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Why some recover fast and others do not

Why some recover fast and others do not


Why some people recover from Lyme disease, while others experience months, years or even decades of chronic symptoms has long puzzled doctors. New research offers some clues to an immune system marker in the blood that is elevated among people with lingering Lyme disease symptoms, even after they’d received antibiotics. 

In the new study, published on May 9 in the Center for Disease Control and Prevention’s Emerging Infectious Diseases journal, researchers found an immune system marker in the blood called interferon-alpha was elevated among people who had been treated for Lyme disease but had lingering symptoms.

Interferon-alpha is one of a handful of key signaling proteins the body makes to tell immune cells to fight off bacteria or viruses. If the blood levels are too high, the immune system can overact, causing pain, swelling and fatigue — symptoms often seen with Lyme disease.

In patients with high levels of interferon-alpha, the immune response to the Lyme bacteria may cause chronic inflammation, even once the infection is gone, said Klemen Strle, an assistant research professor of molecular biology and microbiology at Tufts University and an author of the new study. 

“We think this is a possible driver of persistent symptoms,” Strle said. And since a number of drugs are already approved to lower interferon-alpha, he suggested the research could mean a possible treatment option for lingering Lyme symptoms. 

The study was small, including 79 people diagnosed with Lyme disease, and found only a link between the higher interferon-alpha levels and the persistent Lyme disease symptoms, not that the immune marker was itself causing the lasting symptoms. A larger clinical trial would be needed to affirm the connection.

Male and female adult black-legged ticks, Ixodes scapularis, on a sesame seed bun to show their relative size.CDC

Anywhere from 30,000 up to 500,000 people develop Lyme disease from a tick bite each year, according to the CDC. For most, the infection is mild and easily treated with antibiotics. About 10% experience symptoms like fatigue and brain fog along with muscle, joint and nerve pain that persists even after treatment. 

The new findings represent a significant shift in understanding why some people infected with Lyme suffer chronic symptoms. Previously, some researchers believed that a specific strain of the spiral-shaped Borrelia burgdorferi bacteria that causes Lyme might be a cause. Others wondered whether undetectable low levels of infection lingered in the body after treatment. The new research suggests that the way the body reacts to the bacteria — not the bug itself — could result in long-lasting symptoms. 

It’s still unclear why some people have elevated interferon-alpha, but Strle said he’s looking into a possible genetic cause. 

Although the interferon-alpha research is still in an early phase, Dr. Roberta DeBiasi, chief of the division of pediatric diseases at Children’s National Hospital in Washington, D.C., called it “very well-designed and interesting.”

“It provides a possible therapeutic target that could be studied in clinical trials to treat these patients,” she said.

For people coping with ongoing Lyme symptoms, any biological explanation for the condition called post-treatment Lyme disease syndrome, or PTLDS, is a step forward.  

Years of Lyme symptoms

Rebecca Greenberg isn’t entirely sure when she first contracted Lyme disease, but she has her suspicions. Greenberg, now 26, clearly remembers her mom tweezing a small, firm tick from the back of her neck after she’d been playing at a playground near Albany, New York, when she was 9 years old. She may have had multiple tick bites from her time spent in the Adirondack Mountains but didn’t worry about them until she started feeling sick at age 15. 

“I was so tired I would tell my mom I couldn’t wake up for school anymore,” said Greenberg, who grew up in upstate New York but now lives in South Florida. “My muscles would hurt, my joints would hurt and I’d get these migraines.” 

Rebecca Greenberg.
Rebecca Greenberg.Courtesy Rebecca Greenberg

Doctors told Greenberg her symptoms were likely hormonal, and when Greenberg landed in the emergency room unable to move the left side of her body, they prescribed anti-anxiety medication and suggested she see a neurologist. Those doctors weren’t much help either, Greenberg said. Her symptoms eventually became so severe she stopped attending school and required a wheelchair. 

It wasn’t until 2011, after Greenberg’s mom posted to Facebook about her daughter’s mystery illness that a pediatrician friend suggested Lyme disease. Antibody tests soon showed Greenberg had been infected with Lyme and two other bacterial infections, babesiosis and bartonella

Even now, she’s still dealing with fatigue and nerve pain. The most debilitating symptoms of her Lyme disease have been the psychiatric effects, including severe anxiety, depression and hallucinations, she said.

“I’m essentially still putting Band-Aids on all of my symptoms,” she said. “One tick turned my life upside down.”

Why diagnosing Lyme is so difficult

 As the geographic spread of Lyme ticks intensifies, there’s an urgent need for more accurate tests that can pick up infection at its earliest stages, researchers and health officials acknowledge. 

“There is no doubt Lyme disease and other tick-borne infectious agents are increasing in prevalence,” Strle said.

The Environmental Protection Agency warns that disease-carrying ticks are most active in warmer temperatures, and climate change will likely mean the insects will increasingly survive the winter and spread to regions beyond the Northeast, Northern California and northern areas of the Midwest.

More on Lyme and other tick-borne diseases

Testing for Lyme disease is complicated, especially for doctors who aren’t familiar with the process, DeBiasi said.

“That leads to many people who have Lyme being missed or people who have symptoms being told they have Lyme when actually they don’t,” she said. “Combine that with bad information on the internet, and you end up with a lot of confusion.”

Part of the problem is that once the bacterium is transmitted from a tick into a human, it rapidly spreads through the body at levels that may be too low for a test to pick up.  

This quickly becomes a detection issue,” Brandon Jutras, associate professor in the biochemistry department at Virginia Tech, explained. 

Serology tests, which look for antibodies in the blood, are the best available method for diagnosing Lyme, experts say. However, antibody tests indicate the immune system has mounted an attack against a virus or bacteria, but can’t determine whether there is an active infection. They don’t work until the immune system generates a sufficient number of antibodies, which can take six weeks or more after an initial tick bite.

The CDC recommends using a combination of antibody tests to diagnose Lyme, including an immunoassay antibody test like ELISA followed by an immunoblot antibody test like the Western blot test. 

Doctors and health officials recognize the need for more reliable Lyme disease tests that can pick up infection early on.

“We need to do better,” said Jutras, who’s working with a team at Virginia Tech to develop a rapid Lyme test that could identify the actual infection from the earliest sign of a tick bite.

“What we really want is a test that says, ‘Does a person still have Borelli spirochete [Lyme bacteria], and do we need to treat it with antibiotics?’” said Dr. Brian Fallon, director of the Lyme and Tick-Borne Diseases Research Center at Columbia University.  

Controversy over ‘chronic Lyme’

Because testing is inadequate, there’s no way to link long-lasting symptoms to the initial Lyme infection. Many doctors avoid a diagnosis of chronic Lyme since the term implies a lingering infection.

“There’s no way to say a Lyme diagnosis from, say, six years ago has anything to do with the symptoms occurring now,” DeBiasi said. “Symptoms like musculoskeletal pain, fatigue, difficulty thinking and depression are nonspecific. There are many, many possible reasons for those symptoms other than Lyme.”

Columbia University’s Fallon prefers the term “long Lyme.”

“‘Chronic’ is a reasonable term if it refers to having symptoms chronically,” Fallon said. “The problem is when someone thinks they have an ongoing chronic infection and need more antibiotic treatments.”

DeBiasis insists the symptoms people experience are real, even if PTLDS experiences are the exception.

As a pediatric doctor, she’s seen panicked parents seek unproven therapies after finding a tick on their child. In a recent study published in the journal Pediatric Research, DeBiasi and colleagues found 75% of children with Lyme disease were better within six months of antibiotics, while 9% had symptoms affecting their functioning after six months. 

“If you give them a little more time, they seem to fully recover,” DeBiasi said.

With the exception of Pfizer and Valneva, which are testing a Lyme disease vaccine in clinical trials, the drug development industry has not, for the most part, focused its energies or dollars on Lyme. Federal research grants are lacking too, Jutras said.

“A lot of private foundations have stepped up to the plate as it relates to funding research for Lyme, but at the federal level, it may be time to revisit some of the priorities as it relates to where we’re spending research dollars.”



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