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From the Townsend Letter
July 2015

Unraveling the Mystery of Bartonellosis
by Scott Forsgren
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Portions from an interview with B. Robert Mozayeni, MD

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As someone who struggled with Bartonella for many years, I know all too well the devastation that this infection can have on one's physical and mental health. While Bartonella can manifest in many different ways within the body, the challenges it presents extend far beyond the physical.
Bartonellosis is a poorly understood condition that is routinely overlooked by mainstream medicine. As a result, many cases go undiagnosed, leading to significant and unnecessary human suffering and substantial costs to society. While available testing options for Bartonella have improved greatly in recent years, there is still no perfect Bartonella assay available. Even when bartonellosis is confirmed through testing, the success of available treatment options is variable, and Bartonella may establish itself as a chronic infection that requires long-term management.
Fortunately for many of us, humans are not the only species affected by the genus Bartonella. In fact, much of the available research comes from the veterinary community, where Bartonella is much more widely acknowledged and better understood than in human medicine.

Veterinary Medicine Leads to Help for Suffering Humans
Edward Breitschwerdt, DVMEdward Breitschwerdt, DVM, is an infectious disease specialist at North Carolina State University College of Veterinary Medicine, an adjunct professor of medicine at Duke University, and chief scientific officer at Galaxy Diagnostics. Early in his career, he focused on vector-borne, intracellular pathogens, including Rocky Mountain spotted fever (caused by a Rickettsial bacterium) and Ehrlichia. Ehrlichia was discovered in animals decades before it was identified in humans. His attention later shifted to Bartonella due to the historical association of one Bartonella species, Bartonella henselae, with cat-scratch disease (CSD).
The connection between the newly discovered bacterium and CSD was initially made by a rickettsiologist, Dr. Russ Regnery at the CDC, who recognized similarities between a newly isolated bacterium from an AIDS patient in Texas and bacteria visualized in lymph nodes of patients with CSD. Regnery made the first isolate of Bartonella henselae from a cat and showed that cats can become chronically infected. This work was the catalyst that led Breitschwerdt down the path of unraveling the mysteries of Bartonella.
As Breitschwerdt lectured at veterinary conferences about Bartonella illnesses in dogs, numerous veterinarians approached him to discuss their own health challenges, such as multiple sclerosis-like conditions and rheumatoid-like diseases. Many had been sick for several years with no clearly defined diagnosis. When he started testing these veterinarians for Bartonella, his research team found that many of them tested positive for Bartonella DNA in their blood. If it were not for the translational research initially done with animals, the genus Bartonella and the disease bartonellosis would likely be even lesser known than they are today. This may be another example in which dogs truly are man's best friend. Over the next two decades, research would demonstrate that dogs often develop the same pathologies as those of their human counterparts.

Bartonella Basics
Bartonella was named after A. L. Barton, who in 1909 identified organisms that adhered to red blood cells. Bartonella is a genus of gram-negative, aerobic bacteria belonging to the Bartonellaceae family and Rhizobiales order. It is in the Alphaproteobacteria class, which is part of the Proteobacteria phylum. Bartonella organisms are considered facultative intracellular parasites, meaning that they may resort to parasitic activity although they do not rely on a host to complete their life cycle. Other well-known pathogenic Alpha­proteobacteria include Ricket­tsia, Anaplasma, Ehrlichia, and Brucella species.
While Bartonella can infect healthy people, it has generally been believed by mainstream medicine that the infection is cleared by the immune system in the majority of cases. Many view these bacteria as opportunistic pathogens in conditions wherein the immune response may be suppressed, such as in AIDS and chronic Lyme disease. As the ability to identify Bartonella has improved, patients with numerous long-term illnesses have been found to harbor the bacteria in their blood and tissues. Additional research is needed to determine what role Bartonella plays in these illnesses. Persistent bloodstream infection with numerous Bartonella species is increasingly being linked to a host of chronic illnesses.
targets erythrocytes (red blood cells), endothelial cells, microglial cells, macrophages, and CD34 progenitor cells.1 Once the infection is in the body, it commonly resides in red blood cells and in the endothelial and pericyte cells lining the blood vessels throughout the body. Bartonella may use these cells and various tissues in the body to hide from the immune system and to establish a chronic, persistent infection.

Bartonella and Human Infection
According to Breitschwerdt, there are nearly 40 different species of Bartonella known today, and 15 of these have been found to infect human beings (see Table 1). The more commonly known Bartonella species include Bartonella henselae, Bartonella quintana, and Bartonella bacilliformis.
Bartonella henselae is the causative agent in CSD. In addition, this Bartonella species can cause numerous symptoms in both immunocompetent and immunocompromised individuals. Infection may result in bacteremia (presence of bacteria in the blood), myocarditis (inflammation of the middle layer of the heart wall), peliosis hepatis (a vascular condition which results in blood-filled sacs in the liver), neuroretinitis (inflammation of the neural retina and optic nerve), bacillary angiomatosis (a proliferation of blood vessels leading to tumorlike masses), enlarged lymph nodes, and fevers.
Bartonella quintana is known as the causative agent in trench fever. It was first described during World War I as over a million soldiers in Europe became infected after exposure to the human body louse. Urban trench fever has reemerged among homeless populations around the world. It may present with fever, severe headaches, back and leg pain, and skin rashes. It can be a factor in endocarditis and may result in bacillary angiomatosis in those coinfected with HIV. Evidence of Bartonella quintana has been found in the dental pulp of soldiers from Napoleon's Grande Armée, and many of his soldiers died from infectious diseases, including trench fever and epidemic typhus (Rickettsia prowazekii).2
Bartonella bacilliformis leads to a condition known as Carrión's disease, or Oroya fever. Carrión's disease was named after Daniel Alcides Carrión, a Peruvian medical student who died after an experiment where he inoculated himself with the bacterium. Bartonella bacilliformis is found primarily in Peru, Columbia, and Ecuador and is transmitted by sand flies. It can have a mortality rate of 40% to 90% in untreated patients.
More recently, other Bartonella species have been associated with human infection. Bartonella clarridgeiae may lead to CSD. Bartonella elizabethae, Bartonella vinsonii subsp. berkhoffii, and Bartonella vinsonii subsp. arupensis may be factors in endocarditis. Bartonella grahamii has been found in the ocular fluids of a human with neuroretinitis.3 Bartonella washoensis has been implicated in myocarditis.4
Candidatus (an interim status for a yet-to-be officially named organism) Bartonella melophagi was discovered in 2009 by Dr. Ricardo Maggi, a research microbiologist working with Breitschwerdt, while testing human blood specimens.5 Candidatus Bartonella mayotimonensis has been identified in a case of endocarditis, and recent evidence suggests that bats may be the reservoir for this Bartonella species.6,7 In that research publication, a compelling statement was made: "This case reinforces the hypothesis that any Bartonella species can cause human infection."
Human infection with Bartonella may be the result of arthropod vectors, including fleas (and flea feces), biting flies such as sand flies and horn flies, the human body louse, mosquitoes, and ticks; through bites or scratches of reservoir hosts; and potentially from needles and syringes in those who are drug addicted. Needle stick transmission to veterinarians has been reported. Bartonella henselae and Bartonella clarridgeiae have been transmitted to cats through blood transfusion. Recently, 3.2% of healthy blood donors in Brazil were found to carry at least one of these two cat flea-associated Bartonella species in their blood.8 Bartonella DNA has even been found in dust mites.9 Fleas have been shown to be infected with Bartonella henselae, Bartonella clarridgeiae, Bartonella koehlerae, and Bartonella quintana; body lice with Bartonella quintana; and ticks with several species of Bartonella.10 Vector biologists and others with extensive arthropod exposures are at increased risk for acquiring Bartonella infections.
Working or living with flea-infested pets or other animals is a notable risk factor for Bartonella, so much so that up to 28% of veterinarians tested positive in one study compared with 0% of controls.11 Cats and dogs exposed to arthropod vectors and that live in close proximity with people put humans at increased risk for acquiring Bartonella infections. The concentration of Bartonella in the blood of an infected cat may be as high as a million times that of an infected human. Recent evidence indicates that many of the Bartonella henselae strains that commonly infect cats are not found in humans, suggesting that virulence factors play an important role in determining pathogenicity and whether or not a cat poses a risk for transmission of a pathogenic strain to a human.
Animals that are exposed to fleas and ticks have a high likelihood of being infected with Bartonella. About half of all cats may be infected with Bartonella, as high as 80% of feral cats and near 40% of domestic cats.12,13 In one study that tested 108 domestic dogs in Peru serologically, 67 of the dogs were seropositive for Bartonella rochalimae, while 43 dogs were seropositive for B. vinsonii berkhoffii.14 In a study of dogs in Iraq, the seroprevalence of Bartonella infection was 47.4%.15 An incidence of 10% has been reported in healthy dogs in the eastern United States, and 35% of coyotes were seropositive for B. vinsonii subsp. berkhoffii in California, with 28% being bacteremic.16
Additionally, although presumably an infrequent mode of transmission, evidence now suggests that Bartonella may be transmitted from mother to child in utero, potentially leading to birth defects.17

Bartonella Symptoms
The symptoms of Bartonella may affect numerous body systems and can range from mild to severe, and may even be fatal.18 Breitschwerdt's own father passed away from complications associated with Bartonella infection.19 One may be asymptomatic or may never become symptomatic enough to pursue medical evaluation. Presenting symptoms may wax and wane over time.
The more common symptoms of Bartonella include swollen lymph nodes, gastritis, sore soles of the feet most noticeable in the morning, fasciculations (muscle twitching), headaches, abdominal pain, striae (irregular areas of skin that look like stretch marks), skin rashes, tender subcutaneous nodules in the extremities, fevers, anxiety, depression, anger, and obsessive-compulsive thoughts or behaviors.
B. Robert Mozayeni, MD B. Robert Mozayeni, MD, has a private rheumatology practice in Rockville, Maryland, and is a leading expert in the treatment of Bartonella. He serves as chief medical officer for Galaxy Diagnostics and works closely with Breitschwerdt. In a recent interview for this article, Mozayeni explained that he sees a pattern of symptoms in his patients with Bartonella infection. He noted that bartonellosis is primarily an infection of the blood vessels, the blood components, and the bone marrow. While Borrelia burgdorferi, the causative agent in Lyme disease, can be found in the blood and as well as outside the vascular system, Bartonella species primarily congregate within red blood cells, endothelial cells, and bone marrow cells. It may also be found in cysts, having been isolated from an otherwise "benign" breast cyst in one patient.
As bartonellosis is principally an infection of the vascular system, it leads to inflammation and endothelial proliferation, disrupting blood flow at the small vessel level, such as in the capillaries and arterioles. The end result is compromised microcirculation throughout the body which can lead to the appearance of fluctuating and migrating symptoms. The manifestation of symptoms is largely associated with where in the body the blood flow compromise happens to be located.

Pain in the soles of the feet upon waking, for example, is likely due to inflammation of the blood vessels in an area that endures ongoing microvascular trauma as a result of regular weight-bearing activity; the pain is then exacerbated by the presence of Bartonella and small vessel inflammatory disease.
Patients may present with POTS (postural orthostatic tachycardia syndrome) or other forms of dysautonomia wherein the autonomic nervous system is affected; this is another manifestation of small vessel disease. The nerves of both the sympathetic and parasympathetic nervous system are compromised in their function due to changes in microcirculation and interruption in blood flow.

In every patient, Bartonella is infecting the vascular system throughout the body. Endothelial infection with Bartonella can damage veins and the valves of veins. Endothelial cells also line the heart valves. However, such infection can progress to infiltrate the deeper connective tissue of the heart in rare cases. This type of deeper heart valve infection with Bartonella is usually detected too late and almost always leads to heart valve replacement surgery. In a recent study of healthy coyotes in California, Bartonella DNA was found in the heart valves of 17% of the coyotes studied, and DNA of the bacterium was preferentially amplified from the aortic valve, the valve most commonly involved in both dog and human endocarditis.20 Fortunately, as a rheumatologist, Mozayeni has not seen anyone in his patient population who has developed serious heart valve complications as a result of Bartonella infection.

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