news Feature http://www.nature.com/naturemedicine Nature Publishing Group Group 200 8 Nature Publishing © The chronic debate over

A small group of doctors—and a large number of patients—say Lyme disease can sometimes manifest as a chronic illness, one that evades conventional medical tests and treatments. The physicians who support this theory flout standard medical guidelines and treat patients with long-term therapies that mainstream researchers say are unproven and potentially dangerous. Coco Ballantyne reports on how the controversy over Lyme disease has become increasing polarized.

It was 1994 and life could not have been better began stalling. “I began to forget,” she says. came day and night, causing embarrassing for Alita Lyons, an aspiring biochemist from “I’d be running an experiment that I had done breaks in conversations and jolting her out Manhattan. As a child, Lyons had dreamed of 1,000 times. I would get halfway through, of deep slumber. working in science, and now, at age 27, she take a break and then come back with no clue As the years passed, Lyons kept pushing had landed her dream job: studying hepatitis where I had left off.” Peering at the rows of herself in the lab, publishing studies and C in a laboratory at the Weill Medical College test tubes she had organized just hours before, even becoming a first author on a well of Cornell University in New York. All day and Lyons would wonder, ‘What’s inside those received research paper3. But her neurological sometimes late into the night, Lyons sat at the tubes, and why are they arranged like that?’ problems were worsening all the time. Some lab bench pipetting chemicals into test tubes The memory lapses were intermittent, but days she would leave the lab to run errands, get and running carefully controlled experiments. other symptoms emerged, including fatigue, lost on city streets she had walked hundreds “It was a typical high-end, high pressure insomnia and involuntary muscle twitching. of times and then have to call friends for laboratory,” Lyons says. “I loved it.” Most people are familiar with the abrupt help navigating back to work. Lyons sought A year or so into the job, Lyons’ experiments muscle contractions that can happen while medical help from distinguished doctors at were humming along smoothly, but her mind falling asleep, but, for Lyons, the twitches Cornell University, Columbia University and

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private physicians in New York. Between 1995 has “major problems with attention, slowed actually pinned down: a corkscrew-shaped and 2004, she says she visited approximately processing speed and memory,” a level of bacterium that came to be called Borrelia 20 doctors. They diagnosed her with diseases impairment that “would make her unable to burgdorferi in honor of its discoverer, Willy ranging from epilepsy to bipolar disorder and work at this time.” Burgdorfer3. prescribed an assortment of medications, Like Lyons, the individuals in this support Lyme disease has since become the most none of which helped. group firmly believe that Lyme disease can be a common tick-borne infection in North Finally, nearly a decade after the symptoms chronic illness caused by a persistent infection America. Last year, the CDC received more than first surfaced, a doctor asked Lyons what that resists treatment. They say the scientific 27,000 reports of the disease, though the true may have seemed to be a string of irrelevant evidence has been spun by the mainstream number of cases is probably much higher, says questions: “Where did you grow up? Where medical establishment to deny the existence CDC epidemiologist Kevin Griffith. The vast did you spend your summers?” Lyons replied of ‘chronic Lyme disease’ and to invalidate the majority of cases occur in the Northeast, the that she had spent nearly every summer of her only treatment that has offered them some Midwest and coastal regions stretching from life on Fire Island, a popular beach destination reprieve: long-term antibiotic therapy. California to Oregon. The disease is also off the southern coast of Long Island. Travel relatively common in Europe, where scientists guides highlight the island’s undulating sand It started in Lyme believe the Lyme bacterium originated4. dunes and pristine wilderness, but they fail In the mid-1970s, doctors in Connecticut Deer ticks, particularly the poppy seed–sized to emphasize that it’s teeming with ticks. began seeing a mysterious pattern of childhood immature ‘nymph’ forms, are tough to spot According to some sources, the 32-mile sliver disease. Clusters of kids living in and around in the shaded woody areas they inhabit. The of land boasts the highest density of deer ticks a town called Lyme were coming down with bites don’t hurt much, so they can easily go of any national park area in the eastern US. joint swelling, pain and other symptoms that unnoticed, particularly if they occur on the The doctor ordered a blood test for Lyme suggested juvenile rheumatoid . The scalp. As the tick sucks in a hearty blood meal, disease, a tick-borne bacterial infection children tended to live near dense woodland it may in turn infect its host with whatever

http://www.nature.com/naturemedicine typically associated with a skin rash, which can areas populated by deer and field mice— microbes may be lurking in its saliva. The Lyme lead to a variety of severe symptoms including animals known to harbor black-legged ticks— bacterium is just one of many disease-causing arthritis and facial paralysis. He told her that and the outbreaks were roughly synchronized bugs that ticks can carry. There are others, she had tested positive for Lyme disease—that with the tick’s feeding cycles. Before the such as babesiosis, a malaria-like parasite that is, positive according to criteria set by the lab onset of arthritis, some of the children had invades red blood cells and whose symptoms that ran the tests. But when judged against developed strange circular rashes where they range from none at all to death5. criteria established by the US Centers for had been bitten by ticks. Lyme disease announces itself in a variety Disease Control and Prevention (CDC), the Connecting the dots, and of ways. Days to weeks after the initial tick results were negative, the doctor acknowledged. his colleagues from Yale University School bite, a person may develop a reddish skin rash And it was the CDC she believed. “I laughed at of Medicine realized that the mysterious called erythema migrans, often resembling him and called him a quack,” she says. childhood arthritis was caused by an infection a bull’s eye with a spot in the middle and a Scientific curiosity drove Lyons to begin transmitted through the bite of a tick2. But it larger surrounding ring. There may be other reading the peer-reviewed literature on Lyme was not until 1981 that the disease agent was early symptoms, including flu-like malaise Nature Publishing Group Group 200 8 Nature Publishing disease. She attended lectures where she met © people with symptoms that were strikingly similar to her own. Eventually she returned to the doctor she had written off and agreed to take another test for Lyme disease—and this time the results came back positive according to CDC standards. Since 2005, Lyons has been on and off oral and intravenous (IV) courses of . She says the drugs have made her feel “95% better,” eradicating some symptoms, although others creep back when she stops treatment. “The disease had been in my body for years,” Lyons says, as she sits among members of a New York City–based Lyme support group; men and women, young and old, all of whom look perfectly healthy. “It’s a problem that we all look so well,” Lyons says. “You’d never believe it unless you had the disease.” A young woman sitting across the table nods her head in agreement; an IV pokes into her arm, pumping a steady current of antibiotics into her bloodstream. “This is really

physiological,” says Lyons, offering as evidence Ballantyne Coco by Photo a neuropsychological exam by doctors at Around the clock: Jones sees patients all day and then spends the evenings handling his legal Columbia University, which indicated she defense against the Connecticut Department of Public Health.

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and body aches. Some people experience heart block, an interruption of the electrical signals that keep the heart pumping at a steady beat. B. burgdorferi can also set up shop in the nervous system, causing temporary paralysis of face muscles or numbness and tingling in fingers and toes. The bug has a penchant for the membranes surrounding the brain and spinal cord and occasionally causes meningitis. If weeks to months go by and the disease goes untreated, sporadic attacks of joint pain and swelling, usually in the knee, may ensue—a sign that the bacterium is living in the body’s collagen-rich connective tissues. Years after the initial tick bite, some patients—including those who received treatment—say they continue to suffer from debilitating neurological problems, including oppressive fatigue and memory loss.

Some claim Lyme can be chronic Istockphoto On a desolate corner in New Haven, Look for the signs: Ticks hide in marsh areas among other places outdoors

http://www.nature.com/naturemedicine Connecticut lies a brown apartment building housing one of the most controversial and And as for therapy, Jones believes that Last year, the Connecticut Medical celebrated Lyme doctors in the US. Pediatrician patients should be given antibiotics, either Examining Board voted to place Jones on Charles Ray Jones says he has treated over orally or intravenously, for two months probation and imposed a fine of $10,000 for 12,000 children for Lyme disease and other beyond the point at which all symptoms have violating standards of diagnosis and treatment tick-borne infections. “The children come disappeared. That could mean several months, for Lyme disease. The court has temporarily from every single state in America, from every or even years, depending on the individual’s stayed the implementation of the order province in Canada, from South America, infection. pending an appeal by Jones to reverse the Central America and every continent abroad,” At the crux of this open-ended treatment decision. Meanwhile, he is fighting a new set Jones says, peering from behind his Coke- philosophy is the notion that the Lyme of complaints by the Connecticut Department bottle glasses. Jones is 79 years old and walks bacterium is exceedingly difficult to kill once of Public Health. The allegations include with a limp, but the royal blue jogging suit he it invades the body. B. burgdorferi has evolved prescribing a patient six weeks of antibiotics wears belies his age. An inscription sewn into to elude both antibiotics and the immune without first conducting a clinical examination Nature Publishing Group Group 200 8 Nature Publishing the back of his jacket reads, “Dr. Charles Ray response, Jones says—“the Lyme bacterium (Jones has since ceased prescribing medications © Jones: Keep marching to fulfill the dream”—a has a lot of nifty ways of surviving, and one without first examining patients in his office, gift from one of the families who have rallied is to lose its outer surface protein coating and according to his office manager). With three behind him in a rebellion against mainstream become pleomorphic [capable of changing lawyers working on the cases, the bill has medicine. form].” He cites studies suggesting that the amounted to thousands of dollars, according Jones contends that the mainstream medical bug has chameleon-like qualities, morphing to Jones. But judging from the scores of community does not appreciate the magnitude between its normal spiral shape and a pictures of smiling kids and homemade thank- of the Lyme disease epidemic, and he believes spherical cystic form6. And because the Lyme you notes covering his office walls, Jones is that the CDC surveillance criteria commonly bug is such an adept survivor, it may cause not alone in the fight. Patients and supporters used for diagnosis allow many severely ill persistent infections even after antibiotic have donated over $200,000 dollars to his legal individuals to slip through the cracks. He treatment, Jones reasons. Researchers have fund, Jones claims. describes some of the children he treats for reported finding the Lyme bacterium in Lyme disease: kids once vigorous and sharp the blood of individuals who have received Chronic Lyme—a hoax? who can no longer get out of bed or concentrate extended antibiotic treatment7, but critics A few miles from the rainbow-decorated walls on their homework. Yet, according to the CDC, claim that other scientists have not been able of Jones’ office, a giant Lego elephant ushers many of these kids do not have Lyme disease. to reproduce the results8. visitors into the Yale-New Haven Children’s To diagnose his patients, Jones relies heavily Jones belongs to small group of self- Hospital. Children with Lyme disease come on clinical judgment and uses laboratory proclaimed ‘Lyme literate’ doctors whose to this institution to see Eugene Shapiro, a analyses that diverge from CDC tests, which treatment approaches fly in the face of standard professor of pediatrics, epidemiology and look for proteins produced by the immune guidelines laid down by the Infectious Diseases investigative medicine. Shapiro helped write system in response to the Lyme bacterium. Society of America (IDSA). The guidelines, the IDSA guidelines, and his perspective on Jones says the CDC diagnostic criteria leave which most doctors elect to follow, recommend Lyme disease could hardly be more different out several key proteins that signal a Lyme no more than a few weeks of antibiotics for from that of Jones. infection, so he sends patient blood samples treating almost all cases of Lyme disease9. In According to Shapiro, the CDC criteria are to specialized laboratories that screen for a the last few years, Jones’ unorthodox protocols reliable for diagnosis, and Lyme disease is broader array of proteins. have landed him in deep legal trouble. almost always easy to treat with a few weeks

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of antibiotics. “B. burgdorferi is highly sensitive truly double blinded12. Considering the risks placebo had small sample sizes and only lasted to antibiotics,” both in vitro and in the body, associated with taking potent antibiotics, the for up to 90 days, says Smith, noting that other Shapiro says. “Most of the patients with overall message from these four studies is that complex infections such as tuberculosis and ‘chronic Lyme’ have no evidence of ever having there is no sustained benefit from long-term leprosy require treatments ranging from 6 to had Lyme disease,” he says. And although they antibiotics, concludes Adriana Marques, chief 36 months. may complain of subjective symptoms such of clinical studies at the Laboratory of Clinical The LDA and other Lyme advocates have as pain and fatigue, they often lack objective Infectious Diseases at the US National Institute rejected the IDSA guidelines and embraced signs that a doctor needs for diagnosing a of Allergy and Infectious Diseases13. an alternative set created by the International disease. “This does not mean these people are But how does one reconcile this clinical trial Lyme and Associated Diseases Society (ILADS), not suffering, only that active infection with B. evidence with the myriad people like Alita Lyons a nonprofit medical society headquartered in burgdorferi is not the cause,” Shapiro says. claiming that antibiotics are their only recourse Bethesda, Maryland. The authors of the ILADS Then what do these people have? “Medically from crushing fatigue, unbearable pain and guidelines recognize chronic Lyme disease and unexplained symptoms,” Shapiro says— other disabling symptoms? “Antibiotics tend to condone the use of antibiotic therapy lasting symptoms such as fatigue and pain that are have other effects,” including anti-inflammatory several months, and they have a library of relatively common in the general population and neuroprotective properties that could scientific literature to back them up. However, but are not caused by a persistent Lyme potentially mitigate arthritic and neurological other researchers assert that studies frequently infection. In fact, some research suggests that symptoms, says CDC epidemiologist Kevin referenced by ILADS have not been subjected up to 15% of the general population may Griffith14. Furthermore, symptoms of chronic to rigorous peer review. “Much of what they suffer from chronic pain and 8% from chronic illness naturally tend to wax and wane, which cite is in more obscure journals,” and contains fatigue10. As far as treatment goes, there is “no may lead patients to attribute ups and downs data “difficult for an outsider to interpret,” evidence that long-term antibiotics for people to changes in their antibiotic regimens. And, says infectious disease specialist William with ‘chronic Lyme disease’ is of any benefit finally, many infections leave enduring effects Bowie of the University of British Columbia

http://www.nature.com/naturemedicine and much evidence of harm to both the on the body after they are cleared up, Griffith in Vancouver, British Columbia. individual and society,” says Shapiro, noting says—“it’s not unique to Lyme.” Lyme disease groups have sharply criticized that overuse of antibiotics can set the stage for But Lyme advocacy groups insist that the IDSA guidelines, which they say restrict the evolution of drug-resistant bacteria. antibiotics are helping kill off the bacteria doctors’ ability to treat the illness and provide There are now four double-blind, placebo- still living in the bodies of individuals with insurance companies with a basis for refusing controlled clinical trials testing long-term chronic Lyme. “The notion that patients are coverage for long-term antibiotic therapy. In antibiotic therapy on subjects who have been responding to anti-inflammatory effects rather fact, the LDA says that 38,000 people signed treated for Lyme disease but still suffer from than antibacterial effects of antibiotics is just an a petition on its website protesting the IDSA ongoing symptoms. One of those studies found unproven theory,” says Pat Smith, president of guidelines. And when the Lyme community that prolonged therapy with the antibiotic the US Lyme Disease Association (LDA). “On rallied for an investigation, the Connecticut ceftriaxone boosted cognitive function the other hand, we do know that antibiotics Attorney General delivered. for subjects, but they relapsed when they are effective for treating infection”—and stopped taking it11. Another trial suggested infections are know to cause inflammation, Trouble in the court Nature Publishing Group Group 200 8 Nature Publishing that ceftriaxone might reduce fatigue, but Smith adds. Studies suggesting that long-term In 2006, Connecticut Attorney General © some critics question whether that trial was antibiotics are no more effective than the launched an antitrust investigation of the IDSA’s process for writing its Lyme disease guidelines. The probe, which ended in a settlement this May, unearthed “undisclosed financial interests held by several of the most powerful IDSA panelists,” including ties to insurance companies, according to statements released by Blumenthal’s office. The link is important since insurers often refuse Lyme disease patients coverage for long-term antibiotic treatments. And, at the end of the 2006 IDSA guidelines, one comes upon a “potential conflicts of interests” section where authors offer disclosures. But documents obtained by Nature Medicine through a Freedom of Information Act request indicate that certain panel members failed to reveal potential conflicts of interest. The Connecticut Attorney General’s office found multiple financial links between panelists and companies that make Lyme disease diagnostics. This is important because the

Newscom guidelines say that there is no convincing after treatment evidence that the Lyme bacterium Spiraling out of control: The bacterium causes Lyme disease causes persistent symptomatic infections, or

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this year, Barthold and his colleagues published a study suggesting that a nondividing but infectious form of B. burgdorferi may persist in mammals even after one month’s treatment of antibiotics. After giving ceftriaxone to mice infected with B. burgdorferi, the researchers exposed those mice to ticks. Not only did the ticks become infected; they transmitted the Lyme bacterium to other mice that had never been exposed to it before16. Another study published this summer by Benjamin Luft’s team from Stony Brook University in New York identified the most common strain of the Lyme bacterium in the US17. On the basis of his findings, Luft suspects that “different strains have different capacities to cause disease,” and the diversity in strains could potentially explain why certain antibiotics don’t work well for some people, he adds. A recent study published this month by Mario Philipp and his colleagues from the Tulane National Primate Research Center in Covington, Photo by Coco Ballantyne Coco by Photo http://www.nature.com/naturemedicine Louisiana suggests that the Lyme bacterium All suited up for fighting Lyme: Parents from Florida gave this jogging suit to Charles Ray Jones to provokes cell death in the nervous system18. thank him for treating their two children. When Philipp’s team cultured B. burgdorferi in brain tissue taken from nonhuman primates, ‘chronic Lyme’—an assertion that hinges on People like Lyons feel cast aside by doctors who the bacteria induced inflammation and caused the assumption that the standard diagnostic tell them their disease is psychosomatic and cell death. “This is the best evidence we have tools are adequate. insurance companies that deny them antibiotic that B. burgdorferi can induce death in neuronal Additionally, according to a statement from treatment. Jones and his compatriots believe they tissues,” Philipp says. the attorney general’s office, “the IDSA’s guideline are helping patients in dire need and that their The clinical implications of such research—if panel improperly ignored or minimized standards of practice are supported by sound there are any—have yet to be determined. But consideration of alternative medical opinion science. Shapiro, on the other hand, thinks the Lyons is convinced that she and other patients and evidence regarding chronic Lyme disease,” IDSA guidelines were formulated with unbiased will be vindicated. “When the truth comes out, excluding evidence suggesting the existence of peer-reviewed research, whereas the science it’s really going to be one of the most astounding Nature Publishing Group Group 200 8 Nature Publishing chronic Lyme disease and blocking participation frequently cited by ILADS and Lyme literate stories in science.” © by scientists and doctors with alternative views. physicians is not rigorous or easily reproducible. The attorney general’s office “has no opinion Meanwhile, some researchers have criticized 1. Lyons, A.J. & Robertson, H.D. J. Biol. Chem. 278, 26844–26850; 2003. on the science” itself, emphasizes spokesman the media for fanning the flames of controversy 2. Steere, A.C., Broderick, T.F. & Malawista, S.E. Am. J. Christopher Hoffman. by feeding the public uncritical accounts of Epidemiol. 108, 312–321; 1978. The IDSA, meanwhile, stands by its guidelines. individuals rebuffed by mainstream medicine 3. Burgdorfer, W. et al. Science 216, 1317–1319; 1982. 4. Margos G. et al. Proc. Natl. Acad. Sci. 105, 8730–8735; “We don’t think there is anything wrong with but then saved by a sympathetic doctor willing 2008. the way the panel was assembled or the way to prescribe long-term antibiotic therapy15. 5. Vannier, E., Gewurz, B.E. & Krause, P.J. Infect. Dis. Clin. North Am. 3, 469–488; 2008. they conducted their deliberations,” says IDSA “No one is absolutely correct on this. There 6. Brorson, O. & Brorson, S.H. Infection 25, 240–246; spokesman Steve Baragona. “We don’t agree is some truth to everybody’s story,” says 1997; Alban, P.S., Johnson, P.W. & Nelson, D.R. at all that there is anything wrong with these Stephen Barthold, who directs the Center for Microbiology 146, 119–127; 2000. 7. Phillips, S.E., Mattman, L.H., Hulínská, D. & Moayad, guidelines,” he says. The evidence we have now Comparative Medicine at the University of H. Infection 26, 364–367; 1998. is pretty solid that long-term antibiotics are not California, Davis. But sadly, Barthold says, the 8. Feder, H.M. Jr. et al. N. Engl. J. Med. 357, 1422–1430; the answer.” discussion about Lyme disease has devolved 2007. 9. Wormser, G.P. et al. Clin. Infect. Dis. 43, 1089–1134; Nevertheless, the IDSA has agreed to cooperate into an ‘it’s them against us’ mentality. “This 2006. with Blumenthal in assembling a review panel disease is difficult,” he notes. “Further studies 10. Aggarwal VR, et al. Int. J. Epidemiol. 35, 468–476; 2006. to reassess the 2006 Lyme disease guidelines and are needed.” 11. Fallon, B.A. et al. Neurology 70, 992–1003; 2008. amend or change them if necessary. A neutral Barthold has hit upon the one—and 12. Krupp L.B. et al. Neurology 60, 1923–1930; 2003. ombudsman chosen by the attorney general’s perhaps the only—point that most everyone 13. Marques, A. Infect. Dis. Clin. North. Am. 2, 341–360; 2008. office and the IDSA will oversee the selection agrees upon: research is paramount. The 14. Rothstein, J.D. et al. Nature 433, 73–77; 2005. of the panel members to ensure they have no Lyme advocacy community is clamoring for 15. Bowie, W.R. Drugs 67, 2661–2666; 2007; Feder, H.M. conflicts of interest. more research. “I think there needs to be more Jr. et al. N. Engl. J. Med. 357, 1422–1430; 2007. 16. Hodzic, E. et al. Antimicrob. Agents Chemother. 52, medical research on medically unexplained 1728–1736; 2008. Moving forward symptoms,” Shapiro says. 17. Qiu, W.G. et al. Emerg. Infect. Dis. 7, 1097–1104; 2008. Few medical issues have been as rife with Lately, scientists studying Lyme disease have 18. Ramesh, G. et al. Am. J. Pathol., doi:10.2353/ controversy and bitter feelings as Lyme disease. been churning out interesting results. Earlier ajpath.2008.080483; 2008.

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