in 70 dogs, about 78 percent. “In our head-to-head comparisons of serology and molecular test results, we found that Bartonella species DNA could be detected from PCR-amplified fresh frozen tissues from a majority of dogs with HSA,” Dr. Breitschwerdt says.

“These methods warrant future studies to compare the ability to screen dogs with HSA for Bartonella infection. This is of critical importance to assess the potential role of Bartonella as a cause or cofactor in HSA.”

Given the predisposition of dogs to HSA and the cancer’s toll on dogs, urgency is warranted for research to learn more about Bartonella and the chronic inflammation and tissue damage it causes. “Because these are emerging pathogens in dogs, the spectrum of diseases associated with Bartonella infection has not been fully elucidated,” says Dr. Breitschwerdt.

Reflecting on the Cohen Foundation study, Dr. Maggi of North Carolina State University says, “We are very positive that at the end of this work, we will have the first battery of treatment options to battle Bartonella infection not just in animals but also in people. Already we have identified several small molecular candidates showing promising anti-Bartonella activity.”

The future may provide quicker diagnoses and more effective treatments for bartonellosis in people and dogs. Ultimately, a better understanding of bartonellosis may help to lessen the risk of hemangiosarcoma in dogs. 

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