Lyme
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“Why the Lyme disease field has become the most polarized field in microbiological science I don’t really understand,” he told me. “It is an enigma to me why people are so fervently religious in their statement that it can’t possibly cause chronic disease to the point they attack their colleagues. Neither side has enough data to assure they are right.” But one thing was clear to Ehrlich: “Orthodoxy has just killed research in Lyme disease.”
So toxic was the notion of persisting Lyme disease that an infectious disease physician at Drexel expressed concern for the university’s reputation if Ehrlich cohosted a meeting of physicians in the International Lyme and Associated Diseases Society; the ILADS group does not hew to prevailing treatment guidelines and holds that Lyme can sometimes be chronic. ILADS, with a few hundred physicians and a core of supporting scientists, is the tick in the scalp of the better-funded, better-connected Infectious Diseases Society of America. The meeting was nonetheless held, in 2015.
Strains, Species. Known and Not.
Once inside of people, B. burgdorferi embarks on an adventure worthy of the 1966 movie “Fantastic Voyage,” in which miniaturized explorers ride a tiny submarine along the turbulent human bloodstream, through a pounding, pulsing heart, and into the body’s deepest, darkest warrens. The goal: to save an important scientist’s life. B. burgdorferi has no such life-saving mission, but its ride is no less stormy and fraught. Through the magic of cell imaging technology, scientists from the University of Toronto watched in real time as this bug latched onto proteins in cells that line blood vessels and swung, bungee-cord style, in flow chambers that simulated the human body, from cell to cell, all neat and controlled. This bacterium, unlike that tiny, tossed vessel, has learned through the process of evolution where it needs to go and how to get there. Imagine that. Each Borrelia species has instinct written into its DNA, depending on its genetic profile.
Within the giant family known as Borrelia burgdorferi sensu lato, there are the three major, but not only, species of spirochetes that cause human illness. They are Borrelia burgdorferi sensu stricto (in the narrow sense) in the United States and Canada, and Borrelia afzelii and Borrelia garinii in western and central Europe, Russia, and China. The Eurasian species B. afzelii is more apt to stay in the skin, in late stages causing painful bluish-red discoloration and swelling—called “acrodermatitis chronica atrophicans”—which may appear months or even years after a tick bite. B. garinii, also widely circulating in Europe and Asia, more typically leads to neuroborreliosis—neurologic Lyme disease—with its meningitis, facial paralysis, gait abnormality called foot drop, and sometimes devastating cognition and motor challenges. Going where nature calls it, Borrelia burgdorferi in North America, like its cousins worldwide, also uses the bloodstream not as a destination but a motorway, exiting quickly and confounding efforts to find it in blood tests. Research suggests this New World species colonizes many more anatomical corners than its European relatives, creating its own distinct havoc. Get a Lyme rash in Slovenia and it will last about fourteen days, a study in the Annals of Internal Medicine reported; get one in New York and it will last just four days but will be accompanied by more systemic symptoms. As a 2016 paper in the journal Emerging Infectious Diseases put it, B. burgdorferi is more often “associated with a greater number of disease-associated symptoms,” including but not limited to arthritis, the disease that led to its discovery in 1970s coastal Connecticut.
Science has a rudimentary knowledge of Borrelia’s many manifestations, with species and strains still emerging, along with evidence that they behave differently and may not be caught by diagnostic tests. Recall the Canadian girl who came back from Europe with Lyme disease and flunked the North American test, along with the Scottish blood samples that turned positive when a different test strain was used. Beyond this, species are still being identified and cataloged, for which, logically, tests don’t exist. The pathogen behind a Lyme-like illness in the American Southeast still hasn’t been identified. Ditto Australia, where, as one study put it, “Four published studies have searched for Borrelia in Australian ticks, with contradicting results.” Officially, Lyme disease does not exist there, despite more than five hundred reports in the scientific literature that suggest some kind of illness like it most surely does.
The unfolding nature of infections caused by Borrelia, with twenty-one genospecies and hundreds of strains so far identified, have added greatly to worldwide uncertainty and the woes of patients. In China, sixty-five B. garinii strains and twenty-two of B. afzelii have been identified. In the United States, one study looked at four hundred variations of Borrelia burgdorferi—“the largest number of borrelial strains from North America ever to be investigated”—and identified those best at entering the bloodstream. Another US study of just fourteen strains found huge variation by strain in the ability of standard testing to diagnosis Lyme disease. Among the study’s 158 infected patients, just 37 percent tested positive for the disease. When a different antibody test was used, the share of positives jumped to 68 percent. Indicative of the gaps in Lyme tests, the strains in eighteen patients weren’t detected at all. Such findings make clear: strains present yet another challenge to the ability of doctors to diagnose and treat.
Nataliia Rudenko is a Ukrainian scientist who for a couple of decades had been studying Borrelia species at the Institute of Parasitology of the Czech Academy of Sciences, authoring dozens of papers with US and European colleagues. In 2016, she came to a Canadian government Lyme disease conference in Ottawa armed with charts and maps that together formed a census of Borrelia burgdorferi’s growing iterations. Tall, brown-haired, and speaking rapidly in fluent English with a Slavic flair, Rudenko was eager to share her startling findings. In 1981, Willy Burgdorfer had identified the spirochete that caused the disease, and everybody thought: problem solved. But no, Rudenko said, “That was the beginning of the problem.”
By 1998, there were ten known species; by 2016, twenty-one. She made it clear that science was not done counting. With that, Rudenko unveiled three progressively marked-up world maps. The first, from ten years earlier, was “very clean and very easy,” she said as the slide lit up. The second, from five years before, was “kind of a mess,” she said, “but, believe me,”—she clicked on her third slide—“it’s nothing like it is now.” Here was the globe of the moment, the known universe of Borrelia burgdorferi sensu lato. From one slide to the next, ovals and arrows and shaded territories blossomed. Names like B. japonica and B. turdi appeared in the Far East; B. bissettii and B. garinii showed up on both sides of the Atlantic. New species cropped up in California, the American South, and Western Europe. Finally, something called Borrelia mayonii appeared in 2016, in the American heartland, a nasty species able to achieve high levels of what’s called “spirochetemia”—namely blood-borne spirochetes. It had been known to have sickened six people and seemed limited though, the implication of all this was, not contained.
By the time of Rudenko’s talk, some four decades into what had become a Lyme disease pandemic, about ten of the twenty-one known B. burgdorferi species had been implicated in causing illness, a drip-drip-drip of reports in science journals that in some cases made waves, in others fell silently into the vast ocean of Borrelia literature. Sometimes, such reports were ignored or dismissed, seen perhaps, as outliers or poor science. Skepticism is a healthy part of science publishing, in which theories must be proved and cases replicated. But, as I have discussed before, there has been reluctance to embrace some findings by a side of Lyme science that sees the threat as exaggerated. Researchers with proven track records and significant publications have been stymied, their findings discounted, when they veer too far from accepted, mainstream Lyme theory. Her publishing record notwithstanding, Rudenko has felt the influence—sting might be a better word—of the tamp-it-down side of the Lyme divide.
In the summer of 2013, a team led by Rudenko sought to challenge long-held beliefs about Lyme disease in the American Southeast. If a tick bi
te there had led to a suspicious rash, it was usually deemed a case of STARI—Southern tick-associated rash illness—or what might be called Lyme-disease lite. STARI was delivered by the bite of a different tick in the Ixodidae family, Amblyomma americanum, also known as the lone star tick. The disease was caused by a pathogen that had yet to be isolated, and it did not lead to the many complications of its more ferocious relative to the north. Home-grown Lyme disease, on the other hand, was rare. At least that was the official stance.
This view was disputed by patient advocates and a key scientist on Rudenko’s team, Kerry Clark from the University of North Florida, who was a leading tick-borne disease pioneer in the South. “Lyme disease is vastly more common down here than anybody has acknowledged,” Clark told me around the time the Rudenko study was getting under way. “The frequency of the disease is way beyond the expected level, and that’s the definition of epidemic.” A dogged researcher who had tested perhaps a thousand human blood samples, Clark had long argued that a large portion of recognized Lyme disease cases in southern states were contracted locally and not, as officials almost always ruled, picked up in travel to the north. He had published findings of DNA from Borreliaburgdorferi in the blood of fifty-three Florida and eight Georgia residents, including eighteen cases in Florida of two rare species not previously known to infect human beings. Significantly, he had found the Lyme pathogen in that most prevalent of southern ticks—the lone star—including one that had sickened a four-year-old Georgia girl.
Among his mounting evidence of Lyme disease in the South, Clark had reported case studies of the disease among residents who had never left the area. In his own blood, he had found the DNA of B. burgdorferi and another exotic species, Borrelia andersonii, after he was bitten by a lone star tick on a trip to collect ticks in Fayetteville, Georgia. That field research left him with a years-long case of Lyme disease—or what he might call Southern Lyme-like illness but certainly not STARI. That vague descriptor, he told me, minimizes and leads to missed and improper diagnosis of the disease.
Denying an Epidemic
It was against this backdrop that Rudenko and Clark joined forces in 2013 with a legend in the science of southern ticks named James Oliver Jr. Oliver, like Clark, had challenged prevailing wisdom on potential Lyme disease in the South, first identifying blacklegged ticks in Georgia in 1993 that had been mistaken for another species. Their project was one all too rare in the science of tick-borne disease: a study of people, their ongoing illness, and its possible cause. Together, they collected and analyzed blood and plasma samples from twenty-four patients from the South with a constellation of ongoing symptoms including “severe headache, nausea, muscle and joint pain, numbness and tingling sensations in extremities, neck pain, back pain, panic attacks, depression, dizziness, vision problems, sleep problems, and shortness of breath.” Among them, 71 percent recalled a tick bite and half had gotten a rash. All had previously been treated for suspected Lyme disease, for which they all, nonetheless, had tested negative. Clearly, this study had three strikes against it from the get go, as far as deviating from mainstream dogma. The researchers were looking for Lyme disease in a verboten area. They were studying patients who were “seronegative”—they didn’t pass standard two-tiered testing. Their subjects had posttreatment conditions that suggested chronic disease.
The team found something. In fact, it might be said they hit a small but significant bit of pay dirt. From the fluids of three patients, the team was able to culture Lyme disease spirochetes, a feat that fails about half the time even when a rash is present and infection is certain. In two Georgia residents, the scientists isolated Borrelia burgdorferi, the first time the spirochete had been cultured in residents from the South. In the third patient, from Florida, they found a strain of a rare species, Borrelia bissettii. Evidence of B. bissettii DNA had already been detected in human samples from the Czech Republic and California. This was the first time the organism itself had been cultured from a patient in North America. In all three cases, this was not spirochetal DNA, often dismissed as the dead remnants of infection. This was living bacteria.
The resulting article struck a nerve at the heart of the Lyme disease divide: “The successful cultivation [of spirochetes] from antibiotic-treated patients might suggest that active infection with persistent Borrelia may be the cause of recurrent symptoms and persistent disease,” it stated. Beyond touching on the nuclear issue of Lyme chronicity, the article included a blunt assessment of diagnostics. “This study would never happen” if the patients had been tested “according to CDC guidelines,” Rudenko’s team wrote. Rather, the patients would have been considered “inappropriate” for study because of where they lived, how they tested, and that they had previously been treated with supposedly curative doxycycline. Yet here were at least three patients, 12 percent of the group, with significant symptoms and active infection that was validated by the gold standard: live cultured organisms.
Using these findings, which were published in the journal Clinical Microbiology and Infection, Rudenko attempted to obtain funding for additional research. Her proposal was rejected with a cutting comment from what she described as a US-based reviewer, whose identity, as in all such reviews, was shielded from her: “I (and most other experts) are extremely skeptical of the publication on which this whole project is based. Certainly there should be evidence that the findings can be reproduced by others before good money is wasted pursuing this line of investigation which almost certainly will be fruitless. I suspect that the investigator is not responsible for fabricating data, but rather that the samples from the United States that were the basis for the publication were tampered with.” This wasn’t just skepticism; this was rejection on grounds that had little to do with the science.
“So, that is how it is,” Rudenko wrote to me in an email in the winter of 2017. In my research for this book, I learned of similar experiences of Lyme disease researchers who try to tell another story. They told me they were not believed—that their science was rejected outright or ignored. The contentions of Rudenko’s grant reviewer were perhaps the most blunt example I had yet come across. A couple of days later, I shared the reviewer’s comments with Rudenko’s coauthor, Kerry Clark, in a conversation about Lyme disease in the South. He was appalled at the inference. “It shows you the depth of some people’s fear of being proven wrong,” he said. At the heart of the issue was whether Lyme disease was real in the South and—the larger implication—whether the tick-borne disease was not just a minor irritant there but a serious public health threat.
A cadre of residents of Florida, Georgia, South Carolina, and North Carolina believes the latter. They meet in support groups in church basements, set up fundraisers to support Clark’s research, post stories of misdiagnosis on websites, and write letters to health officials and legislators. This surely does not an epidemic make. But these agitators, like their comrades in other states and countries around the world, have been trying to tell us something, as is the science behind them. They have instead been told that science and medicine have it covered on Lyme disease in the South, and that it has been found to be rare.
Nonetheless, consider this. North Carolina has one hundred counties, just five of which had been declared “endemic” for Lyme disease by 2017, a designation given by health authorities when at least two cases are confirmed in each. But say a patient in North Carolina goes to the doctor with what looks like an erythema migrans rash. In an endemic county, a physician will call this Lyme disease. Just over the border—a line that ticks and the mammals that carry them frequently ignore—the diagnosis will be STARI. No tests are needed in the endemic county to confirm Lyme disease; tests are required to confirm Lyme in the nonendemic county. But if the test comes back positive in the nonendemic county, it will frequently be interpreted by a doctor to be false. After all, if the county is not endemic, physicians have repeatedly been warned, Lyme disease is unlikely. Be suspicious of potentially false positives, the dogma goes. This s
cenario, played out many times as reported by patients, serves to reinforce a highly questionable status quo. It keeps reported Lyme cases low—and patients untreated.
“It is interesting to contemplate the dilemma created by this practice,” wrote Marcia E. Herman-Giddens, a member of the Tick-Borne Infections Council of North Carolina in 2012 in a letter to Clinical Infectious Diseases journal. “Without positives, there is no Lyme disease; if there is a positive, it is likely false.” A clear example, she wrote, of “circular thinking.” Indeed, this kind of thinking pervades Lyme disease, reinforcing prevailing beliefs generally as well as in the South. As a press release on a study by the United States Geological Survey put it in January 2017: “Lyme disease is very uncommon in the South.” The USGS study announced then, as reported in the previous chapter, had analyzed blacklegged ticks—the kind that carry Lyme disease—and found them highly averse to southern heat. They consequently stayed hidden in the brush and away from human beings. But lone star ticks, the study dutifully noted, are well acclimated to southern living and “readily seek hosts high up in the vegetation well above the leaf litter.”
That’s where Kerry Clark found them, took them in for testing, and teased out Borrelia burgdorferi from a few. It wasn’t easy, likely because not many ticks were infected and the concentration of spirochetes was low. Clark’s findings of Lyme disease in Florida and Georgia patients were so controversial that a team of government scientists tested more than a thousand lone star ticks in an attempt to replicate them. The study, published in 2015 and led by the US Army Public Health Command, found “weakly positive” indications of the organism in a small share of the ticks but concluded that Borrelia infection in lone star ticks was “not confirmed.” So two major questions remain unanswered for Lyme disease in the South: Does the lone star deliver the infection? And if not, precisely what organism causes STARI?