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Abstract
When Durland Fish studies tick-borne infections, he has a standard routine, one that simulates the way nature itself transmits bacteria - from tick to mouse and back again. "First," explains the Yale entomologist, "we take uninfected ticks and put them on infected mice. Those ticks become infected and when later placed on clean mice, transmit the bacteria to them." To make sure he's doing the experiment right, Fish does a parallel experiment using clean mice and ticks every step of the way. When the experiment works, ticks placed on the infected mice will acquire the microbe but those placed on the control mice will not.
| Lyme disease experimental controls revealed a new spirochete. |
For nearly 20 years, Fish has used his system to chart the complex biology of Lyme disease, caused by the spirochete Borrelia burgdorferi and transmitted by the Ixodes tick. But one day recently, something was out of place. "We put clean larval ticks on clean mice in the control part of the experiment," he recalls, "and when those ticks molted to the nymphal stage, we found they were filled with spirochetes." Viewing the spirochetes under the microscope, Fish guessed that they were B. burgdorferi. But subsequent DNA analysis showed he was wrong - the mystery microbes closely resembled B. miyamotoi, a relapsing fever spirochete from Japan, not the same as the ones that cause Lyme disease. Because it's unlikely that the Japanese spirochete could traverse the globe to infect ticks in New Jersey and New York, Fish suspects the microbe is something new.
Fish has since discovered that the new spirochete, still unnamed, is common. Present in New York, Connecticut, Rhode Island, and New Jersey, it accounts for 10 to 20 percent of all those bacteria previously thought to be B. burgdorferi, the proven agent of Lyme. "I've been looking at spirochetes for nearly 20 years, and I always assumed I was seeing Borrelia burgdorferi," he says. "But like everyone else, I was wrong. We were amazed that there was another organism right before our eyes and we never recognized it."
| Is this unnamed spirochete responsible for chronic Lyme disease? |
But still more notable is the potential for this unnamed spirochete, if implicated in human disease, to help explain the phenomenon of chronic Lyme disease, a condition that has provoked passionate debate in the medical community for years. Acute Lyme disease, marked by arthritic, neuropsychiatric, and cardiac symptoms, generally occurs after B. burgdorferi bacteria are transmitted via tick. But a subset of patients, about 10 to 20 percent of those diagnosed with the disease, do not respond to antibiotics or recover their health. Are they sick because they are still infected with B. burgdorferi sequestered deep within their bodies, because Lyme has triggered an autoimmune disease, or because of something else? While theories abound, a comprehensive explanation for chronic Lyme has never been found.
This new, unnamed spirochete could explain much. "We think this is a significant discovery," Fish states. "No one yet knows if the organism infects people, but if it does, it could explain a lot about unexplained illness." The numbers speak for themselves. "It turns out that between 10 and 20 percent of what we thought was Borrelia burgdorferi was not - it was this other organism," Fish explains. Meanwhile, it's estimated that between 10 and 20 percent of those with Lyme disease don't sufficiently respond to first line antibiotics, remaining symptomatic and becoming what's referred to as "chronic."
| The new spirochete may have caused 10-20% of Lyme cases. |
Could many of these individuals carry infection with the newly discovered spirochete and not Lyme disease at all? Fish believes it's possible. "Of 100,000 people with Lyme disease," he states, "we would expect between 10,000 and 20,000 to be infected with this other Borrelia instead." And while Fish suspects the new Borrelia responds to the same antibiotics as Lyme disease, he notes that success of the treatment would still depend upon where in the human body the new organism goes. "The antibiotics would work if they could get to it," he explains, "but that information is unknown."
Fish's new spirochete, moreover, is just one of half a dozen microbes traced, in recent years, to the Ixodes scapularis tick endemic throughout the Northeast and known to transmit Lyme disease. Residing in the tick alongside Fish's new, unnamed spirochete and its second cousin, B. burgdorferi, are the rickettsial infection ehrlichia and the bacterial infection bartonella, both known to gravitate to the brain and central nervous system, the malaria-like protozoan, Babesia, which lives in the blood, and a virus associated with encephalitis. Among the observations clarified by these coinfections, alone and acting in concert, are the diversity of reported symptoms; the varying patient responses to a range of different medications; and the lack of evidence, in some apparently infected individuals, for exposure to B. burgdorferi, the infectious agent of Lyme disease.
| The only clues were berrylike clusters in his white blood cells. |
One of the first to grasp the connection between tick-borne coinfection and inexplicable illness was Johan Bakken, a physician at St. Mary's Medical Center in Duluth in 1990, when an elderly man arrived with a high fever and what seemed like a severe case of the flu. Along with others on the St. Mary's staff, Bakken suspected the presence of a bacterial infection and treated the patient with high-dose antibiotics. Despite the treatment the patient declined rapidly, and three days later he died. What could be wrong with him? The only clue, the physicians said, were berrylike clusters inside his white blood cells.
Bakken soon realized the "berries" were similar to those characteristic of ehrlichiosis, caused by a rickettsiae just discovered in the Lone Star tick. The only problem was that Lone Star came from the South - certainly not Minnesota or northern Wisconsin, where the elderly man lived. After sending a sample of the man's blood to an expert in Texas, Bakken received confirmation of the seemingly impossible: the patient had had ehrlichiosis. Weeks later, when a second severely ill patient presented with a flulike illness and berrylike clusters in the blood, Bakken treated with the antibiotic tetracycline, known to cure ehrlichiosis, instead of the antibiotics used for the dying man the month before. This time, the patient's spiking fever plummeted overnight and the condition resolved.
| Northern erlichiosis is transmitted by the deer tick. |
Hoping to learn how his decidedly northern patients had contracted a disease thought endemic to the South, Bakken sent some blood down to Galveston, Texas, where a scientist named Stephen Dumler, now director, Division of Medical Microbiology, Department of Pathology, the Johns Hopkins Medical Institutions, was put on the case. "Within five minutes of examining the samples," Dumler reports, "I was convinced it was something completely different from the human ehrlichiosis we had already identified." The difference Dumler ultimately documented was in the white blood cells. The southern version of the disease infected white blood cells called monocytes, but samples from the North showed infection in a different type of white blood cells called granulocytes. Dumler's research has since revealed that the northern version, called human granulocytic ehrlichiosis, or HGE, is caused by the rickettsiae Ehrlichia phagocytophila and is transmitted by the deer tick in Minnesota, Wisconsin, and throughout the East.
Peter Krause, specialist in pediatric infectious disease at the University of Connecticut, meanwhile, reports a fourth tick-borne infection - the protozoan parasite Babesia microti. Krause started studying the pathogen 15 years ago, after writing a chapter on it for a textbook. Today, Krause and his colleague, Harvard entomologist Andrew Spielman, have added significantly to our knowledge of the disease: Babesia is part of the disease reservoir sustained by the white-footed mouse and, like Lyme disease, is transmitted by the Ixodes tick. B. microti is found in abundance in southern New England and New York, including the Connecticut, Rhode Island, Massachusetts shoreline, and eastern Long Island, and in Minnesota and Wisconsin as well; different species of the parasite can be found in Missouri, California, and Washington State. "Most people don't realize," Krause adds, that the prevalence of this infection has been "greatly underestimated."
| Patients can have babesiosis and Lyme disease simultaneously. |
Though babesiosis and Lyme disease are transmitted by the same tick, Krause states, they differ in terms of symptoms and treatment protocol. Lyme disease can present with a rash, while Babesia does not. Both may cause flulike illness, including fever and sweats. Lyme disease is treated with amoxicillin and doxycycline, while Babesia requires combination therapy with either clindamycin and quinine or azithromycine and atovaquone. "For patients with both Lyme disease and babesiosis," he states, "the best strategy is to treat both diseases simultaneously." This is especially important "because patients with Lyme disease and babesiosis experience more symptoms for greater duration than patients with Lyme disease alone."
Finally, scientists have traced the microorganism, Bartonella henselae, to the disease spectrum of chronic Lyme. The most compelling report comes from Eugene Eskow, a New Jersey physician whose recent publication in the American Medical Association's Archives of Neurology describes several patients suffering continuous headaches, memory loss, fatigue, and joint pain despite treatment for Lyme [1]. Eskow already knew that Bartonella, a cause of cat scratch fever, transmitted through the scratch or bite of a cat, could be found in the same species of wild mice that serve as reservoirs for Lyme disease. He'd read that Dutch and Polish scientists had found the microbe in abundance in ticks. Could the presence of Bartonella be responsible for the persisting symptoms in some patients still symptomatic after standard treatment for Lyme disease? To find out, he tested four such patients without recent exposure to cats and found evidence of the microbe in their spinal fluid and blood.
| Antibiotic treatment for Bartonella has cured persistent Lyme disease. |
For all these patients, treatment with antibiotics not commonly used for Lyme disease itself made all the difference. Take the case of a 14-year-old boy who came to Eskow with gradually worsening knee pain, headaches, and fatigue. At first, with negative tests for Lyme, as well as Babesia, the boy was treated empirically with a 6-week trial of the antibiotic doxycycline to no avail. Unable to find a problem in the boy's brain scan, Eskow ran further tests and found Bartonella-specific DNA in his central spinal fluid and blood. The boy was treated with 6 weeks of the antibiotic cefotaxime sodium, and his symptoms promptly resolved. Another patient, a 15-year-old girl with a history of Lyme disease, had begun to relapse following an 8-week course of treatment with oral doxycycline. After she tested positive for Bartonella, Eskow treated her with intravenous azithromycin, a medication shown in the peer-reviewed literature to be effective against Bartonella, and in 14 days her symptoms, too, resolved.
Alone and in combination, the pathogens covered here are likely to make us ill. Yet for each known infection, another tick-borne pathogen may be awaiting discovery in the wings. "We are just starting to understand the full range of infections that we might get," says David Persing, widely recognized for his work in detecting vector-borne infections by polymerase chain reaction, or PCR, first at the Mayo Clinic and now as vice president of molecular biology at Corixa Corporation and medical director of the Infectious Disease Research Institute in Seattle, Washington. "I don't think we know half of the agents that are potentially transmissible by ticks."
| Active B. burgdorferi weren't found in chronic Lyme patients. |
Despite evidence that a growing menagerie of coinfections can explain unresolved diseases, the argument over chronic Lyme continues unabated, often without a nod to the findings from the field. The debate was fueled in recent months by a National Institutes of Health (NIH) study on treating chronic Lyme with a specific course of therapy - one month of the intravenous antibiotic Rocephin followed by two months of the oral antibiotic doxycycline, both recommended for acute Lyme disease [2]. The study team at New England Medical Center and Tufts University found the treatment protocol ineffective for the chronic patients in the trial. Testing these subjects for DNA evidence of active B. burgdorferi infection, the scientists came up empty-handed as well. "Experience with other chronic infectious diseases caused by persistent bacteria," the Tufts team concluded in the New England Journal of Medicine, "suggests that it is unlikely that more prolonged antibiotic therapy or a different combination of antibiotics would result in greater improvement than was observed in this study." The clear implication: in terms of chronic Lyme, active bacterial infection is unlikely to be an issue at all.
What, then, could be wrong? "Researchers should investigate autoimmune and other processes to determine whether they play a role in a least some of the symptoms of chronic Lyme disease," the Tufts researchers suggest.
| The auto-immune hypothesis is the "chronic disease theory-of-everything." |
One such theory holds that Lyme disease converts to chronic fatigue syndrome or fibromyalgia, poorly understood entities with Lyme-like symptoms but no known cause or cure. Another hypothesis is a "chronic disease theory-of-everything," in which antibodies generated from infection recognize not just the invading organism but also human cells. The human cells, the theory goes, are lined with "molecular mimics," molecules so similar in structure to those of foreign organisms that the immune system becomes confused and attacks the patient even after the invading microbe is gone. It is "autoimmune" disease, say advocates of this idea, that accounts not just for lupus and multiple sclerosis, but also chronic Lyme.
Yet many infectious disease specialists believe such theories may be difficult, if not impossible, to prove. Persing, for instance, calls the possibility of autoimmune damage by cross-reactivity with a human protein "remote." "There is probably some cross-reactivity with almost every infectious agent we encounter," he states. "If this were a significant factor, we might all die of autoimmune disease at age three upon getting any number of viral infections. The immune system is smarter than that. Based on the evidence, it's still too early to say whether this is happening at all."
| "We might also need to consider the persistence of other infections." |
"Most of the time, Borrelia burgdorferi bacteria will clear the system, especially with antibiotics," Persing adds. "When nonspecific symptoms do not resolve, we feel that may be due to a subtle immune deficiency we have not successfully identified or possibly the persistence of proinflammatory components of the dead organisms. But we might also need to consider the persistence of other infections that we have not identified, especially those spread by the same tick." Ehrlichia, Babesia, and Bartonella are some of the culprits Persing points to, along with a potential host of other organisms yet to be found.
Alan Barbour, professor of infectious disease at the University of California at Irvine, and one of the world's top experts on tick-borne disease, thinks coinfections may explain many patient reports as well. "I agree with Dave Persing that coinfections, especially with Babesia, could contribute to the symptom complex that is popularly referred to as 'chronic Lyme,'" he states, insisting that quotation marks be put around his use of the term because the Lyme disease spirochete, B. burgdorferi, may or may not be involved. "Lyme disease is caused by Borrelia burgdorferi, period," says Barbour, "but chronic Lyme is a broad and complex phenomenon that may include other tick-borne infections."
| "The new Borrelia may be transmitted more efficiently." |
Given its recent dismissal of active infection as a cause of chronic Lyme, the Tufts team may have to revisit or, at least, qualify its work. The scientists studying chronic Lyme, for instance, reached their conclusions without checking for Bartonella, even though tests were available. And while no one yet knows whether Fish's new Borrelia causes human disease, the study scientists did not consider this possibility, let alone test for the organism. How could they? It had not been discovered when they did the bulk of their work, and even now, a test does not exist. "Technically, the study was correct in its conclusion that patients had no DNA evidence of living Borrelia burgdorferi," says Fish, but it is impossible for these researchers to know, absolutely, that their subjects carried no active tick-borne infection at all. While we have no way of knowing how or even if the new Borrelia plays a role, he adds, "it's worth noting that it infects mice, and every organism we have been able to transmit to mice has affected people as well." What's more, the new Borrelia should be transmitted more efficiently than B. burgdorferi, he says. "The reason is that B. burgdorferi must travel from the tick gut to its salivary glands to infect people and that takes some time, but the new Borrelia live in the salivary glands from the start."
Despite his intriguing discovery, Fish cautions that without more evidence, physicians must resist the temptation to assign all chronic Lyme disease to other tick-borne pathogens. "There is really no reason to suspect tick-borne over other infectious agents that are new or unknown," he states, adding that "some experts believe chronic Lyme is no different and no more prevalent than the spectrum of nonspecific complaints found in populations outside Lyme endemic areas. Should we blame ticks for all unexplained illness?"
| When symptoms persist, coinfection must be investigated. |
Yet for those remaining ill following treatment for Lyme disease, coinfection must be investigated and ruled out. "The persistent symptomatology might be attributed to several factors - first, coinfections," Eskow says in the Archives of Neurology article. "In addition to transmitting B. burgdorferi, a tick may harbor other pathogens, including Babesia, Ehrlichia, and Bartonella species. These multiple pathogens may survive Lyme antimicrobial therapy and be responsible for the persistent symptoms in individuals with post-Lyme syndrome. The importance of considering these coinfecting agents in the differential diagnosis cannot be overstated."
The first step in clarifying the situation, says Barbour, would be to study each tick-borne microbe and the disease it causes individually in the lab. It's important to know the specific infection you are targeting and the disease you have connected it with in any effort to determine whether or not specific antibiotics over any given time frame will work, he explains. "I think we need to get back to an organism-based definition of the infection," states Barbour, and when it comes to treating disease, "we need a more empirical approach to conditions that don't fit in that diagnostic box."
| "These pathogens interact." |
Fish goes further still. After the microbes have been studied individually, he notes, we've got to understand the ways in which they interact with each other - in nature, in other animals, and within ourselves. "We know these ticks transmit more than one pathogen at a time," he states, and that inside the human body, "these pathogens interact."
As with most scientific quests, says Barbour, "there is still a lot to learn, but at least there are organisms identified. It remains for researchers to understand what happens when someone is infected with more than one of them at a time."
Pamela Weintraub is a former staff writer at Discover, former editor-in-chief of Omni Internet, and the author of 15 books on health and science.
Targeting Lyme Disease Bacterium - a brief report of a second major Borrelia antigen, OspC. From Trends in Biochemical Sciences, 2001, 26:4:222. Full text available from BioMedNet.
Borrelia Pathogenesis Research in the Post-Genomic and Post-Vaccine Era - reviews recent data about the parasite that causes Lyme disease. From Current Opinion in Microbiology, 2000, 3:86-92. Full text available from BioMedNet.
Host-Pathogen Interactions Promoting Inflammatory Lyme Arthritis: Use of Mouse Models for Dissection of Disease Processes - reviews recent research. From Current Opinion in Microbiology, 2001, 4:3:274-279. Full text available from BioMedNet.
Lyme Disease, Babesia Infection, and Human Ehrlichiosis in the United States - covers the history, prevention, treatment, diagnosis, and epidemiology of these diseases. From the Centers for Disease Control.
American Lyme Disease Foundation - provides prevention and education information for patients.
Lyme Disease Foundation - nonprofit medical health-care agency dedicated to finding solutions to tick-borne disorders.
Lyme Disease Network - offers news, abstracts, and resources.
Vector Ecology Laboratory - covers current research on tick ecology and tick-borne pathogens.
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