Researchers on the front line in a ‘gangbusters’ year for Lyme disease

Before winter had even ended, the warnings came in: 2017 was going to be a bad one for Lyme disease. Anecdotally, the experience of Anne Norris, an infectious disease physician and associate professor of clinical medicine at Penn’s Perelman School of Medicine, backs this up.

“This has been a tremendous year for Lyme disease, and tick-borne disease in general,” she says. “It’s just gangbusters.”

Whether or not this year winds up an outlier, it’s clear that cases are on the rise as the disease marches steadily across the Northeast and Midwest. According to the U.S. Centers for Disease Control and Prevention, there were nearly 30,000 confirmed cases in the nation in 2015—though actual cases may have been closer to 300,000—up from fewer than 12,000 two decades earlier.

 

In the lab and in the clinic, faculty at Penn are paying attention to Lyme disease. Their research, observations, and science-driven care are augmenting our understanding of the infection, clearing up confusion that surrounds it, and getting patients—human and animal—the treatments they need.

Lyme disease is caused by Borrelia burgdorferi, a bacterium carried by ticks in the genus Ixodes. Ticks aren’t born infected; they must feed from an infected mammal, such as a mouse, chipmunk, shrew, or deer, to be capable of transmitting the disease.

Over his career, Dustin Brisson, an associate professor in the School of Arts & Sciences’ Department of Biology, has devoted energy to investigating each component of the Lyme disease system: bacteria, vector, and host. He comes at his studies with the perspective of an evolutionary biologist.

“In my research I try to take a bacteria-eye view of things,” Brisson says. “I view the bacteria not as a pathogen, but as an organism that’s just trying to get by. It wants to reproduce, it wants to eat, it wants to do all of those things that other organisms want to do.”

This line of thinking has led him to examine how, for example, B. burgdorferi has evolved highly variable surface proteins to keep the immune system guessing, and how blacklegged ticks have exploited their environment to expand into new territories.

A 2015 study by Brisson and colleagues used data collected from the New York State Department of Health to track how ticks have moved to colonize new areas. They found the ticks generally moved south to north in a stepping-stone fashion. This mirrors anecdotal reports that ticks used to be absent from certain areas as recently as the early 2000s, and are now abundant.

Brisson’s team is also interested in the environmental and climate conditions that support tick populations. Using satellite landscape and climate datasets, they’ve begun to identify characteristics of the environments that seem to be most hospitable to ticks.

“It’s not just if there is forest, but how close the forest is, what’s the shape of the forest, how much edge is there,” Brisson says. “Additionally, winter temperature is important and summer rainfall is important. These values predicted tick density with surprising accuracy, and not surprisingly, this correlated with human Lyme incidence rates.”

Brisson notes that such information could help predict future tick migrations and Lyme disease cases as the disease expands in range.

Though much of Brisson’s research concerns questions related to the biology of ticks, their animal hosts, and the Lyme disease bacteria, one area of work seems close to enacting real changes in how the infection is approached in the clinic. In a project with Charlie Johnson, a professor in Penn Arts & Sciences’ Department of Physics & Astronomy and director of the Nano/Bio Interface Center, Brisson is helping develop an improved diagnostic test for Lyme disease.

 

The current test detects the presence of antibodies—the immune system’s response to the bacteria. The problem is that antibodies may be undetectable for a month after a tick bite, and even then may indicate an infection that has long been cleared, not a current case of disease.

Johnson and Brisson are developing what they hope will be a more sensitive and specific test.

“The idea is we’re trying to detect the bacteria directly, as opposed to the antibody response,” Johnson says. “That could be very useful in the early stages of infection when there is no antibody to detect.”

The team is employing a graphene-based chemical sensing platform that Johnson’s group has applied to detecting other biologically relevant molecules. The sensor works by attaching part of an antibody to B. burgdorferi-specific proteins to graphene. When the appropriate protein binds to the antibody, the graphene produces a specific electrical readout.

Johnson and Brisson reported an initial success using carbon nanotubes in 2013, and have since refined the sensitivity many times over.

“In the next year we’re going to be working with artificial blood samples, where we have real blood to which we’ll add bacteria, and in the year after that we’ll be wanting to work on real human samples,” Johnson says.

 

Such an improved diagnostic would offer considerable clarity to many of Anne Norris’ patients. While many cases of Lyme disease are caught early and effectively treated with antibiotics, Norris, as a specialist, sees patients whose conditions are not so straightforward.

A decade ago, she reviewed her last 100 cases of suspected Lyme disease.

“Only about a third of those patients had ever met Borrelia burgdorferi,” she says. “The other two-thirds had no clinical or laboratory evidence of ever having Lyme disease. But 98 percent of them had been on antibiotics, many of them for four to six months, 10 had had spinal taps they didn’t need and six had had intravenous antibiotics they shouldn’t have had.”

Norris says that while she indeed is able to successfully treat many patients who are very sick with Lyme disease, she sees many others suffering with symptoms that turn out to be something else entirely.

“I diagnose a lot of inflammatory arthritis, a lot of sleep apnea, sometimes hepatitis C or other inflammatory conditions,” she says.

Still, Norris underscores that Lyme disease is hugely prevalent in the Philadelphia region. As a state, Pennsylvania has almost twice as many Lyme cases as any other. And Norris and colleagues at Penn Medicine are seeing other serious tick-borne diseases on the rise as well, including those caused by the bacteria Anaplasma and the parasite Babesia.

“If you’re suspicious you have a tick-borne illness, I would say there is a lot of misinformation out there,” Norris says. “I really advise people to get their information from websites that end in .edu and .gov and of course to reach out to their doctor.”

Penn’s human hospitals are not the only places that see Lyme disease patients. At Penn’s two veterinary hospitals, Ryan Hospital for small animals and New Bolton Center for large animals, the infection is also on clinicians’ minds.

Kathryn McGonigle, a clinical associate professor in internal medicine at the School of Veterinary Medicine, says it’s not uncommon for her to see dogs with symptoms of Lyme disease.

“The top symptoms we see are fever, lethargy, and lameness,” she says. “But less then 10 percent of dogs that are infected wind up sick.”

As in humans, treatment involves antibiotics. And for those that test positive for the disease, McGonigle and her colleagues recommend additional testing, particular to monitor kidney health, as kidney disease is a potential complication associated with infection in dogs.

The good news is that, just as in humans, there are many strategies to avoid pets getting infected. Certain collars and topical treatments can repel or kill ticks, and McGonigle recommends checking dogs’ fur after exploring in an environment that might be home to ticks, though it can be challenging to find the poppy-seed-sized nymphs in a thick coat of fur.

A positive blood test in one’s dog should also be a sign that the potential for a human case is present.

“Very simply, if your dog is exposed to it, then you should be aware that Lyme is in your environment,” McGonigle says.

Given the prevalence of ticks in fields and forests in the region, it makes sense that many horses have encountered B. burgdorferi. At the New Bolton Center, Amy Johnson, an assistant professor of large animal medicine and neurology, estimates that about half of the horses she sees have been infected with the bacteria. As in dogs, most of these animals show no signs of infection.

But some do, and the results can be serious. While lameness is not thought to be a common manifestation of Lyme disease in horses, Johnson says, the animals can develop neurologic disease, eye inflammation, and skin masses. The neurologic disease can be difficult to treat and eye problems can lead to blindness. Johnson’s research has focused on developing a better understanding of these syndromes. She’s also looking for better diagnostic strategies.

“It’s not as easy as a blood test,” she says. “I’m trying to figure out the best way to interpret Lyme testing in horses and what other information is needed to determine whether a horse’s disease is truly due to Lyme.”

An underlying element of confusion, sometimes even controversy, has surrounded Lyme disease since the condition was named in the 1970s. It’s what has drawn the attention of Robert Aronowitz, a historian and physician who is professor and chair of the Department of History and Sociology of Science in Penn Arts & Sciences.

In his scholarly work, Aronowitz has explored how Lyme disease was said to have been "discovered" in Lyme, Conn., in the 1970s, but in fact a parallel condition known as erythema chronicum migrans (also the name for the spreading red rash associated with infection) had been known in Europe for many decades prior. Aronowitz argues that this narrative of Lyme disease as a “new” disease has shrouded the condition with unanswered questions, as he writes in a 2012 article about efforts to develop a Lyme vaccine: “What is Lyme disease? Who gets to decide?”

In that piece, published in Milbank Quarterly, Aronowitz discusses the development of two Lyme disease vaccines in the 1990s; one never made it to market, the other was pulled after three years. He notes that despite the vaccines’ medical efficacy, they failed due to social factors, notably rejection by the chronic Lyme community, who believe Lyme disease can cause lasting pain and fatigue and should be treated with long-term courses of antibiotics. This community, after initially supporting vaccine development, ended up against it, believing it could actually cause Lyme disease.

“These societal issues and controversy are still here 20 years later,” Aronowitz says. “New vaccines are being developed and there is talk of trying to test them in clinical trials and seek regulatory approval, but unless the medical and scientific communities pay attention to these underlying problems, I don’t think the effort will succeed.”

Lacking a vaccine, prevention is still key when it comes to avoiding Lyme disease. For both humans and pets, removing a tick within 24 to 36 hours of attachment makes infection extremely unlikely, so performing tick checks after being outdoors is key. Norris recommends DEET on the skin and permethrin-treated clothing to help keep ticks away.

“Education has been my mini-mission,” she says. “I try to educate my patients about insect repellant and avoiding tick-bite exposure, and I try to educate providers about the finite world of Lyme disease—what it does and what it really does not do.”

Photo: Protective collars and topical treatments can keep disease-carrying ticks away from dogs, says Kathryn McGonigle of Penn Vet. Though most dogs infected with Borrelia burgdorferi don’t show symptoms, more serious complications, such as kidney disease, can result.