Biotechnology scientist Donna Needham works with blood samples. Dr. Edward Breitschwerdt and Ricardo Maggi of NCSU founded Galaxy Diagnostics to cultivate the Bartonella bacteria.
BY SARAH AVERY - Staff Writer
A bacterial infection typically spread by fleas, lice and biting flies could be more prevalent than many think, and may have been transmitted from a mother to her children at birth, scientists from N.C. State University say.
Dr. Edward Breitschwerdt, an infectious disease veterinarian and one of the world's leading researchers of bacteria called Bartonella, has for the first time documented evidence that the pathogen may have been passed between family members.
Although more studies are needed to back up his findings, Breitschwerdt and colleagues describe the case of a mother and father who began battling chronic aches, fatigues and other symptoms soon after they were married. When their twins were born in 1998, the daughter died after nine days from a heart defect, and the son developed chronic health problems.
Using tissue from the daughter's autopsy and blood from the surviving family members, Breitschwerdt's team discovered that the entire family was infected with the same species of Bartonella bacteria, despite having no shared exposures to flea or lice infestations. Bartonella is known to causes such illnesses as trench fever and cat scratch disease, and it is increasingly suspected of triggering a variety of aches and inflammations that doctors have been unable to diagnose.
"I think we have stumbled across something that is of monumental medical importance," said Breitschwerdt, whose findings were published recently in the Journal of Clinical Microbiology.
Proving the mother-child transmission could be difficult, however. Little funding is available for such research because the bacteria are still not considered a major source of human disease.
Dr. Michael Kosoy, who heads the Bartonella laboratory for the Centers for Disease Control and Prevention in Fort Collins, Colo., said scientists are only beginning to build evidence that Bartonella infections may be more common than previously thought.
"Bartonella are circulated around the world in many animals, but there are different Bartonella species, and the question is how can they be transmitted to humans?" Kosoy said, noting that most known cases have been transmitted from biting insects. He said the NCSU findings about the potential family transmission are compelling but inconclusive.
Dozens of strains
At least 26 strains of Bartonella have been named worldwide, and the list is growing. The most notorious Bartonella infection is cat scratch disease, a fever illness passed to humans from flea-infected cats. Fleas are the primary hosts, and they spread the bacteria in their feces.
Other Bartonella strains spread more serious diseases. Kosoy is studying how often heart inflammation is caused by a Bartonella that thrives among rat fleas in Thailand. He has already established that about 25 percent of unexplained fever illnesses among a group of patients there was caused by Bartonella .
"This is not limited to cat scratch," Kosoy said. "That's just the tip of the iceberg."
Breitschwerdt said he thinks the bacteria may be the hidden cause behind a host of chronic symptoms - muscle aches, neurological problems, fatigue, arthritis - that defy diagnosis.
About two years ago, Breitschwerdt began testing blood samples from a doctor in Maryland, who was curious whether Bartonella infections might be causing problems for some of his patients.
"There are lab tests showing inflammation," but no discernible cause, said Dr. Robert Mozayeni, a Yale-educated rheumatologist who practices in Rockville, Md.
Mozayeni contacted Breitschwerdt and his NCSU colleague, Ricardo Maggi, who together developed a more sensitive test for Bartonella. Routine blood tests fail to detect Bartonella because they search for antibodies that the body is slow to produce.
Instead, Breitschwerdt and Maggi figured out how to cultivate the bacteria in the laboratory from blood samples of infected people. They founded a company called Galaxy Diagnostics to handle the laboratory volume.
Of Mozayeni's mystery patients tested at the lab, nearly 20 percent had Bartonella infections.
"I suspect this is going to be one of the causes of rheumatoid arthritis and a few other things, but it's too speculative right now to say," Mozayeni said.
Human testing
More studies are needed, and Mozayeni has joined Breitschwerdt and Maggi in the diagnostic company to oversee human testing.
"Certainly, the prevalence of Bartonella infection in people with chronic illness is higher than I would have ever guessed, but we still don't know what that means," Breitschwerdt said.
Among the biggest unknowns is how to treat people who have been infected. The effectiveness of antibiotics depends on which strain of Bartonella is at work, and with so many strains, treatments can be hit or miss.
Breitschwerdt said the family in his most recent study declined to comment about their experience. He said they were having difficulty finding a doctor.
"It is very difficult to find a physician who wants to see someone with a chronic illness that is poorly defined," he said, adding that many such patients often think they have Lyme disease, a tick-borne bacterial infection with similar symptoms - and stigma. "With an unexplained illness, it becomes problematic."
Doctors familiar with lyme disease believe that Bartonella is one of the co-infections often transmitted by deer ticks, along with the lyme bacteria. It causes its own set of painful symptoms. An accurate, dependable lab test for this bacterium would be a powerful tool in the battle against tick-borne diseases
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I am rather surprised that Dr M is only finding bartonella in 20% of patients. I expected it to be much higher.
And I think Dr B is under estimating the number of lyme patients who have both infections.
Besides the cost of $633 hubby's doc quoted for the Galaxy test, his doc doesn't feel he is stable enough to come off antibiotics to get a more reliable test. But after treating nonstop for 2 1/2 years for bartonella I sure wish we had a definitive diagnosis of the species involved.
On a positive sign though, hubby's bloodwork is the best it has been in 2 1/2 years -- the recent combo of Rifampin and Factive plus Mino and Zithromax seems to have slowed down the destruction of red blood cells considerably. Now if he would start feeling better and his symptoms would improve then I would think we were finally making some real progress.
We do plan to repeat the Clongen bloodslide in June. At $100 that test is much more reasonable to use as a screening test, plus both F lab and Clongen have found bacteria while hubby has been on antibiotics.
Bea Seibert
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MariaA
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Even if there's not a staff member with Lyme at the N&O, it's becoming soooooooo extremely prevalent in central NC that people are becoming aware of it or at least aware that the aggressive lone star ticks are insane there. I'm not sure that totally translates into doctor awareness but 'normal' people are much more freaked out than they were in the past. I've been to a couple of large parties lately where so many different people said, without knowing I had Lyme, that they knew someone who picked up Lyme in Chatham County, for instance.
-------------------- Symptom Free!!! Thank you all!!!!
I got my Lyme complete with a bulls eye rash after camping in North Carolina 16 YEARS ago!
I guess that is also when I got the Bartonella- no way to know, tough.
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MariaA
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Hey, offtopic- since so many Lymies in NC have to be treated out of state:
To anyone from NC who goes to see Washington DC or NY area LLMD's, I'm trying to put together an informal 'rideshare' list so that people can coordinate driving or traveling together and maybe lower their expenses.
Please PM me an email address if you'd like to talk about this further. I've posted about this before and only got about 3 people responding so far, but it'll work well once we have a few more, I think.
-------------------- Symptom Free!!! Thank you all!!!!
hshbmom
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Is the Yale-educated rheumatologist in Rockville, MD an LLMD? ...or an ILADS member?
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During the summer of 2007, migratory joint pain developed in my (E.B.B.) 86-year-old father, previously an ironworker, farmer, and World War II veteran. Because of occasional tick attachments, a Borrelia burgdorferi ELISA was performed; antibodies were not detected, and no treatment was instituted. In the fall, subtle memory loss developed, and he fell twice a few weeks apart. Dad jokingly blamed the falls and the memory loss on "old timer's disease." Subsequently, episodes of subtle confusion and more frequent memory loss generated family concern as to what the future might hold. On December 15, he broke his left femur during a fall while climbing 2 stairs to enter our home. Despite having successfully climbed those stairs thousands of times in the past, he would never climb those or any other stairs again.
Retrospectively obvious, a pattern of insidious illness characterized by joint pain, memory loss, and incoordination, not recognizable by my father or other family members, had begun before that summer. Medically stable historical problems included coronary artery disease, atherosclerosis, carotid artery occlusion, hypertension, and atrial fibrillation. During the previous year, a normocytic, normochromic, nonregenerative anemia persisted. Despite normal serum iron, total iron binding capacity, ferritin, and vitamin B12 values, anemia was attributed to intestinal blood loss. When examined in May 2007, before anesthesia for endoscopy, mood and affect were appropriate, recent and remote memory were intact, insight and judgment were good. A hiatal hernia, mild antral gastritis, and duodenitis were visualized.
Initial Hospitalization When my father was hospitalized December 15, 2007, with a broken femur, a resting pill roll tremor and cogwheel rigidity were suggestive of Parkinson disease. Preoperative neurologic consultation identified severe confusion, inattention, and an inability to answer questions. Short-term memory and problem-solving abilities were decreased. There was mild ptosis of the right eye, normal cranial nerves, mild asterixis, and hand weakness. Laboratory abnormalities included anemia, hypercreatinemia, an elevated aspartate aminotransferase level, and hyperglobulinemia. Due to the severity of the femoral fracture, the femoral head was excised and replaced with a bipolar femoral prosthesis.
Postoperatively, poor mentation was considered a sequela of general anesthesia and peri-operative analgesics. For more than a week, dementia persisted. He did not recognize family members and had near constant hallucinogenic activities, including agitation, tying knots, sawing motions, and constantly pulling covers, bed clothes, and fluid lines. Severe hematuria developed after he pulled an inflated Foley catheter from his urethra. Concurrent gastrointestinal bleeding of undetermined cause necessitated multiple blood transfusions. Other complications included difficulty swallowing and paralytic ileus. Repeat abdominal radiographs, in conjunction with stool softeners and laxatives, failed to alleviate gastrointestinal complications. Eventually, he refused food and became severely bloated. Endoscopy performed on December 26 identified severe necrotizing esophagitis, multiple plaques, and a stricture attributed to Candida albicans and herpes zoster. C. albicans esophagitis is known to accompany HIV infection, leukemia, or an unidentified source of immune suppression (1,2). Shingles, caused by herpes zoster, occurred during the previous Thanksgiving and can be associated with immunosuppression, stress, or an aging immune system (3,4). Mentation and gastrointestinal abnormalities improved after starting treatment with fluconazole, acyclovir, and symptomatic medications for erosive esophagitis. However, confusion, lack of orientation, hyponatremia, hypokalemia, and hyperglycemia remained problematic until discharge to a physical therapy center on December 31.
Second Hospitalization During the next week, strength and mental capacities improved rapidly and discharge to the home environment was scheduled for January 9. On that morning and while driving to Maryland to build entry ramps, I was informed by cell phone that my father fell out of a chair and became nonverbal and that a stroke was suspected. For me, the roller coaster illness ultimately leading to his death would take an unbelievable turn of events. Upon his transfer to the neurology service, encephalopathy, asterixis, Parkinsonian-type tremor, hypoactive reflexes, pinpoint and minimally reactive pupils, and cogwheel rigidity were found. Verbal communication was absent, but he would grimace with pain whenever extremities were manipulated. An urgent computed tomography scan did not identify intracranial abnormalities.
When I was a boy, my father used the expression "something is fishy in Denmark" to imply that something was astray. Based upon historical events, I suspected something was being missed. Laboratory findings included anemia (hemocrit 34%), a normal leukogram (leukocytes 9,100 cells/μL, 2% band neutrophils), mild hypokalemia, hypoalbuminemia, hyperglycemia, increased serum alkaline phosphatase level, erythrocyte sedimentation rate of 79, and hypergammaglobulinemia. Thoracic radiographs identified mild bilateral pleural effusion. Because an undefined infectious source of immunosuppression seemed plausible, and fever (maximum temperature 38.6�C) occurred 24 hours after neurologic decompensation an infectious etiology was pursued. Nasal methicillin-resistant Staphylococcus aureus, blood, urine, and cerebrospinal fluid (CSF) cultures were negative. CSF results, including those for special stains, were unremarkable. Serologic results for Treponema pallidum, Borrelia burgdorferi, Rickettsia rickettsii, Bartonella henselae, Bartonella quintana, and HIV were negative. Results of CSF herpes simplex PCR and a test for T. pallidum antibodies were negative.
On January 11, results of magnetic resonance imaging and magnetic resonance angiography were interpreted as a left posterior stroke with no active bleeding. Initial treatment included intravenous acyclovir, fluconazole, vancomycin, ceftriaxone, ampicillin, and dexamethasone.
Translational Research and the Practice of Medicine Because I direct the Intracellular Pathogens Research Laboratory (IPRL) at the North Carolina State University College of Veterinary Medicine, aseptically obtained blood and CSF samples were kindly provided for testing. Results of PCR (5,6) specific for Anaplasma, Ehrlichia, and Rickettsia species were negative. Bartonella 16S-23S intergenic spacer primers (7) repeatedly generated amplicons of different sizes from blood and CSF, respectively. Compared with GenBank sequences, the blood amplicon was most similar (434/465bp) to Candidatus Bartonella volans (strain FSq-1, EU294521) isolated from a southern flying squirrel (Glaucomys volans) and Candidatus Bartonella durdenii (391/422bp) amplified from Orchopeas howardi (GenBank accession no. DQ 336386), a flea found on eastern US gray squirrels (Scinrus carolinensis), and a Bartonella sp. (446/492bp, EF125214) identified in ground squirrels (Spermophilus danricus) in the People's Republic of China. The novel rodent Bartonella sequence obtained from my father's blood had an 18-bp insert at positions 2047 or 334 in EU294521 and DQ336386, respectively. Previously, our laboratory had never worked with rodent Bartonella species and had never amplified a 300-bp internal transcribed spacer region amplicon from >3,000 animal or human blood samples. After several unsuccessful cloning attempts, the CSF amplicon was most similar (393/394 bp) to B. henselae (NC-005956). Blood and CSF, cultured by using Bartonella α Proteobacteria growth medium (BAPGM) (8), did not result in the growth of a Bartonella species.
Clinicians and Scientists Working Together After Bartonella PCR results became available, treatment with piperacillin and tazobactam were continued for 3 weeks until discharge. Levetiracetam was added to the patient's treatment because a generalized seizure occurred shortly after antimicrobial drugs were given. On January 18, severe dependent edema of the right elbow resulted in fluid leakage through intact skin. For 3 weeks, Dad remained semicomatose, disoriented, agitated, and encephalopathic. Hallucinations continued, accompanied by frequent involuntary motor movements. Diabetes mellitus and a large decubital ulcer on the right heel developed. During the fourth week, mentation improved, and he could rise and stand for brief periods. On January 28, he was discharged to a rehabilitation facility, with instructions to receive doxycycline and rifampin 2�/d for 13 days. Blood samples, obtained aseptically before discharge, were again submitted to the IPRL. After BAPGM pre-enrichment and subculture, B. vinsonii subsp. berkhoffii genotype II was isolated, and sequential serologic testing identified a rising titer to B. vinsonii subsp. berkhoffii but did not detect B. henselae antibodies (Table). After a brief, emotionally traumatic stay at the rehabilitation facility, Dad returned home to be cared for by 4 sons, his wife of 60 years, and other family members. Each week a different son slept by his bed, which was relocated to the family living room.
Home Again at Last During the next 3 weeks, there was substantial and progressive improvement in physical capabilities and a return of normal mental capabilities, including exceptional short- and long-term memory. Appetite normalized, and despite severe atrophy, muscle strength increased so he could stand, walk with assistance, and, although a daily struggle, access the bathroom. A February 10 blood sample obtained while he was receiving oral antimicrobial drugs was Bartonella PCR negative, and no bacteria were isolated in BAPGM. During this precious 3 weeks, our father joked, laughed, and vividly recalled wartime friends and other experiences. On March 1, 2008, he opened Christmas presents with our family. I should have been there.
Third and Final Hospitalization On March 4, ≈2 weeks after the course of oral antibiotics was completed, agitation and disorientation returned, and mental status deteriorated. Within 24 hours, Dad was hospitalized, where fine motor tremors of the right hand and wrist, asymmetric edema involving the right leg, and edema of the penis and scrotum were noted. He was afebrile and nonverbal and could not follow simple commands. Hematocrit was 30.2%, platelet count 557,000 cells/μL, and leukocyte count 7,800 cells/μL with a normal differential count. Serum biochemical abnormalities included hyperglycemia (glucose 218 mg/dL), hyperglobulinemia (3.6 g/dL), and increased alkaline phosphatase activity (169 IU/L). Urinalysis abnormalities included proteinuria with occasional hyaline casts.
Lorazepam was administered to control the agitation and restlessness. The warfarin dose was increased and heparinization initiated for a potential cerebrovascular accident. Due to the prior documentation of Bartonella infection, intravenous doxycycline, rifampin, and gentamicin were administered, and total parenteral nutrition was instituted. Again, shortly after initiation of antimicrobial drugs, a seizure occurred. Bartonella spp. were not amplified or isolated from a 1-mL blood sample obtained 4 days after initiation of treatment with antimicrobial drugs. During the next 3 weeks, while intravenous antimicrobial drugs were administered, our father again remained encephalopathic, with frequent hallucinations, severe agitation, and near-constant mental confusion. On March 14, intravenous methylprednisolone for potential immune-mediated vasculitis elicited no improvement in mental status. Similar to the previous treatment course, improvement in mental status, coherent communication, and renewed ability to recognize family members occurred during the fourth hospitalization week.
A Battle Lost On April 4, Dad was discharged to our home and oral antimicrobial drugs (doxycycline and rifampin) were dispensed. Despite all efforts by medical professionals, members of our family, and our tough 86-year-old father, protracted illness and prolonged hospitalizations had resulted in mental and physical debilitation, severe muscle wasting, and profound weakness. More important, he had lost his desire to live. After discharge, there was minimal neurologic improvement. Before the availability of April 4 IPRL test results, he began to refuse all medications. The identical rodent Bartonella DNA sequence was again amplified from his blood, but no bacteria were isolated.
Four weeks later my father died, on Friday, May 2, at 5 pm, around quitting time for an old iron worker. My mother and youngest brother were at his side. After his death, blood culture results from another sample obtained by the hospice nurse on April 28, 2008, became available. B. vinsonii subsp. berkhoffii genotype II was amplified and sequenced from the enrichment BAPGM blood culture. As direct extraction of DNA from blood was negative, growth of viable bacteria in liquid culture was implicated (8,9).
Groundhogs, Fleas, and the Genus Bartonella Following our father's death, I recalled a small, 0.5-cm, raised, firm lesion within his right eyebrow that developed during the summer of 2007 and would spontaneously hurt or burn, causing him to rub or squeeze the lesion. The mass disappeared after he began taking antimicrobial drugs in 2008. Retrospectively, I suspected a rodent flea bite above the eye had transmitted a novel Bartonella species, which we sequenced from his blood after each hospitalization. All known Bartonella spp. have preferential animal reservoir hosts, and each uses arthropods or animal bites and scratches as the primary modes of transmission (10-12). Dad would occasionally capture mice, rats, skunks, and groundhogs in the barns. Groundhogs were transported in the car trunk to a distant location for release, potentially leaving behind fleas. Therefore, 3 Candidatus Bartonella spp. isolates were provided by Dr. William Nicholson, a colleague at the Centers for Disease Control and Prevention in Atlanta. After sequencing, the 16S-23S intergenic spacer region of a ground squirrel (Candidatus Bartonella durdenii), a flying squirrel (Candidatus Bartonella volans), and a groundhog (Candidatus Bartonella monaxi) isolate, the most similar GenBank sequence was Candidatus Bartonella volans. There was no perfect match with these 3 isolates. However, sequences from Dad's blood clustered with a squirrel Bartonella subgroup. This observation supports the presence of a novel Bartonella species on the eastern shore of Maryland, an as yet undefined animal reservoir, and an unknown arthropod vector.
Regardless of the mode(s) of transmission, repeated molecular documentation of a novel rodent Bartonella sp. and B. vinsonii subsp. berkhoffii supports the unexpected failure of 2 intensive courses of intravenous and oral antimicrobial drugs to eliminate these fastidious, intravascular bacteria. During the first two hospitalization periods, there was similar and progressive improvement in neurologic signs and mental capabilities that began during the fourth week of antimicrobial drug administration. Pre-enrichment BAPGM growth of B. vinsonii subsp. berkhoffii from blood obtained 4 days before death supports persistence of viable organisms. Recently, antimicrobial drug resistance genes have been characterized in B. bacilliformis, B. henselae, and B. quintana by in vitro serial passage (13-15). Retrospectively, the relapse in encephalopathic signs might have been avoided if antimicrobial drugs were continued for a longer interval after discharge from hospital 2, and blood cultures were optimally obtained and sequentially tested to confirm therapeutic elimination.
Elimination of Bartonella spp. by antimicrobial drugs in immunocompetent patients may be more difficult to achieve than is currently appreciated (16). Although co-infection with B. henselae and B. vinsonii subsp. berkhoffii has been previously reported, DNA of 3 Bartonella spp. was detected in our father. Based on repeatable PCR testing, a small quantity of B. henselae DNA was in the January CSF sample. Because PCR amplicon contamination was never detected in any negative control, laboratory error is considered unlikely. Although the BAPGM enrichment approach has improved molecular detection and isolation of some Bartonella spp. from human patient samples (9,16-18), a rodent Bartonella sp. isolate was not obtained. Unfortunately, 8 weeks can be required from inoculation of BAPGM until a subculture agar plate isolate is characterized by DNA sequencing. Therefore, IPRL test results were often not available to Dad's physicians in a timely manner.
Age, Bartonella spp., and Immune Suppression? Suspicion of an undetermined source of immune suppression and recent tick exposures were primary factors motivating testing in the IPRL. Previously, B. vinsonii subsp. berkhoffii was shown to induce immunosuppression in experimentally infected dogs (19,20). In retrospect, occult infection with Bartonella spp. may have contributed to shingles at Thanksgiving and necrotizing C. albicans esophagitis after hospitalization for the fractured femur. Recently, B. quintana lipopolysaccharide was found to have antiinflammatory properties (21). Immune suppressive factors may facilitate persistent intravascular Bartonella infection without inducing obvious infection indicators, such as fever, tachycardia, leukocytosis, and CSF pleocytosis. Fever was documented once and mild neutrophilia for 3 of 48 blood counts. Thrombocytosis, previously associated with B. henselae (22), was documented 14 times.
Ecologic Complexity of Bartonella spp. Because of my father's long-standing atherosclerosis and because BAPGM will grow a spectrum of seemingly difficult to isolate bacteria (8,23), pre-enrichment blood cultures and Bartonella internal transcribed spacer region PCR had been performed in September 2005 and August 2006 (Table). Bartonella spp. were not amplified or isolated, which suggests infection occurred after the summer of 2006. Transmission of B. henselae, B. vinsonii subsp. berkhoffii, and B. alsatica can occur as a result of a scratch from a cat, a dog, or a wild rabbit, respectively (17,24-26). Cats are the primary reservoir for B. henselae, whereas dogs and coyotes are the only reported reservoir hosts for B. vinsonii subsp. berkhoffii genotype II in North America (27). Recently, B. vinsonii subsp. berkhoffii genotype II was isolated by BAPGM blood culture from a cat with recurrent osteomyelitis (E.B. Breitschwerdt, unpub. data), which suggests that a bacteremic cat might facilitate transmission of this subspecies. My parents had an old (≈21 years of age) exclusively outdoor barn cat that would occasionally scratch. The cat could not be tested because it died in 2007. B. henselae and B. clarridgeae have been transmitted experimentally by transfusion to cats (24). Because B. vinsonii subsp. berkhoffii seroconversion occurred during hospitalization, transfusion-associated transmission is also possible. The exact timing and mode of transmission of B. henselae, B. vinsonii subsp. berkhoffii, and the rodent Bartonella sp. to our father cannot be established. However, his illness serves to illustrate the medical and ecologic complexity of this genus.
Occult Infection and Chronic Illness Reconstructing the history of a chronic illness is always difficult and remains an unexacting science due to known, unknown, and undetermined factors that influence disease expression over time. Experimental studies that used rodent models have emphasized the ability of Bartonella spp. to invade erythrocytes and vascular endothelial cells (28). In vitro studies indicate that B. henselae can infect macrophages, microgial cells, dendritic cells, and CD34+ progenitor cells (29). B. henselae and B. vinsonii subsp. berkhoffii have been amplified from dog lymph node aspiration samples (30). Thus in a given patient, Bartonella organisms likely infect a substantial number of cellular targets. B. henselae infection induces chronic arthritis in a subset of cat scratch disease (CSD) patients, and atypical CSD manifestations are more likely to develop in elderly patients (31,32). In the context of arthritis, B. henselae and B. vinsonii subsp. berkhoffii were repeatedly isolated from joint fluid from a dog in which repeated antimicrobial drug therapy was not successful (33). Although a spectrum of acute and generally self-limiting neurologic manifestations have been historically described in CSD patients, B. henselae and B. vinsonii subsp. berkhoffii were only recently isolated from patients with chronic neurologic and neurocognitive abnormalities (16).
We propose that the initial arthritic signs, short-term memory loss, and incoordination were premonitory signs of Bartonella spp. infection, and that persistent infection contributed to localized edema, nonregenerative anemia, thrombocytosis, hyperglobulinemia, and a protracted debilitating illness accompanied by hallucinations, agitation, seizures, and death. Agitation, disorientation, and combative behavior have been reported in association with CSD and physicians have implicated Bartonella spp. as contributors to agitation and treatment-resistant depression (34,35). Memory loss and a spectrum of neurocognitive complaints have also been reported in immunocompetent persons infected with B. vinsonii subsp. berkhoffii and B. henselae (9,16,17).
My Father and "One Medicine" In recent years, there has been renewed interest in the concept of "One Medicine" (36). I hope that lessons from my father's death can reinforce the importance of "One Medicine." However, as in the past, rhetoric may not result in needed increases in resource allocation to enhance educational, research, service, and public health capabilities of the veterinary profession (37). In the context of vector-borne infectious diseases, zoonotic diseases, food safety, zoologic medicine, and environmental medicine and ecosystem health, to name a few areas, veterinarians continue to make major contributions that ensure and enhance the daily health of animals and humans. Because of a research focus in comparative infectious diseases and knowledge of the biologic, immunologic, and pathophysiologic behavior of Bartonella spp. in a spectrum of animal species, a veterinary research laboratory was able to assist with the management of my father's illness.
As is often true of research at the bedside and the laboratory bench, new lessons and challenges arose from the collective efforts of doctors, nurses, veterinarians, research scientists, and others attempting to heal my father. I and my family remain sincerely grateful to the many doctors, nurses, and other caregivers who contributed to the management of my father's surgical and medical problems. Because of the severe encephalopathic and combative nature of his behavior, this was frequently not an easy or pleasant task. During his illness, I was struck by several items: 1) most nurses are absolutely amazing, caring, and dedicated professionals; 2) in human medicine, unlike veterinary medicine, no physician claimed or accepted the responsibility to be my father's doctor; and 3) for many reasons, I found the human healthcare system to be frayed, if not broken. Whether blame lies with the insurance companies, our litigious society, the profit-based motivations of hospital administration, the increased complexity of medical technology, or the medical education of physicians, it really does not matter. As my father would say, "It is no way to do business." I have taught internal medicine at a College of Veterinary Medicine for 32 years. During that time, every sick animal on our medical service had at least 2 doctors (1 being a student), who were directly responsible for the animal's care, for frequent communications with the owner, and for communications with the referring veterinarian. In our increasingly complex hospital environments, every patient needs a personal advocate or designated doctor to represent his or her interests.
Epilogue Some years ago in a conversation with my mother I suggested that the term natural death may well represent an oversimplification of the processes that end a person's life. My father and our family were substantially affected during his illness. Each day, from initial hospitalization until his death, there was at least 1 family member at his side. In the eyes of family and friends, my father was a great man in so many respects. He was a loving husband, a caring father, diligent worker, and a friend and supporter to many persons. Potentially, his illness illustrates a complex interaction between intravascular Bartonella infection and complex disease expression, provides documentation for an as yet uncharacterized zoonotic rodent Bartonella sp., and offers disconcerting evidence supporting antimicrobial drug ineffectiveness and clinical evidence supporting the concept that persistent infection with >1 Bartonella spp. may lead to immunosuppression and opportunistic infections with organisms such as herpes zoster and C. albicans. As in his life, Dad would want this story to benefit others after his death. We hope that it does.
Acknowledgements We thank William Nicholson for providing the Candidatus Bartonella isolates for comparative DNA sequencing, Natalie Cherry for sequencing the internal transcribed spacer region of the 3 Candidatus isolates, Julie Bradley for performing serologic testing, Barbara Hegarty for preparing Bartonella antigens, and Tonya Lee for providing editorial assistance.
Dr Breitschwerdt is a professor of medicine and director of the Intracellular Pathogens Research Laboratory, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, NC. His research interests include diagnosis and treatment of vector-borne intracellular pathogens.
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hshbmom
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Peggy Munson's blog: a long, three-part article about Peggy's struggle with Bartonella
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I have had the test done by Dr B at Galaxy and came back positive for 3 strains of Bart. One VERY positive. I don't remember which ones though, I don't have a copy of the report with me.
I had a negative Bart smear from Fry Labs.
Although expensive, I am confident that my Bart treatment will be more effective since they will know which abx to use for the strains that I have. My daughter MAY have congenital lyme and we will probably have her tested using the same test. I would be very interested in seeing if her strains match mine (but really HOPING she's not sick at all).
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CD57
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I thought that Galaxy was not able to tell what abx to use against the bart they were finding -- in other words they were in the same position as the Fry Labs -- finding stuff but as they are not doctors, not being able to tell what to treat it with?
I had my blood tested in December as part of the research. They did not find anything although they said I had been on abx for so long that could be why.
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hshbmom
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Dr. Breitschwerdt is also affiliated with Duke University Medical Center.
Edward Breitschwerdt, DVM Chief Scientific Officer
Dr. Breitschwerdt is an internist and professor of medicine and infectious diseases at North Carolina State University's College of Veterinary Medicine. He is a co-director of the Vector Borne Disease Diagnostic Laboratory which has been testing animals for vector borne infections, including Bartonella since 1984. With over 200 peer-reviewed publications, Dr. Breitschwerdt is a internationally recognized leader in the area of Bartonella research, diagnosis, and treatment. As consequences, he has consulted widely upon an array of infectious diseases for many large companies in the veterinary diagnostics, therapeutic, and vaccine industries.
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hshbmom
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Bartonella vinsonii subsp. berkhoffii and Bartonella henselae bacteremia in a father and daughter with neurological disease Breitschwerdt EB, Maggi RG, Lantos PM, Woods CW, Hegarty BC, Bradley JM.
Bartonella vinsonii subsp. berkhoffii is an important, emerging, intravascular bacterial pathogen that has been recently isolated from immunocompetent patients with endocarditis, arthritis, neurological disease and vasoproliferative neoplasia. Vector transmission is suspected among dogs and wild canines, which are the primary reservoir hosts. This investigation was initiated to determine if pets and family members were infected with one or more Bartonella species.
Methods
PCR and enrichment blood culture in Bartonella alpha Proteobacteria growth medium (BAPGM) was used to determine infection status. Antibody titers to B. vinsonii subsp. berkhoffii genotypes I-III and B. henselae were determined using a previously described indirect fluorescent antibody test. Two patients were tested sequentially for over a year to assess the response to antibiotic treatment.
Results
Intravascular infection with B. vinsonii subsp. berkhoffii genotype II and Bartonella henselae (Houston 1 strain) were confirmed in a veterinarian and his daughter by enrichment blood culture, followed by PCR and DNA sequencing. Symptoms included progressive weight loss, muscle weakness, lack of coordination (the father) and headaches, muscle pain and insomnia (the daughter). B. vinsonii subsp. berkhoffii genotype II was also sequenced from a cerebrospinal fluid BAPGM enrichment culture and from a periodontal swab sample. After repeated courses of antibiotics, post-treatment blood cultures were negative, there was a decremental decrease in antibody titers to non-detectable levels and symptoms resolved in both patients.
Conclusions
B. vinsonii subsp. berkhoffii and B. henselae are zoonotic pathogens that can be isolated from the blood of immunocompetent family members with arthralgias, fatigue and neurological symptoms. Therapeutic elimination of Bartonella spp. infections can be challenging, and follow-up testing is recommended. An increasing number of arthropod vectors, including biting flies, fleas, keds, lice, sandflies and ticks have been confirmed or are suspected as the primary mode of transmission of Bartonella species among animal populations and may also pose a risk to human beings.
hshbmom
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Potential for Tick-borne Bartonelloses Angelakis E, Billeter SA, Breitschwerdt EB, Chomel BB, Raoult D. Emerging Infectious Diseases, Volume 16, Number 3 - March 2010.
Abstract As worldwide vectors of human infectious diseases, ticks are considered to be second only to mosquitoes. Each tick species has preferred environmental conditions and biotopes that determine its geographic distribution, the pathogens it vectors, and the areas that pose risk for tick-borne diseases. Researchers have identified an increasing number of bacterial pathogens that are transmitted by ticks, including Anaplasma, Borrelia, Ehrlichia, and Rickettsia spp. Recent reports involving humans and canines suggest that ticks should be considered as potential vectors of Bartonella spp. To strengthen this suggestion, numerous molecular surveys to detect Bartonella DNA in ticks have been conducted. However, there is little evidence that Bartonella spp. can replicate within ticks and no definitive evidence of transmission by a tick to a vertebrate host.
hshbmom
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Bartonellosis: an emerging infectious disease of zoonotic importance to animals and human beings Edward B. Breitschwerdt, DVM; Ricardo G. Maggi, PhD; Bruno B. Chomel, DVM, PhD and Michael R. Lappin, DVM, PhD Journal of Veterinary Emergency and Critical Care, Volume 20, Issue 1, Pages 8-30.
� Objective To provide a review of clinically relevant observations related to Bartonella species as emerging pathogens in veterinary and human medicine.
� Data Sources Literature as cited in PubMed and as generated by each of the authors who have contributed to various aspects of the clinical understanding of bartonellosis.
� Human Data Synthesis Important historical and recent publications illustrating the evolving role of animal reservoirs as a source of human infection.
� Veterinary Data Synthesis Comprehensive review of the veterinary literature.
� Conclusions In addition to inducing life-threatening illnesses, such as endocarditis, myocarditis, and meningoencephalitis and contributing to chronic debilitating disease, such as arthritis, osteomyelitis, and granulomatous inflammation in cats, dogs, and potentially other animal species; pets and wildlife species can serve as persistently infected reservoir hosts for the transmission of Bartonella spp. infection to veterinary professionals and others with direct animal contact.
*Dr. Breitschwerdt is also an adjunct professor of medicine at Duke University Medical Center.
Disease Caused By Insect Bites Can Be Transmitted To Children At Birth, NC State Researcher Finds
For Immediate Release Tracey Peake | News Services | 919.515.6142
Release Date: 05.05.2010 Filed under NCSU Home, Releases
A North Carolina State University researcher has discovered that bacteria transmitted by fleas-and potentially ticks-can be passed to human babies by the mother, causing chronic infections and raising the possibility of bacterially induced birth defects.
Dr. Ed Breitschwerdt, professor of internal medicine in the Department of Clinical Sciences, is among the world's leading experts on Bartonella, a bacteria that is maintained in nature by fleas, ticks and other biting insects, but which can be transmitted by infected cats and dogs as well.
The most commonly known Bartonella-related illness is cat scratch disease, caused by B. henselae, a strain of Bartonella that can be carried in a cat's blood for months to years. Cat scratch disease was thought to be a self-limiting, or ``one-time'' infection; however, Breitschwerdt's previous work discovered cases of children and adults with chronic, blood-borne Bartonella infections-from strains of the bacteria that are most often transmitted to cats (B. henselae) and dogs (B. vinsonii subsp. berkhoffii) by fleas and other insects.
In his most recent case study, Breitschwerdt's research group tested blood and tissue samples taken over a period of years from a mother, father and son who had suffered chronic illnesses for over a decade. Autopsy samples from their daughter-the son's twin who died shortly after birth-contained DNA evidence of B. henselae and B. vinsonii subsp. berkhoffi infection, which was also found in the other members of the family.
Both parents had suffered recurring neurological symptoms including headaches and memory loss, as well as shortness of breath, muscle weakness and fatigue before the children were born. In addition, their 10-year-old son was chronically ill from birth and their daughter died due to a heart defect at nine days of age.
Results of the parents' medical histories and the microbiological tests indicated that the parents had been exposed to Bartonella prior to the birth of the twins, and finding the same bacteria in both children, one shortly after birth and the other 10 years later, indicates that they may have become infected while in utero.
Breitschwerdt's research appears online in the April 14 Journal of Clinical Microbiology.
``This is yet more evidence that Bartonella bacteria cause chronic intravascular infections in people with otherwise normal immune systems, infections that can span a decade or more,'' Breitschwerdt says. ``Also this new evidence supports the potential of trans-placental infection and raises the possibility that maternal infection with these bacteria might also cause birth defects.''
The Department of Clinical Sciences is part of NC State's College of Veterinary Medicine. Dr. Breitschwerdt is also an adjunct professor of medicine at Duke University Medical Center.
-peake-
Note to editors: An abstract of the paper follows.
``Molecular evidence of perinatal transmission of Bartonella vinsonii subsp. berkhoffii and B.henselae to a child'' Authors: Edward B. Breitschwerdt, Ricardo G. Maggi and Patricia E. Mascarelli, NC State University; Peter Farmer, Department of Pathology, North Shore University Hospital Published: April 14, 2010 in Journal of Clinical Microbiology
Abstract: Bartonella vinsonii subsp. berkhoffii, Bartonella henselae or DNA of both organisms was amplified and sequenced from blood, enrichment blood cultures or autopsy tissues from four family members. Historical and microbiological results support perinatal transmission of Bartonella species in this family.
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