Clinical Considerations of Chronic Lyme Disease Part I: Pathophysiology

Chronic Lyme disease has long caused debate throughout the medical community, from how to diagnose it to how to properly treat the illness. In the meantime, patients suffer from misdiagnosis, mismanagement, and are even told it is all in their heads. This article discusses some of the myths and misconceptions about the historic infection and touches on some of the clinical considerations and complications that must be understood when addressing each new Lyme case.

 Lyme Disease, An Umbrella Term

First, Lyme disease is an umbrella term that refers to the infection caused by the Borrelia species bacteria and its associated vector-borne pathogens, or coinfections. According to the CDC, it is the most common vector-borne disease in the United States with 300,000 new cases reported each year (1). 

In the 1970s, an unusual cluster of children in Lyme, CT were diagnosed with arthritis, later to be identified as Lyme disease. Although it was named in the ‘70s, the Borrelia spirochetes have been shown by genomic analysis to have split off as unique organisms at least 100 million years ago, with the earliest detections of the infection recorded in medical literature in the late 1880s (2). There is ongoing debate about where it comes from and how it is transmitted. 

Borrelia and its coinfections are said to not only be transmitted by the black-legged tick, but also, according to recent evidence, by other vectors such as spiders, fleas, mites, and mosquitos (3). Additionally, Lyme spirochetes have even been found in semen and vaginal secretions as well as in cord blood, which backs clinical claims of sexual and in-utero transmission (4). 

Originally thought to be found only in the United States in the New England territory, the Midwest states of Wisconsin and Minnesota, and the Northern Pacific states, Lyme disease has now been identified in all 50 states and across all continents, including the Arctic and Antarctica. Different strains of Borrelia can be seen throughout these different regions and are associated with their own unique set of symptoms (5).


The rate at which Borellia is transmitted from vector to host is also under debate. It is said that transmission of Borrelia organisms occurs with a tick attachment of somewhere between 10 minutes and 72 hours. More commonly, transmission occurs in less than 16 hours. Ultimately, transmission rate depends on many factors including the type of tick (hard vs soft), species, location of spirochetes in the tick, if the tick is partially fed (most are), and the health or weakness of the host’s immune system. (6)

Acute vs. Chronic

There is not a very clear definition between acute and chronic Lyme disease, but clinically speaking acute Lyme refers to those who are infected and treated right away without residual symptoms. According to Dr. Joseph Burrascano, a board member of International Lyme and Associated Diseases Society (ILADS), chronic Lyme presents with three major criteria (7): 

  1. Illness presents for at least one year.
  2. Persistent major neurological involvement (such as encephalitis/encephalopathy)or arthritic involvement.
  3. Continued active infection with Borellia regardless of prior antibiotic therapy.

Regardless of the definition, it is known that patients treated earlier in the illness fare better than those whose treatment is delayed (8).

The Great Imitator – Signs and Symptoms

Lyme disease, known as the “Great Imitator,” can easily be confused with other illnesses and infections. Its symptomology often overlaps common chronic conditions such as chronic fatigue syndrome, fibromyalgia, a number of autoimmune arthritic conditions, and MS to name a few. The most prevalent symptoms include fatigue, headaches, fever, joint pain, arrhythmia, parathesis and other neuropathies, and a pathognomonic skin rash called erythema migrans, or more commonly referred to as the “bulls-eye rash.” Although pathognomonic, the rash is not present in every Lyme case. In fact, the estimate for rash occurrence is a very wide range of 27% to 80% (9). In reality, the rash is probably only seen in about one-third of people who get Lyme disease, so this should not be used as a way to screen someone for Lyme, but rather can be used in lieu of testing to confirm a Lyme diagnosis. 

A Stealth Infection

Lyme is known as a stealth infection due to multiple factors such as its ability to morph between different spirochetal and atypical forms, to reside both extracellularly and intracellularly, and to change its outer protein surface markers.

Borrelia’s ability to morph between forms may require different treatment approaches. Besides the spirochetal form of Borrelia, there are also different atypical, cystic (round bodies) and granular forms (10) which it tends to morph into when under adverse conditions. These atypical and cystic forms can be much harder for our immune systems and antimicrobials to penetrate, creating a shield-like effect. 

Additionally, Borrelia can be found in fluid or tissue compartments, extracellular matrix, or intracellularly, creating more complexity and difficulty in delivering therapies effectively. There is not yet a single antibiotic that is effective in both compartments or extracellular and intracellular delivery, resulting in the need for combination therapy, conventionally seen as multiple antibiotic use (7)

Its ability to change its outer protein surface markers makes Borrelia not only challenging to identify on labs for diagnosis, but also difficult to be appropriately identified and addressed by our immune systems. This aspect of its pathophysiology is perhaps one of the main reasons why Lyme can be seen as a persistent infection and creates such systemic chaos.

Borrelia burgdorferi, one of the most common US strains of Borrelia, has been shown to evade host immunity through up- and down-regulation and molecular changes to various surface-expressed outer surface proteins (11), and to reduce the functionality of the innate immune response (12), including inhibition of complement activation and the adaptive immune response (13). What results are body-wide inflammation and cytokine storms that in essence create an autoimmune-like picture and immune dysfunction of the host.

Complications – Coinfections and Opportunistic Infections 

Treatment for Lyme disease is complicated by the fact that it takes much more than addressing bacterial load to resolve the infection once it becomes chronic. The other key areas to address are immune regulation, inflammation control, sleep disturbances, rebuilding a healthy gut barrier and brain barrier, reducing neuroinflammation, supporting cardiovascular integrity, and reestablishing appropriate autonomic control. On top of the body-wide systems affected by Lyme itself, careful consideration should be given to addressing coinfections and opportunistic infections.

Coinfections refer to a handful of infectious pathogens often transmitted at the same time as Borrelia. The most common ones include anaplasma, babesia, bartonella, chlamydia, ehrlichia, mycoplasma, and rickettsia (6). Their presence is so common that a diagnosis of Lyme disease almost always includes at least one coinfection, if not more. This can lead to complications of diagnosis and treatment. Each has its own set of symptomatology that often overlap, as well as require its own set of antimicrobials and treatment approaches and timelines. For example, babesia is a parasite. It is often required to be addressed first, or at the beginning of treatment, as it can be a more stubborn, immunosuppressive infection (7). Opportunistic infections are those that take advantage of a compromised immune system. Such infections may be viruses like EBV, CMV, and HHV6. For this reason, treatment protocols should make sure to target immune modulation to prevent opportunistic infections from thriving. 

As you can see, there are many complications and considerations when dealing with chronic Lyme disease. Understanding its pathophysiology is key to putting together a multifactorial approach for best treatment outcomes.


  1. “Lyme Disease.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 16 Dec. 2019, 
  2. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.24.
  3. Luger, S. “Lyme Disease Transmitted by a Biting Fly.” New England Journal of Medicine, vol. 322, no. 24, 1990, pp. 1752–1752., doi:10.1056/nejm199006143222415. 
  4. Middelveen, Marianne J et al. “Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions.” F1000Research vol. 3 309. 18 Dec. 2014, doi:10.12688/f1000research.5778.3
  5. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.17.
  6. Buhner, Stephen Harrod. Healing Lyme: Natural Healing of Lyme Borreliosis and the Coinfections Chlamydia and Spotted Fever Rickettsioses. 2nd ed., Raven Press, 2015, p.37.
  7. Burrascano, Joseph. “Advanced Topics in Lyme Disease Diagnostic Hints and Treatment Guidelines for Lyme and Other Tick Borne Illnesses.” 16th ed., 2008. 
  8. Bechtold, Kathleen T., et al. “Standardized Symptom Measurement of Individuals with Early Lyme Disease Over Time.” OUP Academic, Oxford University Press, 23 Nov. 2016, 
  9. Johnson, Lorraine. “LYMEPOLICYWONK: How Many of Those with Lyme Disease Have the Rash? Estimates Range from 27-80%.”, 10 Apr. 2014, 
  10. Miklossy, Judith, et al. “Persisting Atypical and Cystic Forms of Borrelia Burgdorferi and Local Inflammation in Lyme Neuroborreliosis.” Journal of Neuroinflammation, vol. 5, no. 1, 2008, p. 40., doi:10.1186/1742-2094-5-40. 
  11. Coutte, Loïc, et al. “Detailed Analysis of Sequence Changes Occurring during VlsE Antigenic Variation in the Mouse Model of Borrelia Burgdorferi Infection.” PLoS Pathogens, vol. 5, no. 2, 2009, doi:10.1371/journal.ppat.1000293. 
  12. Miller, Jennifer C., et al. “Gene Expression Profiling Provides Insights into the Pathways Involved in Inflammatory Arthritis Development: Murine Model of Lyme Disease.” Experimental and Molecular Pathology, vol. 85, no. 1, 2008, pp. 20–27., doi:10.1016/j.yexmp.2008.03.004. 
  13. Bernard, Quentin, et al. “Borrelia Burgdorferi Protein Interactions Critical for Microbial Persistence in Mammals.” Cellular Microbiology, vol. 21, no. 2, 2018, doi:10.1111/cmi.12885.