Lyme

by Mary Beth Pfeiffer

Seronegative is a rejected word in the modern debate over Lyme disease, at least on the side that believes the disease is easily diagnosed and the pathogen, killed by limited antibiotics. But the notion that actively infected people might test negative wasn’t always anathema. In 1988, the New England Journal of Medicine ran a different article, entitled “Seronegative Lyme Disease,” with Raymond Dattwyler as the lead author. Dattwyler and five coauthors had studied seventeen patients who, after early treatment for Lyme disease, had developed cases the paper called “chronic,” another term that has been soundly rejected. The patients were infected, the researchers believed, even though their test results were no different from normal controls. “The presence of chronic Lyme disease cannot be excluded by the absence of antibodies against B. burgdorferi,” they wrote. Instead, they cited other immune responses in their patients—similar to what nontraditional Lyme doctors do—as “evidence of infection.”

  The divergent paths taken by physicians on that paper says a lot about the Lyme debate. When I asked Dattwyler about the seronegative concept, he disavowed the paper as a product of a naïve time in Lyme history. “We didn’t know all the nuances that were built into that stupid organism,” he said. But two of the other authors, David Volkman and Benjamin Luft, still believe it to be true: some people with the bug don’t test positive. I told Luft of Dattwyler’s dismissal of the paper they coauthored. He said, “I don’t know what the hell he’s talking about.”

  In late November of 2016, one of the nation’s leading Lyme disease pediatricians, at least according to prevailing thought, gave a by-the-guidelines talk at a New York City symposium entitled “Infectious Diseases in Children.” Here, Eugene Shapiro, a balding, white-bearded professor at Yale School of Public Health, told his audience of physicians that Lyme rashes show up in lots of different ways, which is a contention of patient advocates who say atypical Lyme rashes are often written off. “Do not think a patient must have a bull’s-eye rash for it to be erythema migrans,” he said. Fine so far. But then Shapiro lapsed into the not-to-worry, Lyme-is-overblown themes that have characterized Lyme dogma. Don’t think every rash you see is Lyme disease, he said, citing eczema, ringworm, and cellulitis as possible candidates.

  But it was when he told the group the following that my mouth dropped. According a to Healio News release, “Shapiro further noted there are no symptoms on their own that should give a pediatrician reason to test for positive results.” Children with body aches, headache, and fatigue usually have something else; “the vast majority of the test results are going to be false positive results,” Shapiro said

  In giving this advice, Shapiro, an author of the Infectious Diseases Society’s Lyme disease guidelines, followed logic that has been so ingrained into the treatment culture that its flaws seem perfectly reasonable. The IDSA logic hinges on an unreliable rash to make a diagnosis. For those without a rash, it forgives tests that aren’t reliable early on but holds they sooner or later will work. This logic lets the spirochete disseminate throughout the body. It holds that diagnosis is nearly foolproof in late stages. So test later. What’s the harm?

  When I asked Shapiro about his comments, he surprised me again. The test was not the problem; the problem was how it was used—its so-called “predictive value.” The test works well on patients with a high risk of tick-bite and specific, measurable signs of illness, like a swollen knee or facial palsy, and not so well on patients with vague complaints. “I’m talking about people with symptomology that’s going on for a little while,” he told me. “It’s a very good test later on.”

  This scenario, of course, leaves out children whose bodies hurt but have no rash. It leaves out patients with joint pain, depression, cognitive issues, and lethargy. The test does not fail these folks, Shapiro believes; if they don’t ever show some objective sign, they simply do not have Lyme disease.

  Shapiro’s philosophy, as told to a roomful of health-care practitioners who would no doubt bring it back to their practices and their patients, was one reason why a faulty test for Lyme disease had been tolerated so long. Because it is the mainstream, IDSA-certified model of Lyme disease care, as published in and embraced by major medical journals. In a functional medical model, the articles in these journals, and the ones that challenge them, should be part of an evolving and nuanced science of Lyme disease. Instead, they represent a fixed view of testing and treatment, repeated in science literature reviews in a kind of say-it-again Lyme loop. I found two dozen such reviews since 2005, for example, in a PubMed search of just one guideline writer’s name with the words “Lyme” and “review.”

  For twenty-two years, by the time Shapiro gave his talk, practitioners have had to rely on a pair of tests that fails to diagnose multitudes of patients and has been found deficient in numerous published papers. The way to solve this problem, to avoid telling doctors not to test children who have a hint of Lyme disease because they may wrongly test positive, is to get a better test.

  CHAPTER 7:

  An Indestructible Pathogen?

  * * *

  In the center of the universe of Lyme disease—orbited by the mice, deer, and birds, the vicissitudes of weather and cataclysm of climate, the chopped-up forests and spreading suburbia, and, of course, the ticks—there is, simply, the bug: The formidable, for some unlucky humans, ferocious family of Lyme disease bugs known as Borrelia burgdorferi sensu lato. The pathogen circulates, it proliferates, it endures like a piece of silver in a marketplace, having few earthly or social boundaries. Borrelia is content to nestle in a dirt-covered tick that has not fed for months, to lay low in the knee of a mutt or a thoroughbred, or to swim in the heart or brain of a billionaire. It will share space in the gut of a tick with other disease-inducing bugs, like Babesia, and sometimes become stronger in the process, more apt to infect than it otherwise would be. It will move from a tick to a mouse to another tick nearby, like passengers transferred between parked buses, and never infect the mouse. Nor will it cripple or kill the many small mammals that it does infect and on which it depends for life. It knows better. Borrelia has allowed these animals—and itself in the process—to live well and prosper. The ones to suffer are people and their dogs, horses, and sometimes cattle, all relatively new additions on the borrelial menu, and all somewhat defenseless against it.

  George Poinar’s tick encased in 15-million-year-old amber, when super-magnified, showed corkscrewed cells that strongly suggested Borrelia (chapter 3). Those coiled black shapes hint at how much time the bug has had to adapt to the tick it inhabits and the wildlife it infects, and vice versa. Indeed, Borrelia and tick, and Borrelia and host—mammals, lizards, birds—live mostly in symbiotic harmony. Were he alive today, Charles Darwin would be delighted, ecstatic in fact, to study the family tree of Borrelia burgdorferi s.l., with its trunks, branches, and twigs that have blossomed over the eons and benefited so well from the process of evolution.

  Like settlers moving to a new frontier, B. burgdorferi’s modern self comes well prepared, able to colonize with a few swift moves. First, it replicates when it senses the tick in which it lives is beginning to feed. Then, it sheds a molecule on its outside called outer surface protein A, OspA for short, and dons another protein, OspC. The first molecule bound it tightly within the mid-gut of the tick, the finger-like projections that can be seen in silhouette beneath the rim of a backlit tick. Without OspA, Borrelia moves freely to the salivary glands—far bigger in ticks than proportionally in people—where perhaps the ultimate feat of evolutionary cooperation occurs. Two proteins, one from Ixodes tick saliva called Salp 15, the other from Borrelia, the OspC, combine—yes, join forces—to assure product delivery from tick to host, allowing the spirochete to plant its flag on mammalian turf and protecting it from death-by-antibody. A Hungarian scientist, Gábor Földvári, called this, in an understatement perhaps, “an intriguing example of co-evolution.” The whole relationship is, in fact, a case study in mutually beneficial coexistence. Beyond the advantages that Borrelia reaps from
the tick, we also know the tick wins too: Ticks that are infected are literally fatter (as in they have more body fat), more resistant to drying up, and able to search farther and longer for food. And by the way, they outlive their uninfected compatriots.

  The real story of Borrelia burgdorferi, the one we care most about, is what happens after that clandestine tick-to-host handoff, as the organism sets up shop, multiplies, and travels throughout the human apparatus. That’s what makes it so dangerous. It can move with its flagella when it wants to and stay put when it needs to. It enters the skin and circulatory system first, of course, moving to joints perhaps, or, depending often on the preference of its assorted species and strains, taking up residence in the central nervous system, the peripheral nervous system, the heart, brain, or even the eyes. This bug knows how to drill through that tight-knit helmet of cells known as the blood-brain barrier, and wreak havoc on memory, understanding, and mental health generally. Lyme disease has been associated with depression, schizophrenia, and obsessive disorders. It can bring on what one study called “pure Lyme dementia,” similar to the madness wrought by another spirochete, Treponema pallidum—syphilis. When B. burgdorferi camps in the joints, it makes movement, for some, excruciating; in the peripheral nervous system, it causes numbness, tingling, or weakness. In cardiac tissue, it slowed the heart rate of a nineteen-year-old Colorado boy with Asperger syndrome to twenty-five beats per minute, causing him to fall and strike his head. He was treated and survived. A seventeen-year-old New York boy, his heart invaded too, did not.

  How B. burgdorferi thrives in the human body is the stuff of scientific mystery, one that Nicole Baumgarth, an immunologist with a degree in veterinary medicine from Hannover, Germany, is determined to unravel. She has spent hundreds of hours in a laboratory at the University of California, Davis, in pursuit of a fundamental question. How, she asks, can this organism so fluidly and artfully evade mechanisms of immune response in ways that few pathogens do? Previous researchers had shown that a magical protein in tick saliva, when injected through the bite of a tick, suppressed invader-fighting T cells essential to human immunity and health, while triggering myriad other unsavory responses. It was also known that people treated for Borrelia infections responded to antibiotics in a way unlike other diseases: with a huge, rapid decline in antibodies that under other circumstances would remain and protect against future infections.

  In her pursuit of the key to the borrelial kingdom, Baumgarth studies mice, many, many mice. For one, they are veritable Borreliaburgdorferi factories, chiefly, though not solely, responsible in many corners of the world for keeping the organism alive and circulating in the environment. For another, they are persistently, chronically infected without being sick—at least not after the initial infection. Find out how the mouse achieves this, and you may have found a cure for intractable Lyme disease.

  I met Nicole Baumgarth—face to face at least, we’d already spoken on the telephone—over an urn of coffee at a conference in New York City in November of 2016. She is tall, like me, with curly red hair, gold-rimmed glasses, and an unassuming manner that says no question is too small. I appreciated this since my endless queries to many scientists, for a book that covers a great many branches of tick, mammal, climate, and germ study, can come off as, well, rather basic. Her research on mice had preceded her: a Lyme physician, among others, had pointed to it as explaining a key mechanism by which Borrelia lays claim to its host with magnificent impunity.

  Baumgarth was introduced at the conference as someone who studies how Borrelia “co-opts” normal defense systems, as a “a mouse translational researcher,” who is using the mouse to figure out the human. “Borrelia, over evolutionary times, established sort of a truce with the mouse immune system,” she began. The mouse, more or less, agrees to host the bug. The bug agrees not to make the mouse sick. “Perfect balance,” Baumgarth called this. In humans, however, “there is no evolutionary adaptation,” she said, no Borrelia truce. There is, instead, all-out war.

  The immune system of a mouse is not all that different from that of a human being. Under normal circumstances, tiny powerhouses called “germinal centers” are activated in the lymph nodes—human or mouse—as a key immune defense from an invading pathogen. They help to build the infrastructure that fights infection and prevents reinfection: the plasma cells that support antibody production; the memory B cells that provide long-term immunity and respond to a recurring threat. In 2015, Baumgarth and her UC Davis team reported a striking discovery. The germinal centers in Lyme-infected mice were abnormal, and the plasma and memory cells failed to develop for months after infection. In fact, the Lyme disease bug was so effective at switching off the immune system that infected mice given the influenza vaccine failed to mount the normal viral antibodies for protection, the team reported in PLoS Pathogens. “What has Borrelia done to establish the suppression of the immune response?” she asked when I spoke to her. Might it be possible to stimulate the parts of the human immune system that Borrelia subverts?

  Dr. Stephen Barthold, a pioneering UC Davis researcher whose path Baumgarth is following, has great respect for Borrelia, having studied it for twenty-five years, primarily in mice. His work earned him election in 2012 to the National Academy of Medicine, among the highest honors a medical or veterinary scientist can achieve. “Once Borrelia gets in the door and establishes infection,” he said in an interview with the Canadian Broadcasting Corporation in 2013, “it can escape host immunity 100 percent of the time.”

  Persistent. Ironclad. Indestructible?

  People like Baumgarth and Barthold often use a particular word to describe the state in which the Lyme bacterium can live in animals and, likely by extension, in people. Borrelia, they contend, “persists.” It leaves its host unable, in quaint scientific parlance, to “mop up” the cells that antibiotics leave behind. The ability of the Lyme disease bug to persist potentially explains why many people stay sick even after they are treated. The figures vary on just how many there are, as I discussed earlier. But consider this from a leading physician in the National Institutes of Health, Adriana Marques, from a 2012 presentation: “Studies of patients with erythema migrans [the Lyme rash] have shown that 0–40% of the patients have persistent or intermittent non-specific symptoms of mild to moderate intensity 6–24 months after therapy.” Now consider that these are the people who were treated early, because they had the confirmatory rash, and who therefore achieve the highest cure rates.

  These persisting cells—dormant, altered, attenuated though they may be—are still very likely infectious, Barthold believes, even after being dosed with frontline antibiotics that have long been recommended for Lyme disease. Borrelia burgdorferi, Barthold told a Congressional hearing in 2012, is “a professional at persisting.” He reeled off five antibiotics that the pathogen had survived in treated animals, and referred to laboratories in four states and Finland that, to that point, had come to identical conclusions.

  Persistence isn’t an unusual phenomenon. All bacteria form persisters even after the animals they’ve infected are treated. Many are harmless, and the immune system can manage them. But some are not. Dormant persister cells, for example, are known to be responsible for the need for extensive antibiotic courses for tuberculosis. In 2014, a Johns Hopkins University team led by Professor Ying Zhang reported that twenty-seven antibiotics were more effective at killing persisting B. burgdorferi cells—some in atypical “round body” forms, others in tough-to-penetrate microcolonies—than the leading Lyme drugs doxycycline and amoxicillin. These included heavy duty antibiotics like daptomycin, used for resistant staph infections, and leprosy drugs like clofazimine; when used with Lyme drugs like doxycycline, they were much more effective at killing persisting B. burgdorferi cells.

  At about the same time, a team of researchers at the Antimicrobial Discovery Center at Northeastern University in Boston, led by a distinguished biology professor named Kim Lewis, similarly sought to test the pharmacological tolerance of
Lyme disease bugs that had survived initial antibiotic treatment. When the researchers tried to kill B. burgdorferi persisters, it was a bit like playing whack-a-mole. They tried three antibiotics—amoxicillin, ceftriaxone, and doxycycline—individually and in every two-drug combination; each time, persisters survived. They tried daptomycin, known to kill pathogens rather than simply slow their growth, and, separately, several experimental compounds, and persisters survived. They turned a corner when they resorted to Mitomycin C, a highly toxic anticancer agent. At last, the persisters were vanquished. As for antibiotics, however, they finally tried a method in which ceftriaxone was applied in “pulsed” doses. Three times it was washed away, and three times the bacteria revived. On the fourth round of dosing, the B. burgdorferi persisters, at last, died.

  The Northeastern researchers, who published their findings in 2015, and those at Johns Hopkins were among a long line of scientists that has wrestled with the Lyme disease pathogen and found it hard to kill. Their results demonstrate the complexity of the infection, which may require different treatment approaches depending on when it is attacked and the persistent form it is in. Clearly, more research is needed. When Stephen Barthold appeared before Congress, part of a hard-fought effort by Lyme disease sufferers to get official attention, he recounted twenty-five years of study into the ability of Borrelia to survive the best weapons of pharmacology and immunity. He had been part of Monica Embers’ groundbreaking research that had tried to kill the infection in rhesus monkeys, only to attach clean ticks afterward and learn they had picked up the bug—from monkeys treated with curative antibiotics. “We can also look in the tissues of the animals that have been treated with antibiotics,” he said, “and we see morphologically intact spirochetal forms.” Which was exactly what he and Embers had found.