My Mother's Story: Tick Borne Ehrlichiosis and a Life Well-Lived

Today is August 2, 2019. Five days ago, Hospice Eastern Shore Maryland was asked to assist with the terminal care of my 95-year-old mother.

Sarah Esther Breitschwerdt, born on May 7, 1924, grew up on a family farm between Baltimore and Washington. The farm was one of few still remaining that could be seen when driving along “old” US Route 1, the highway used by forefathers of our country, when traveling between Philadelphia, Pennsylvania, and Washington, DC. Shortly after World War II (WWII) ended, my Mother married my Father who had served with the Army Air Corps in England during the second “great” war. As the Breitschwerdt name originated in Germany (translation broad sword) in the 1200’s, it has always struck me as strange that my father loaded bombs in England to be dropped on Breitschwerdt families in Germany and likely on the graves of our ancestors. Clearly, history is dynamic, but seemingly repetitious.

When I (E.B.B.) was about 2-years old, my parents purchased the family farm in Howard County Maryland from my grandparents. Subsequently, they raised four sons on that farm, of which I was the oldest, one of many postwar babies. To understand my mother's story, you have to understand the farm, where it all began. My father was an ironworker and my mother a housewife who cut hay, raked hay, baled hay, and milked the family cow twice daily, until I and subsequently my brothers were old enough to do so. For those who have never milked a cow or baled hay, you have really missed interesting and, at times, challenging life experiences. However, to a person, we cherished growing up/living on that small farm in central Maryland. In addition to the work, there were endless hours playing catchers among the barns, baseball in the cow pasture, fishing in the small stream that flowed through the farm, and swimming or ice skating (depending upon the weather) in the very special farm pond that our parents built for us. Because our “upbringing” was special in so many ways, I am saddened by the fact that the United States continues to lose small family farms, as the land is replaced with housing developments or farms are amalgamated into large corporate entities. Something gained and something lost.

For several decades while my parents raised four sons, my family farmed nights (after my dad got home from a day on steel beams most often in Baltimore), weekends, and holidays, during which time my mother managed the house, the bills, the farm, and her four sons. Thinking back, our mother was an amazing business person, farm manager, and effective organizer. Although no son proved to be musically inclined, much less gifted, there were accordion lessons, piano lessons, and trips to the dentist or doctor, and three sons sequentially participated in the Civil Air Patrol. Civil Air Patrol proved to be the perfect organization to “round out” the education of semi-isolated farm boys, whose closest neighbor was a good 30-min walk away. Note, I said walk, not ride!

Each brother was born 3 years apart, except the youngest brother who came along 6 years after the third in line, 15 years separating the oldest and the youngest. During the decades in which my brothers and I were growing up, attending school, and ultimately graduating from the University of Maryland, there were repeated efforts by realtors to purchase the family farm, which was located in the middle of very valuable development properties in the Baltimore/Washington corridor. It has never ceased to amaze me that our parents were able to balance the many demands on their lives while providing the necessary funds to send four sons to college. Truly, a tribute to their work ethic and my mother's ability to balance the books! As will become important in my mother's story, ticks were prevalent on our dogs (Rhipicephalus sanguineus, commonly referred to as brown dog ticks) and among the hedgerows (most likely Dermacentor variabilis, commonly referred to as the America dog tick). Dog and human tick infestations were common, but essentially ignored as a source of disease. Many of our contemporary tick borne pathogens, including but not limited to Anaplasma phagocytophilum, the cause of anaplasmosis in cats, dogs, horses, and humans, Borrelia burgdorferi, the cause of Lyme disease in animals and humans, and Ehrlichia chaffeensis and E. ewingii, tick borne pathogens that infect cats, dogs, and humans had not yet been discovered or alternatively were not associated with human illness (Eisen et al. 2017, Johnson et al. 2018). Ignorance was bliss, perhaps?

After selling the family farm, my parents moved to a beautiful farm on the Eastern Shore of Maryland. In 2005, mother was diagnosed with non-Hodgkin's lymphoma, which was successfully treated with chemotherapy. She and her doctors “beat the cancer” as the disease remained in remission at the time of her death. By this time in our family's history, I had become a veterinarian, a board certified veterinary internist, and a professor of medicine and infectious diseases at North Carolina State University (NCSU) College of Veterinary Medicine. My research laboratory team (it really does take a team to accomplish research) had and was focusing on tick borne organisms (referred to medically as pathogens) that cause Anaplasmosis, Babesiosis, Ehrlichiosis, and Rocky Mountain spotted fever. So for me, ticks went from innocuous pests attached to dog ears to vectors of disease that in some instances led to serious morbidity and mortality in animals and humans.

In 1992, Dr. Russ Regnery at the Centers for Disease Control and Prevention (CDC) made the association between a newly discovered bacteria in AIDS patients and a bacterial organism responsible for Cat Scratch Disease (CSD) (Regnery et al. 1992). Before 1990, “we” did not know that any animal or human in North America was or ever had been infected with a Bartonella species (Karem et al. 2000, Breitschwerdt 2014). Considering the high prevalence of bacteremia in reservoir hosts, the fact that human and veterinary microbiologists had never previously grown these bacteria from animals or human patients was amazing. Failure to grow (isolate microbiologically) these bacteria was, in part, related to their very slow dividing time (∼22 h). Thus, cultures were not maintained for an adequate time to facilitate bacterial isolation (Karem et al. 2000, Breitschwerdt 2014). In 1992, because of research involving AIDS patients, “we” knew that immunocompromised humans could be infected with either Bartonella quintana, the historical cause of Trench Fever in World War I and WWII, or B. henselae, the subsequently discovered cause of CSD (Relman et al. 1992). During the ensuing decades, at least 38 novel Bartonella species would be discovered by researchers around the world (Breitschwerdt 2014, Okaro et al. 2017, Cheslock et al. 2019). When Dr. R.G.M., senior research scientist in our laboratory, confirmed Bartonella spp. infections in both my mother and father, enhancing medical understanding of this genus became personal.

Beginning in 1993, Dorsey Kordick began her PhD research in my laboratory, initially focusing on the role of cats belonging to patients with CSD, as reservoirs for B. henselae (Kordick et al. 1995, 1997). Following isolation of the first Bartonella species (officially named B. vinsonii subspecies berkhoffii in collaboration with the Special Pathogens group at CDC) from a dog anywhere in the world (Kordick et al. 1996), our research focus shifted to understanding the extent to which Bartonella spp. caused disease in dogs. Now, over two decades later, dogs have proven to be a naturally-occurring “animal model” for human bartonellosis, and vice versa, as dogs and humans develop identical or anatomically similar pathology in association with Bartonella spp. infections (Breitschwerdt et al. 2013, Álvarez-Fernández et al. 2018). Subsequently, members of our research team reported Bartonella bacteremia in cattle (Cherry et al. 2009), deer (Chitwood et al. 2013), dolphins (Harms et al. 2008), horses (Cherry et al. 2012), sheep (Maggi et al. 2009), and whales (Maggi et al. 2008), to name a few of the domestic and wildlife species published as a result of collaborative research endeavors. Beginning in 2003 (NCSU Institutional Review Board Approval, IRB 4925-03), in collaboration with Dr. Chris Woods, an infectious disease physician at Duke University Medical Center, our research team began to investigate the prevalence of Bartonella spp. infection in veterinary workers, a seemingly occupationally at risk group due to frequent exposures to arthropods (fleas, lice, and ticks) and infected animals (Lantos et al. 2014). As we published over 100 articles with Bartonella in the title, we found ourselves in an increasingly strange, complex, and rapidly changing world that involved a genus of bacteria not known to exist in North America before the AIDS epidemic.

Although not a new concept, there has been a strong resurgence and emphasis in recent years on “One Health.” So what does One Health have to do with my mother? Because it is estimated that 75% of novel, emerging infectious diseases are zoonotic (i.e., originate from or infect animals, as well as humans), the study, diagnosis, treatment, and prevention of vector borne zoonotic diseases continue to benefit from a One Health approach. In 2005, during chemotherapy for non-Hodgkin's Lymphoma, Dr. Maggi in our research laboratory PCR amplified Bartonella DNA from my mother's blood. In 2009, my research team described my father's medical care during the last 4 months of his life, a period during which three different Bartonella species were repeatedly amplified and sequenced from my father's blood specimens (Breitschwerdt et al. 2009). The reservoir host(s) and mode of transmission (presumptively an arthropod vector) for one of these organisms, referred to as Bartonella volans-like, have as yet not been identified nor has the organism been isolated in a microbiology laboratory. We subsequently amplified DNA of this organism from dogs and another human patient (Cherry et al. 2011). Along with the many other unanswered questions relative to the genus Bartonella, I hope to ultimately know from whence and how DNA of this organism ended up in my father's blood.

Back to Mom! Fortunately, our mother's health remained good until the winter of 2018, when problems with poor short term memory escalated into problems with inappropriate reasoning. Mom was developing some form of dementia, which was compromising her ability to make rationale associations and decisions. In 2019, she also began experiencing a series of medical problems, including pneumonia and recurrent urinary tract infections, most likely caused by less mental emphasis on personal hygiene. Over the ensuing 7 months, taking care of our mother, which was now shared by my three younger brothers, became increasingly challenging as her overall mental capabilities continued to gradually deteriorate. Then, 2 weeks ago, there was a very rapid deterioration in her physical condition. She could no longer take her daily half mile walks and was increasingly weak to the point that she required assistance to stand. Her appetite diminished. She became complacent and would sleep for extended periods. When she began vomiting and refusing food, her physician ordered a complete blood count, serum biochemical profile, and urinalysis and urine culture. The good news was no urinary tract infection. The bad news was no obvious biochemical reason for the seemingly rapid deterioration in her physical and mental capabilities.

However, in reviewing the complete blood count values, I was “struck” by a pattern that I have seen frequently in dogs with ehrlichiosis during my 40-year career as an academic veterinary internist (Breitschwerdt et al. 1987, Hegarty et al. 1997). The pattern consisted of a mild thrombocytopenia, lymphocytosis, and a low neutrophil count, without a left shift, a frequent pattern in humans with ehrlichiosis (Eisen et al. 2017). With some degree of trepidation, as this combination of hematological abnormalities is far from specific, I suggested that my mother might well have a tick borne disease. At the time, my brothers and sister-in-laws did not recall a tick bite. Nor did I initially! Most days driving home from work, I would call my mother to have a very similar conversation to the one we had the day before, which she would no longer remember due to progressive memory loss. Within a couple of days, I had convinced myself that mom mentioned having removed a tick. When I somewhat jokingly asked if she had saved it, she said she had flushed it down the toilet. One of several controversies surrounding tick borne diseases is whether it is rational to test embedded ticks for known tick borne pathogens. There are good arguments for and against tick testing. I have repeatedly reflected on the fact that I did not recall the tick conversation with my mother, perhaps a function of a far too occupied life or alternatively I too am losing my short term memory. Medically, many people afflicted with a tick borne disease do not recall an attached tick.

Continued vomiting, refusing food, and progressive encephalopathy resulted in hospitalization the next day. Primary differential diagnoses, including urosepsis, pneumonia, and thromboembolism, illnesses often documented in the elderly, were systematically ruled out. Blood cultures were negative; a computed tomography scan failed to identify evidence of aspiration pneumonia or thromboembolism. Now febrile, ampicillin sulbactam was administered. Within 48 h, azithromycin was added to the antibiotic regimen. Medically, doxycycline is the only antibiotic known to be effective for the treatment of ehrlichiosis (Eisen et al. 2017). On the third day of hospitalization, when PCR performed by the Mayo Clinic confirmed E. chaffeensis, intravenous doxycycline was administered. PCR assays for E. ewingii, E. muris, and A. phagocytophilum were negative. Whether solely or only partially responsible for the subsequent improvement is/was impossible to determine, but within 24 h vomiting ceased and the severe encephalopathic agitation observed throughout hospitalization subsided. As a systemic blood borne infection, ehrlichiosis causes vomiting, pneumonitis, and encephalitis. After discussions among the brothers and our mother's doctors, a decision was made to discharge to hospice care. Today is Sunday, August 4, 2019. Our mother died at my brother's home between midnight and 4 AM.

I began writing this article out of a feeling of helplessness. My mother was in Maryland. I was in North Carolina. Her quality of life had deteriorated gradually during 2019, and her recent history was medically and emotionally complicated for all concerned. For me personally, I had gone out on a limb with my brothers, and likely my mother's doctors, suggesting that her acute deterioration was potentially associated with a tick borne disease, caused by a pathogen that my research group had studied intermittently over the years. As I have reflected on my mother's life and the circumstances surrounding her death, there is perhaps an important reason to finish this/her story. Where to start?

My initial academic appointment (i.e., a real job) was at the School of Veterinary Medicine, Louisiana State University. Because the temperature and humidity in the southeastern United States provide an optimal environment for vectors, and because in the 1970's veterinarians and pet owners did not have safe and highly effective acaricide products to prevent tick attachment or kill ticks once beginning their bloodmeal, ticks and tick borne diseases were plentiful. As a young veterinary internist, I was fascinated by the variability in clinical and hematological presentations, as well as the diagnostic and therapeutic complexity associated with ehrlichiosis in dogs (Breitschwerdt et al. 1987). When I joined the faculty at NCSU 6 years later, I and most other veterinary researchers considered ehrlichiosis the most important tick borne disease of dogs worldwide. Although our understanding of tick borne diseases has improved substantially, ehrlichiosis likely remains the most important canine tick borne disease (Mylonakis et al. 2019). Historically, E. canis was the sole known cause of ehrlichiosis in dogs. With research, we learned that dogs can be infected with E. chaffeensis, E. ewingii, E. muris, and Panola Mountain Ehrlichia (Breitschwerdt et al. 1998, Kordick et al. 1999, Beall et al. 2012, Hegarty et al. 2012, , Qurollo et al. 2013, Qurollo et al. 2019). We subsequently came to realize that dogs could be concurrently infected with more than one Ehrlichia species or concurrently infected with other tick or flea transmitted pathogens.

Shortly after arriving at NCSU, I was fortunate to work with Dr. David Walker, an MD pathologist, among the foremost rickettsiologists in the world. David, Dr. Willy Burgdorfer, for whom the Lyme disease spirochete Borrelia burgdorferi was named, and I worked together (One Health) to begin to characterize the pathogenesis of Rocky Mountain spotted fever (RMSF) a potentially fatal tick borne disease in dogs (Breitschwerdt et al. 1988, Davidson et al. 1990). Approximately 2 years before the first publication of human ehrlichiosis in the New England Journal of Medicine in 1987 (Maeda et al. 1987), I shared my fascination with canine ehrlichiosis with David, during a conversation in his office at the University of North Carolina Medical School. We have both reflected on this conversation, as Dr. Walker went on to devote a substantial portion of his career to the study of ehrlichiosis, including efforts to develop a safe and effective vaccine for use in animals and humans (Saito et al. 2016).

In 1993, I was fortunate (for many reasons) to participate in my only academic sabbatical with the Division of Infectious Disease, at Duke University Medical Center. Once again, having shared my enthusiasm for the medical complexity of the genus Ehrlichia, we did a prospective study of patients with acute onset febrile illness and recent tick attachment. Each year, North Carolina and Oklahoma report the highest number of human RMSF cases. Surprisingly, more patients had ehrlichiosis than RMSF (Carpenter et al. 1999), and one patient was coinfected with E. chaffeensis and R. rickettsii (Sexton et al. 1998). Due to sequential exposure to different tick species, we now consider coinfections in dogs as the norm, rather than the exception (Breitschwerdt et al. 1998, Kordick et al. 1999, Suksawat et al. 2001, Yabsley et al. 2008, Diniz et al. 2010).

In 1995, while my parents lived on the Eastern Shore of Maryland, my father developed an acute onset febrile illness. My father loved to drive and work on old Mercedes cars. As such, he generally had one licensed for use on the state highways and two in the woods for parts. That summer, while removing parts from one of the cars, he acquired several ticks, not an unusual occurrence for anyone in rural settings. Two weeks later, my mother related that my father was acting crazy. How so I asked? “He wanted a sewing needle, but did not know why he wanted it.” OK mom, I will call tomorrow. Next day, “Your father is crazier than ever!.” Mom, I will drive to Maryland tomorrow morning. When I entered the kitchen, my father was encephalopathic and did not recognize me, symptoms associated with life-threatening ehrlichiosis (Paddock et al. 1997). It was a Friday afternoon, perhaps one of the worse times to be extremely ill and one of the worse times to reach his doctor. Like my mother, my father was thrombocytopenic, but profoundly neutropenic. His response to doxycycline was dramatic and he returned to his “non-crazy” state of mind. Because of his tick attachment history and laboratory abnormalities, I obtained blood collection tubes from a local veterinarian (One Health), and E. chaffeensis DNA was amplified in my research laboratory from my father's blood. I was subsequently informed that his was the first documented case of ehrlichiosis on the eastern shore of Maryland.

In 2002, I got a call from Dr. Cathy Williams, the attending veterinarian at the Duke University Lemur Center. As I knew little to nothing about lemurs, I was surprised that Cathy was consulting with me, until she explained that the febrile lemurs in question were thrombocytopenic and had attached Amblyomma americanum, the tick that transmits E. chaffeensis and E. ewingii to animals and humans (One Health). Treatment with doxycycline resulted in disease resolution (Williams et al. 2002).

In 2013, I received a communication from a physician in Chicago, who requested to be entered into our Bartonella research study. After testing failed to implicate bartonellosis, at her request our research team targeted the DNA of other tick borne organisms. Molecular diagnostic testing confirmed E. chaffeensis, E. ewingii, and Anaplasma platys (Breitschwerdt et al. 2014) DNA in the woman, her daughter, and her dog's blood. Subsequently, A. platys was documented as a cause of other human infections (Maggi et al. 2013, Arraga-Alvarado et al. 2014). Investigation of this family provided the first molecular confirmation of chronic Ehrlichia species infection in humans.

Panola Mountain Ehrlichia, closely related to E. ruminantium, a serious tick borne pathogen of cattle in Africa and some Caribbean islands, was first described through collaborative One Health investigations in Georgia (Loftis et al. 2008). Subsequently suspected as a human pathogen (Reeves et al. 2008), Dr. Barbara Qurollo in our laboratory first documented infection with this organism in a dog with a progressive lymphocytosis, accompanied by thrombocytopenia (Qurollo et al. 2013). Testing documented clonal T cell expansion of intermediate to large lymphocytes, indicative of lymphoma. When Panola Mountain Ehrlichia DNA was amplified and sequenced from the dog's blood, chemotherapy was aborted. Treatment with doxycycline resulted in resolution of hematological abnormalities during a 2-year follow-up.

My primary motivation for generating this communication was to honor my mother, an amazing woman in so many ways. My other motivation is to add my voice to those of many who believe that tick and other vector borne pathogens are of substantially more medical importance than is currently appreciated. Both of my parents acquired E. chaffeensis infections on two different farms during their later years. I acquired R. rickettsii (RMSF) on my North Carolina farm from the same tick that transmitted E. chaffeensis to my parents (Breitschwerdt et al. 2011). Vector competence for A. americanum transmission of R. rickettsii was subsequently confirmed by Dr. Michael Levin, a vector ecologist at CDC (Levin et al. 2017). Both of my parents had DNA confirmed infections with one or more Bartonella species, a genus that continues to be underappreciated as a cause of animal and human suffering throughout the world (Breitschwerdt 2014, Cheslock et al. 2019). As in her life, Mom would want her story to benefit others after her death. We hope it does.