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Research by Intracellular Pathogens Research Lab Advances Understanding of Bartonella--the 'stealth pathogen'

The following article by the Veterinary Information Network (VIN) News Service profiles the ongoing Bartonella research being conducted by the Intracellular Pathogens Research Laboratory (IPRL) within the CVM Center for Comparative Medicine and Translational Research. Directed by Dr. Ed Breitschwerdt, the work of the IRPL is an example of the “One Medicine” concept and the importance of the connections between animal and human health and veterinary and human medicine.


By: Edie Lau
For The VIN News Service

The pathogen best known for causing cat scratch disease is responsible for a host of serious illnesses in humans that may be misdiagnosed due to lack of awareness in the medical community.

Researchers studying the Bartonella genus of bacteria say veterinarians and veterinary staff, along with others who work with animals — including groomers, trainers and shelter and rescue organization personnel — are at particular risk of infection owing to their frequent exposure to animals and animal parasites such as fleas.

“I think it’s more common than we think in the veterinary community,” said Dr. Bruno Chomel, a DVM and professor in the Center for Vectorborne Diseases at the University of California, Davis.

The scope and significance of Bartonella infection among humans in veterinary circles and at large is just beginning to be understood.

Twenty years ago, only two Bartonella species were known. One, B. henselae, was identified as the agent behind cat scratch disease, a condition believed to be transmitted by a cat scratch or bite that causes swelling of the lymph nodes along with fever, headache, fatigue and/or poor appetite. Conventional wisdom said — and says still — that “cat scratch fever” is nothing to worry about for most people: Except in those with immune system deficiencies such as AIDS, the infection goes away on its own or with a short course of antibiotics. Bartonella became synonymous with mild illness.

But researchers say the picture is more complicated than that. Today, the number of Bartonella species identified is 26 and counting. Species exist that co-evolved with dogs, cattle, squirrels and ground hogs. Arthropods including fleas, lice and possibly ticks transmit the germ to mammals.

Those who study Bartonella characterize it as a “stealth pathogen” because of its ability to evade detection even at levels that cause illness. The bacterium has been found to invade and colonize a variety of cell types — not only blood cells such as erythrocytes and macrophages but vascular endothelial cells and dendritic cells of the nervous system, as well.

This enables the microbe to disperse throughout the body and manifest in a wide range of debilitating conditions, including neuromuscular problems and endocarditis, a serious infection in the valves of the heart. Complicating diagnosis, many symptoms are non-specific. They include fatigue, headache, memory loss, insomnia, muscle pain and joint pain.

Ignorance in the medical community of the disease and its many possible forms has profound effects on those who come down with a clinical infection.

Dr. Kathy Tater, a veterinary dermatologist in Massachusetts, is a case in point. Tater said she visited nearly 20 health-care providers in different institutions over the course of a year before she was diagnosed with Bartonella — and that was only because through her own reading, she found a laboratory with a sensitive test designed specifically to detect the elusive pathogen.

“What I found was that most physicians have not heard of Bartonella. They have heard of cat scratch disease, but that is not the same as knowing about Bartonella infections,” said Tater, who is recovering. “They were not aware that other strains of Bartonella existed, and they were not aware of how to test a person for Bartonella.”

Her story is familiar to Dr. Edward Breitschwerdt. A veterinary internist who directs the Intracellular Pathogens Research Laboratory at North Carolina State University College of Veterinary Medicine, Breitschwerdt has looked at hundreds of cases of suspected human Bartonella infections. Commonly, patients see a variety of specialists — cardiologists, neurologists, rheumatologists, internists, infectious-disease experts and the like — on their journey to a Bartonella diagnosis, Breitschwerdt has found.

As a veterinarian, he became by accident the go-to guy for people such as Tater. Breitschwerdt’s focus was developing better detection tools for infections in dogs, in which Bartonella similarly is hard to find. The approach he hit upon is to first “enrich” the test sample of blood by culturing it in insect growth media rather than mammalian growth media, the standard culture for bacteria. Through this step, the population of bacteria builds up, making the microbes easier to find.

As Breitschwerdt lectured at veterinary conferences about the new diagnostic approach for dogs, a curious thing happened. Veterinarians would come up afterward and say that they’d been sick. They wondered whether they might be infected by this stealth pathogen.

“If there were 100 veterinarians in the audience, there might be three or four who would come up to me,” Breitschwerdt said. “They raised the question. I did not.”

That ushered Breitschwerdt into the human world of Bartonella infection. He began accepting human samples for analysis. “After we developed this novel approach and had a fair amount of data that said it seemed to be working in people,” he said, “I tried to find a veterinary or human diagnostics company that would be willing to work with us or at least license the technology from the university.”

But the test isn’t simple or cheap, and the idea of devoting significant resources to a pathogen that isn’t widely recognized as important was a hard sell, he said. No one bit.

Breitschwerdt and others ultimately started their own company, Galaxy Diagnostics, to handle the work.

As word spread of Breitschwerdt’s expertise, human samples flowed in from people in veterinary medicine and beyond. He estimates that he’s tested 700 patients over the past three years. “Overall, we’re running about 31 percent positive. That’s very high,” he noted. “Very high for an organism that is not supposed to be in the blood of immunocompetent people.”

Breitschwerdt began doing studies on human subjects. One subject was Dr. John Barnes, a small-animal and exotics practitioner in Uvalde, Texas.

Barnes, 54, was diagnosed with multiple sclerosis (MS) in 2005. Up to that point, he was a healthy man who jogged regularly and ran up and down bleachers at the local high school for exercise.

One day, shortly after a bout of 103-degree fever and vomiting that he attributed to food poisoning, Barnes was jogging around a track. On the third lap, his left leg stopped cooperating, causing him to stumble. A week or so later, Barnes began tripping again while jogging, this time on the second lap.

Thus began his journey through the medical system. One physician suspected a herpes virus. Another thought it might be Guillain-Barre, a rare neurological syndrome in which the body’s immune system attacks part of the peripheral nervous system. Following an MRI and spinal tap, Barnes was told he had MS and that he would likely end up in a wheelchair.

Barnes was not so sure. “I wasn’t trying to balk at the diagnosis but because I had this huge fever (five months earlier) in December when all of this started, I thought maybe I had something else,” he said. “It sounded more inflammatory and (like an) infection.”

By chance, while conferring with a colleague at Texas A&M University about an oncology case, Barnes mentioned his condition. The colleague knew Breitschwerdt was doing a study involving veterinarians and veterinary technicians. She recommended Barnes get in touch with him.

It turned out that Barnes had an infection of B. henselae, the same species of Bartonella that causes cat scratch disease. His case and that of five other similarly infected patients was published in a study that appeared in the Journal of Clinical Microbiology in September 2008.

Whether the Bartonella infection had anything to do with his neurological symptoms or was mere coincidence was a point of debate and discussion among various doctors. “I have so many ologists, I don’t know what I’m doing,” Barnes commented wryly.

His condition worsened in the meanwhile. He fell frequently, once breaking a rib.

Finally in August 2007, he was prescribed two antibiotics to combat the Bartonella: doxycycline and rifampin. Within a month, he said his toes, which had had a cadaverous gray tone, “started pinking up.”

A couple months later, he noticed his fatigue lifting. By the following summer, he could stand on one leg, cross the other over his standing knee and look at the bottom of his foot — a position he had not been able to assume in three years.

His odyssey didn’t end there, unfortunately. Barnes stopped taking the antibiotics after a year. Breitschwerdt continued to monitor his blood. At first, Barnes was negative for Bartonella. But six months later, the bacteria reappeared.

Barnes went back on antibiotics. In February this year, he sent another blood sample to Breitschwerdt. The B. hensalae showed up still, and this time, not one strain, but two.

Was it the result of a new exposure or something that had been in hiding? The answer may never be clear.

Barnes said that as far as he knows, in 26 years as a clinician, he has never had a patient with a Bartonella infection. But he has spent plenty of time among animals and in the outdoors. “My dad was a vet,” he said. “I was always catching frogs and toads (as a boy). So I think I’m exposed to all this junk.”

Despite the ongoing infection, Barnes said he is doing much better — on the order of 60 to 70 percent improved, in his estimation. That tells him that while he truly may have MS, there’s a relationship between his MS and Bartonella.

“I’m not saying I have just Bartonella or just MS,” he said. “But what if, of all the 400,000 people with MS right now, what if 2 percent of them are Bartonella-induced? People get their panties in a wad if I say that Bartonella causes MS. But (the diagnosis of Bartonella infection) helped me. I should be in a wheelchair right now.”

For Breitschwerdt, solving the mysteries of Bartonella has turned personal. In 2007, his 86-year-old father came down with a Bartonella infection that eluded medical professionals until Breitschwerdt ran the samples himself the following year. The researcher gave a moving account of the experience in the article “A Groundhog, a Novel Bartonella Sequence, and My Father’s Death,” published in the U.S. Centers for Disease Control and Prevention journal Emerging Infectious Diseases.

Dr. Michael Kosoy, chief of the Bartonella Laboratory at the CDC in Fort Collins, Colo., said the pathogen’s potential public health impact is taken more seriously in Europe and Asia, where Bartonella is appreciated as a cause of endocarditis and other serious ailments. In this country, by contrast, its importance is “very, very much unrecognized,” Kosoy said.

How the CDC Bartonella lab is supported illustrates the point: Kosoy said that although his lab is part of the Division of Vector Borne Diseases, most of its funding comes from the Global Diseases Detection Division. In other words, the CDC sees Bartonella infection more as a risk abroad than here.

Assuming that ever was true, conditions rapidly are changing. Kosoy said Bartonella species specific to rats in Asia and in Australia recently turned up in the California seaport cities of Los Angeles and Oakland. “They travel with ships around the world,” Kosoy said.

Lack of recognition of Bartonella’s possible role in illness isn’t absolute, of course. A few physicians are very aware of the pathogenic potential of the germ. One is Dr. B. Robert Mozayeni, a rheumatologist in North Bethesda, Md., whose quest to help patients with rheumatic conditions often confused with Lyme disease — a tick-borne illness — led him to Bartonella.

“In some studies of ticks, there was a significant prevalence of Bartonella,” Mozayeni explained. “Also, a significant percentage of cats carry Bartonella.” From taking their medical histories, Mozayeni said he has learned that a significant fraction of his patients contracted their illness from their cats.

Further research led Mozayeni to Breitschwerdt. Now the two work together: Mozayeni is chief medical officer in Breitschwerdt’s startup company, Galaxy Diagnostics.

To date, Mozayeni has evaluated some 400 patients with known or suspected Bartonella infections, some coming from as far away as Nevada, Idaho, Florida, and even other countries, such as Brazil and the Netherlands.

In his experience, Bartonella-infected patients respond with notable consistency to treatment. “The consistency with the way they responded (positively) made me more convinced that this was a causative microbe, not just an incidental finding,” Mozayeni said.

As a biomedical researcher trained at Yale University and the National Institutes of Health, Mozayeni called the Bartonella work “the most exciting translational medicine I’ve seen —where we’ve gone from bench to bedside. I see such huge positive impacts on my patients’ lives every day,” he said. “... The results have been nothing but spectacular. Most patients have gone from chronic disabled to revitalized, active people because we’ve been able to lock on this microbe.”