The Unanswered Questions of Lyme Disease

Originally published by A Voice For Choice Advocacy on August 20, 2026.

EDITOR'S SUMMARY: Lyme disease has been recognized for decades, yet some of its most consequential questions remain unsettled. From diagnostic blind spots and persistent symptoms to co-infections, overlooked pathogens and provocative clues buried in its history, the disease continues to challenge easy explanations. As tick-borne illness spreads, understanding what remains unknown may be just as important as what science has already established.

On a warm day in 1970, a tiny eight-legged creature emerged from the leaf litter of a Wisconsin woodland. Drawn by the carbon dioxide drifting from a nearby mammal, it stretched its front legs into the air until they brushed against skin. Its unsuspecting host was a man. Blind but exquisitely adapted to find its next meal, the arthropod began its slow ascent, searching for a warm, sheltered patch of skin. There, using a mouthpart equipped with cutting blades and backward-facing barbs, it pierced the surface and anchored itself in place. As it fed, it released a cocktail of compounds that dulled pain, prevented clotting and suppressed the man's local immune response. At the same time, microbial passengers slipped silently into the wound, entering the bloodstream unnoticed with little initial opposition.

Days later, an unusual expanding rash appeared around the bite: a red ring that would eventually become one of Lyme disease's most recognizable warning signs. Physicians treated the man with intramuscular penicillin, and the rash disappeared within days. At the time, however, no one knew exactly what had caused it. It would take several more years — and an unusual cluster of arthritis cases among children and adults in Lyme, Connecticut — before researchers recognized they were dealing with a distinct tick-borne disease. The breakthrough came in 1981, when Swiss-American medical entomologist Willy Burgdorfer identified a slender, corkscrew-shaped bacterium in blacklegged ticks collected on Shelter Island, New York. The organism would eventually bear his name: Borrelia burgdorferi.

Today, Lyme disease is the most common vector-borne illness in North America — meaning it is transmitted through organisms such as ticks or mosquitoes. It is passed on by infected Ixodes ticks, a genus that includes several species of hard-bodied ticks. In the eastern United States, Lyme disease is spread primarily by the blacklegged tick (Ixodes scapularis), while the western blacklegged tick (Ixodes pacificus) transmits the disease along the Pacific Coast.

Over the past three decades, Lyme disease has expanded dramatically beyond its historical strongholds in New England and the Upper Midwest. Reported cases have more than tripled since the mid-1990s, and the Centers for Disease Control and Prevention estimates that roughly 450,000 Americans are diagnosed and treated each year. Some experts attribute the expansion to changing land use, suburban development, warming temperatures that lengthen the active season for ticks and growing deer populations. Although deer do not carry the Lyme bacterium in a way that infects ticks, they play an important role in the tick life cycle, helping populations thrive and spread into new areas.

The growing number of Lyme disease cases is concerning not only because the infection is becoming more common, but because it can be remarkably difficult to recognize. Even when you seek medical attention early, diagnosis is far from straightforward. No single laboratory test can conclusively verify or rule out Lyme disease, and the standard two-tier antibody test — an enzyme immunoassay (EIA), followed by an immunoblot (commonly called a Western blot) — relies on your body's immune response rather than detecting the bacteria directly.

During the first few weeks of illness, before enough antibodies have developed, these tests can miss up to half of infections. They also cannot distinguish between an active infection and one that occurred months or even years earlier. As a result, healthcare providers are encouraged to consider a patient's symptoms, history of tick exposure and physical findings — not laboratory results alone — when making a diagnosis. Some Lyme specialists also use additional laboratory methods that can help detect co-infections that standard testing may not capture, such as polymerase chain reaction, fluorescence in situ hybridization and T-cell assays.

When Lyme Becomes Complicated

Lyme disease generally progresses through three recognized stages: early localized, early disseminated and late disseminated disease, although the stages can overlap and not every patient experiences each one. Early infection often produces an expanding rash — sometimes the characteristic bull's-eye pattern — along with fever, fatigue and muscle aches. Left untreated, the bacteria can spread through the bloodstream over the following weeks or months, affecting the nervous system, heart and joints. People vary in their response to infection, with environmental, genetic and biological factors playing a role. In some individuals, the immune system overreacts, which can drive systemic inflammation that damages tissues even after the bacteria have been cleared. In others, persistent infection can lead to neurological complications, arthritis and other inflammatory conditions.

The sooner treatment begins, the better the chances of a good outcome. Patients with suspected early Lyme disease — particularly those with the distinctive rash or symptoms combined with known tick exposure — are often started on antibiotics before laboratory results are available or antibodies have had time to develop. Standard treatment usually includes doxycycline, amoxicillin or cefuroxime. But Lyme disease does not always follow a straightforward course. Researchers continue to study how Borrelia burgdorferi interacts with the immune system and adapts to stressful conditions, which may explain why some infections are more difficult to treat than others.

When diagnosis is delayed, symptoms persist or co-infections are present, some patients turn to integrative care, which combines conventional treatment with complementary therapies and lifestyle changes. Depending on the practitioner, this may include botanical antimicrobials, nutritional support, sleep optimization and anti-inflammatory diets intended to promote overall health. Two commonly discussed approaches are the Cowden Protocol, which uses rotating herbal extracts such as Samento, Banderol and Cumanda, and the Klinghardt Protocol, which combines botanical preparations with supplements and other therapies aimed at addressing factors such as biofilms — communities of microorganisms that adhere to surfaces — detoxification and co-infections. Common components of the Klinghardt Protocol include cistus tea, andrographis, artemisia, propolis and chlorella.

When symptoms continue or recovery stalls, some integrative practitioners look beyond Lyme disease itself for other factors that may be contributing to your condition. Because ticks can transmit multiple pathogens, you may be evaluated for co-infections such as Babesia, Bartonella, Anaplasma, Ehrlichia and Rickettsia, which can produce overlapping symptoms and require different treatments. They may also consider factors such as mold exposure, mast cell activation, mitochondrial dysfunction, gastrointestinal health and nutritional deficiencies.

Mold exposure may also warrant consideration when symptoms persist. If you spend time in a water-damaged building, you can develop fatigue, brain fog, headaches, muscle and joint pain, dizziness and cognitive difficulties — many of which can resemble symptoms attributed to Lyme disease. Ongoing mold exposure may contribute to inflammation or otherwise delay recovery. When significant indoor mold or water damage is identified, addressing the source through appropriate inspection and remediation is an important first step. Improving ventilation and indoor air quality with HEPA filtration can further limit contact with mold, while other approaches may include binders such as activated charcoal, bentonite clay or chlorella, adequate hydration and nutrition, and strategies to address inflammation.

A Controversial Chapter

The possibility that something beyond Borrelia burgdorferi could contribute to persistent illness is not new. In fact, it was a question that occupied Burgdorfer himself late in his career. While analyzing blood samples from patients with suspected Lyme disease, he noticed evidence of another organism — a rickettsia related to bacteria responsible for diseases such as typhus and Rocky Mountain spotted fever. He had previously encountered the organism in ticks in Switzerland and nicknamed it the "Swiss Agent." Today it is known as Rickettsia helvetica. Burgdorfer believed it might contribute to illnesses attributed to Lyme disease, particularly because the two infections can present similarly, with fever, headache, muscle pain, fatigue, rash, and neurological or cardiac complications. He developed a diagnostic test for the organism, but it never became part of routine Lyme testing in the United States.

For decades, Burgdorfer's observations received little attention. Then, in 2016, investigative reporters at STAT obtained boxes of his personal papers that had been discovered in his garage after his death. The collection included laboratory notebooks, correspondence with colleagues and unpublished blood test results suggesting that Burgdorfer had continued thinking about the Swiss Agent long after Borrelia burgdorferi became accepted as the primary cause of Lyme disease. The findings revived a question that remains unresolved: could some patients diagnosed with Lyme disease actually have another tick-borne infection — or perhaps more than one?

Near the end of his life, Burgdorfer began making statements that surprised even longtime colleagues. In interviews and private conversations, he suggested the original Lyme outbreak may not have been entirely natural, raising the possibility that it was connected to Cold War-era biological weapons research. His comments attracted attention because of his professional history. Long before discovering Borrelia burgdorferi, he spent decades researching tick-borne diseases while collaborating on federally funded programs connected to Fort Detrick, a center of U.S. biological weapons research during the Cold War. Historical records show that military scientists investigated insects and arthropods as potential disease vectors, although they do not definitively establish that Lyme disease originated from such research. Burgdorfer's expertise extended well beyond Lyme disease, encompassing plague, relapsing fever, typhus, Q fever and other vector-borne illnesses.

Another site that has become part of the debate is Plum Island, located in Long Island Sound near the Connecticut coast. In 1952, the U.S. Army Chemical Corps constructed a biological research laboratory there. The extent to which the facility was used before the island was transferred to the Department of Agriculture in 1954 for research into foreign animal diseases remains unclear. Its proximity to Lyme, Connecticut, and its Cold War history have fueled speculation that the emergence of Lyme disease in the region was connected to research on the island. However, no definitive evidence has established that Lyme disease originated at Plum Island or escaped from the facility.

The idea of using insects to spread disease is well documented. Japan's Unit 731 experimented with plague-infected fleas during World War II, and both the United States and the Soviet Union later investigated arthropods as potential carriers of disease. Lyme disease wasn't the only tick-borne mystery puzzling researchers during that period. In 1968, physicians identified the first U.S. case of babesiosis on Nantucket — a malaria-like parasitic illness that infects and destroys red blood cells.

Within a few years, what The Boston Globe described as the world's largest known outbreak had emerged there. Even experts struggled to explain why. In science writer Kris Newby's 2019 book "Bitten," CDC researcher Andrew Spielman, who specialized in tropical diseases, is quoted as saying: "We have no satisfactory explanation for the clustering of cases on Nantucket." Meanwhile, Martha's Vineyard also reported cases of Rocky Mountain spotted fever, adding to a growing pattern of unusual tick-borne illnesses in the region.

Another tick was attracting attention. Unlike blacklegged ticks, which typically wait on vegetation for an unsuspecting host to brush past, Lone Star ticks actively seek out humans and animals. As their range has expanded across the eastern and central United States, so too has the number of illnesses associated with them. In addition to transmitting pathogens that cause illnesses including Heartland virus and Rocky Mountain spotted fever, Lone Star ticks are the primary U.S. species linked to alpha-gal syndrome — a potentially severe allergy to red meat. In people with alpha-gal syndrome, eating beef, pork or lamb can trigger hives, gastrointestinal symptoms or even life-threatening anaphylaxis.

Whatever its origins, the questions surrounding Lyme disease extend far beyond how it first emerged. More than four decades after Borrelia burgdorferi was identified, researchers continue to debate how best to diagnose the disease, explain persistent symptoms and improve treatment for the growing number of people affected.

The Questions That Remain

While many patients recover completely after early treatment, others spend months or even years searching for answers as persistent symptoms disrupt their work, education and daily lives. The disease has earned the reputation of an "invisible illness" because those affected may appear outwardly healthy despite experiencing debilitating fatigue, chronic pain or cognitive impairment. When you look healthy but know something is wrong, the search for answers can become exhausting in its own right. You may move from doctor to doctor, struggle to explain what you're experiencing or begin to wonder whether anyone will be able to tell you why you still don't feel well. Living without an explanation can become another burden you carry.

Acknowledging these challenges, HHS Secretary Robert F. Kennedy Jr. announced a broad federal initiative in 2025 aimed at improving the nation's response to Lyme disease and other tick-borne illnesses. The plan includes developing more accurate diagnostic tools, standardizing treatment protocols, expanding research into advanced therapies, strengthening prevention programs and partnering with Tribal communities, including the Wampanoag Tribe, to reduce tick populations on wildlife before infected ticks reach humans.

Kennedy has spoken publicly about his family's experience with Lyme disease, noting that his wife and all six of his children were affected and that one son experienced paralysis for nearly a year. That close connection has helped elevate Lyme disease on the federal agenda as officials work to improve diagnostics, expand research and address tick-borne illnesses more broadly. Those efforts come as tick exposure remains widespread. Dr. Stephanie Haridopolos, director of National Health Communications for the Office of Surgeon General, says approximately 31 million Americans are bitten by ticks each year:

"Not all of them get Lyme disease but we know at least half a million do. Twenty percent of those who get Lyme disease go on to develop persistent symptoms associated with Lyme disease have autoimmune dysfunction and inflammation in their body that can take years to rectify."

Haridopolos emphasizes that preventing tick bites remains the best defense against Lyme disease and other tick-borne illnesses. She recommends covering exposed skin, tucking pants into socks, using EPA-registered repellents and treating clothing and gear with permethrin — a synthetic insecticide modeled after the natural insecticidal compounds found in chrysanthemum flowers — when spending time in wooded or grassy areas.

If you prefer plant-based alternatives, several botanical repellents are available. Cedar oil, neem oil, oil of lemon eucalyptus and diluted apple cider vinegar have shown varying degrees of effectiveness against ticks, although they generally provide shorter-lasting protection and require more frequent application. Essential oils and vinegar should always be diluted and should never be applied directly to attached ticks or broken skin. No matter which repellent you choose, a thorough tick check after spending time outdoors is essential. Carefully inspect your body, use a sticky lint roller to remove unattached ticks from clothing, place dry clothes in a dryer on high heat for at least 10 minutes and inspect your pets before bringing them indoors.

If you discover an attached tick, don't wait for a healthcare provider to remove it. Using fine-tipped tweezers, grasp the tick as close to the skin's surface as possible and pull upward with steady, even pressure, avoiding twisting or jerking — as this can cause parts of the tick to break off and remain in the skin. Once the tick has been removed, thoroughly clean the bite site and your hands with soap and water, rubbing alcohol or hand sanitizer. Rather than discarding the tick, consider placing it in a sealed plastic bag or container. If symptoms develop in the following days or weeks, identifying the tick species or testing it for pathogens may provide helpful information for your healthcare provider's evaluation. If any mouthparts remain embedded, leave them alone — your skin will usually expel them naturally as the area heals.

Post-treatment Lyme disease syndrome (PTLDS) refers to a constellation of symptoms — including fatigue, pain, cognitive difficulties and sleep disturbance — that persist for six months or more after standard antibiotic treatment. Estimates suggest that between 10 and 20 percent of treated patients experience some degree of lingering symptoms, though the figure varies across studies. The cause remains contested.

While PTLDS is recognized within the medical literature, researchers continue to debate what causes these lingering symptoms. Some studies suggest they result from immune dysregulation or residual inflammation after the infection has cleared, while others continue to investigate whether persistent infection, co-infections or other biological mechanisms may be contributing. Burgdorfer's research into the Swiss Agent adds another layer to that debate. Investigative journalist Charles Piller wrote in STAT after reviewing Burgdorfer's papers and interviewing infectious disease researchers:

"While the evidence is hardly conclusive, patients and doctors might be mistaking under-the-radar Swiss Agent infections for Lyme, the infectious disease specialists said. Or the bacteria could be co-infecting some Lyme patients, exacerbating symptoms and complicating their treatment — and even stoking a bitter debate about whether Lyme often becomes a persistent and serious illness."

Whether Lyme disease's origins are connected to Cold War research may never be answered. The documents Burgdorfer left behind raise intriguing questions but do not provide definitive proof. What is certain is that Lyme disease is no longer a rare illness confined to a handful of wooded counties. As warming temperatures expand tick habitat and millions of Americans venture outdoors each year, the disease carried by the tiny parasite that quietly climbed onto a Wisconsin man more than half a century ago has become one of the country's fastest-growing vector-borne threats.

For families hiking forest trails, children playing in tall grass, gardeners tending backyard flower beds and pet owners whose dogs unknowingly carry ticks indoors, awareness remains the first line of defense. A careful tick check after time outside may seem like a small habit, but it has the potential to prevent an illness that, for some, can alter the course of a lifetime. If you do become ill, early diagnosis remains essential. Because tick-borne infections can be difficult to recognize and may occur alongside other pathogens, persistent symptoms deserve careful attention. Work closely with your integrative practitioner, ask questions and seek further evaluation rather than assume every lingering symptom has a simple explanation.

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