As a kid in rural Connecticut in the early 2000s, Kathleen McWilliams was well acquainted with the danger of ticks. After days spent playing outside in the wooded areas around her house, “our home routine was you brushed your teeth, you went to the bathroom, and you did a tick check,” she said.

So when, at age 15, McWilliams suddenly spiked a 104-degree fever, her mom immediately thought Lyme disease, the tick-borne illness caused by the bacterium Borrelia burgdorferi. She requested a Lyme test. While they waited for results, McWilliams’s symptoms morphed into near-constant dizziness and achy joints, two more markers of the disease.

But, after two weeks had passed, they got surprising news: Her Lyme test came back negative.

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Had it been positive, McWilliams’s doctor would have prescribed a high dose of antibiotics that would quickly clear the infection. Without that diagnosis, McWilliams’s symptoms worsened while the doctor ran a second Lyme test at her mother’s insistence. She recalls classes in which she was so dizzy she struggled to stay upright, and soccer games in which her knees and shoulders throbbed.

“I remember feeling pretty frustrated about it, because as somebody who was never sick, it was really hard to be so sick, and not have any answers,” she said.

Two weeks later, their suspicions were confirmed: McWilliams tested positive for Lyme. After a course of antibiotics, the disease and her symptoms disappeared.

Her ordeal is a common one; every year, some 300,000 people in the United States are diagnosed with Lyme disease, according to the Centers for Disease Control and Prevention, and that number is on the rise. Some people wait months or years to get a correct Lyme diagnosis. And their cases highlight a problem: Tests for Lyme in the first month of infection are frequently wrong. When diagnosed and treated early the infection is a simple one to get rid of, but left untreated it can cause a myriad of lingering symptoms, from severe arthritis to short-term memory problems.

Now, a number of research groups are working to improve Lyme tests to catch infections in the early stages. One avenue being studied by the CDC aims to create a Lyme “signature” of small molecules in the blood — an approach that, in early testing, catches a dramatically higher share of early infections.

A tricky diagnosis

Presently there’s only one Food and Drug Administration-approved laboratory test for Lyme disease: a blood test that relies on detecting antibodies, proteins the body’s immune system makes in response to the disease. But while this approach is good at diagnosing the disease at later stages, it can miss the disease early on when antibody levels are low. In the first three weeks after infection, the test only detects Lyme 29 to 40 percent of the time. (The test is 87 percent accurate once Lyme spreads to the neurological system, and 97 percent accurate for patients who develop Lyme arthritis). The CDC cautions that because the test is not likely to be positive until 4 to 6 weeks after infection, doctors who suspect Lyme based on symptoms should prescribe antibiotics even if the test is negative.

In practice, however, this doesn’t always happen. “I have to use clinical judgement quite often in early Lyme,” said Dr. Daniel Cameron, who leads a private practice specializing in Lyme in Mt. Kisco, N.Y., and has been treating Lyme for 30 years. “But there are doctors who are still waiting for that [positive] test, and if they can’t confirm it with a test, they’re reluctant to diagnose Lyme, and they don’t treat.”

He added that some doctors may hesitate to diagnose based on symptoms because they are accustomed to using highly accurate tests for other diseases, or because Lyme symptoms can look like those of multiple other illnesses, such as chronic fatigue or fibromyalgia.

In recent years, concerns about unreliable Lyme testing have even pushed state governments to get involved. In 2013, Virginia passed a Lyme Disease Testing Disclosure Act requiring physicians to inform patients that a negative Lyme test does not necessarily mean they are Lyme-free, and Maryland followed suit in 2016 with a similar law.

“Lyme disease is a serious problem here in the United States and we really need to find solutions to some of the limitations that we have, particularly in diagnosing this infection,” said Claudia Molins, a microbiologist at the CDC. “We want a test that can be used within the first two weeks of infection and that does not rely on antibody production.”

So Molins and her colleagues are focusing on metabolomics — an approach that, rather than testing directly for the immune response to the infection, instead looks for a wide spectrum of collateral damage.

Specifically they’re looking for so-called metabolite biosignatures: the litany of sugars, peptides, lipids, amino acids, fatty acids, and nucleotides normally present in the blood.

Infections like Lyme, the thinking goes, change the levels of these things — and they do so in a predictable, measurable way.

Molins and her team tested that hypothesis by tapping a unique CDC resource — freezers filled with well-characterized blood serum samples. They used serum from 89 early Lyme patients, within the first month of infection, and 50 healthy controls to develop an algorithm to detect Lyme blood signatures.

The researchers then tested that algorithm on a larger sample of serums and found that they could diagnose 88 percent of early Lyme cases, and could differentiate Lyme from other diseases (including mononucleosis and fibromyalgia) 93 percent of the time. The results were published in a 2015 study in Clinical Infectious Diseases.

Microbiologist Elli Theel, who directs the Infectious Diseases Serology Laboratory at Mayo Clinic, calls the 2015 study “incredibly promising.” “The sensitivity they showed just in early Lyme disease patients was very high, the highest I’ve actually seen,” she said.

In an upcoming publication, the researchers also showed that metabolomics can differentiate Lyme from a similar tick-borne disease called southern tick-associated rash illness (STARI). The disease causes similar symptoms as Lyme, including a bullseye rash, and occurs in overlapping geographic regions. Currently there is no laboratory test to diagnose STARI, and little is known about how the disease progresses and how to treat it, something Molins hopes will change with better testing.

Moving to clinics

Now, the researchers are trying to make metabolomics more practical in clinical settings. Their main hurdle is equipment: Laboratories like theirs use a different kind of mass spectrometer than hospitals do, so the team is currently adapting their technique for a mass spectrometry platform already used for diagnosing metabolic birth defects in many hospitals.

“Really it makes sense to try to target a platform that’s already available instead of reinventing the wheel, so to speak,” Molins explained.

They are also working on developing better biosignatures and algorithms for identifying Lyme based on new blood samples they recently collected from clinics affiliated with Colorado State University and New York Medical College. Eventually they will begin real-time testing on patients’ serum samples collected in clinics and mailed to the CDC.

“People are very scared of having Lyme disease, and with reason. And so if you can more accurately tell them if they have this infection or not, I think it’s also [good] for their own ease of mind and understanding what they’re dealing with,” Molins said. “I think we owe it to the patients to give them a proper diagnosis.”

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  • My world has been turned upside down by Lyme, I believe full well. I’m a mom of four and have been suffering to get by. I know when it all started, but didn’t know then, what I know about Lyme now. Unfortunately – a gave misfortune – my Dr is no longer willing to listen to the odd set of symptoms that have been plaguing for four years…flu, followed by joint pain, followed by trigeminal neuralgia pain, then occipital neuralgia pain, worst headache of my life for 10 months, chronic muscular aches, leg tremors … with all my labs, scans & MRI’s coming back negative. Thank goodness for the internet! After watching multiple testimonial videos online – I can cry tears of rejoice that one day I will finally be correctly diagnosed. Problem is I live in Eastern WA & it’s not been easy even trying to locate a Dr. my most recent scare has been the heart palpitations. I dream of getting healthy again. I’d love to find a Dr who will treat this with wholeness in mind. Any help would be SO welcomed!

    • Same advice given to previous woman…….you need to find a Lyme Literate MD or practitioner who is treating according to ILADS guidelines. Go to Lyme Disease .org or seek out a LD Support Group, where you should get good references. There are both of these in Eastern WA. Tests are not used for diagnosis; so do not accept: “your test was negative you don’t have Lyme”. Recognition of Co-infections is critical ! Good luck

  • Answer to Kim Horne. FORGET tests past or present; your first doctor was correct in doing a clinical diagnosis and treating accordingly. The fact that you are relapsing is common. Follow my suggestions posted on Sept. 10 @ 7:28 PM. Find a LLMD !! FYI: I agree with Christina Morris; there is so much misleading & harmful information out there ! I don’t know who STAT are; but, I find much of their output to be less than accurate. If need to, contact me at . I hope you find help soon… jane

  • Go to ILADS directory of LLMDs or Lyme Disease .org. You can also go to Bill Rawls list of Support Groups by state. They will have access to ILADS trained doctors; that is what you need ! Good luck…. Jane in RI

  • The information in this article is so inaccurate it left me frustrated. The current tests for Lyme are not in any way accurate. As someone who has spent the last decade studying everything Lyme, I can tell you they’re 80% false. As Lyme enters your body within the first couple months you might show antibodies. After that the Lyme has connected with your immune system, getting it to accept the Lyme as friend not for. Your body then stops producing antibodies to fight it. The longer you have Lyme the less likely you are to test positive. Please don’t post info that will influence many on their way to self diagnosis. This info can harm them.

  • I’ve been suffering from Lyme symptoms for over 10 years. When I had lyme10 years ago I only had 3 titers but My doctor said the symptoms were there so she treated me for Lyme for 18 months with IV antibiotics and I seemed to be 90% better. I am having similar symptoms for the past two years. I’ve had all kinds of test with no positive results. Drs tested for Lyme (3 titers again) and said I was Neg for Lyme. Is there any place close to Delaware that I can try to get the new type of testing that you spoke of in the article? ( unfortunately my doctor from 10years ago has retired)
    Thank you in advance for your help
    Kim Horne

    • Kim, contact a rheumatologist and ask if they would help you find a lab that conducts and prepare a sample for “experimental” testing. Several years ago (2015), after a negative result on the standard test, I visited a rheumatologist about extreme joint swelling. She submitted samples of my synovial fluid (from the joint) and got a positive result. We did that test twice more during the course of treatment. The last test was negative and the battle was over.
      That was the good news, now the not so good news, the test cost me over $300 for each and because it was experimental, it was not covered. I’m grateful that improvements in testing and diagnosis are finally here but wish the FDA and insurance firms would step up and make this a covered service.

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