Lyme Disease (Borreliosis) and CIRS: What Is Known?

Most people with Lyme disease (borreliosis) recover after a course of antibiotics. But some keep having fatigue, pain and problems with memory or concentration for months afterwards. Mainstream medicine calls this post-treatment Lyme disease syndrome (PTLDS). Its cause is unknown.

Dr Ritchie Shoemaker’s group sees many of these cases differently. They call them a form of CIRS (Chronic Inflammatory Response Syndrome): an inflammatory illness that, in their model, the Lyme bacterium sets off and that keeps going after the infection has been treated. That view comes almost entirely from Dr Shoemaker’s own clinic and colleagues. No independent study has tested it.

This article explains both views, how much evidence lies behind each one, and what you can do if you have not recovered.

What is post-treatment Lyme disease syndrome?

Lyme disease is an infection caused by Borrelia bacteria. Ticks spread it. Doctors usually treat it with a few weeks of antibiotics, and international guidelines describe how to diagnose and treat it [1].

In 2006 the Infectious Diseases Society of America (IDSA) proposed a research definition for symptoms that last after treatment [2, 3]. In plain words, PTLDS means that:

• you have had Lyme disease that was documented and treated, and its objective signs went away,
• you have fatigue, widespread muscle and joint pain and/or problems with thinking that began within 6 months, have lasted at least 6 months and make daily life harder, and
• no other illness explains the symptoms.

Well studied PTLDS is real and can be disabling. Researchers at Johns Hopkins University studied a carefully defined group of patients. People with PTLDS had far more fatigue, pain, sleep problems and depressive symptoms than healthy people, and a clearly lower quality of life. Yet physical examination and routine laboratory tests showed few abnormalities [4].

How common is it?

Estimates vary with the definition. A prospective US study followed people who were diagnosed and treated promptly for early Lyme disease. Prospective means that people were followed forward in time.

• About 14 in 100 (13.7%) met the study’s criteria for post-treatment Lyme disease.
• About 4 in 100 (4.1%) of people who had never had Lyme disease met the same criteria [5].

Being female and having lived through more traumatic life events also raised the risk [5].

What causes persistent symptoms after Lyme disease?

Preliminary research Nobody knows. A review by Johns Hopkins researchers lists the main ideas [3]:

• bacteria or bacterial remnants that stay in the body
• an immune system that is out of balance, through inflammation or autoimmunity (the immune system attacking the body’s own tissues)
• changes in how the nervous system handles pain and other signals, called central sensitisation

Well studied What is well established is that more antibiotics do not help most people with these symptoms.

• In two placebo-controlled US trials, 90 days of antibiotics, given into a vein and then by mouth, helped no more than placebo [6]. A placebo is a dummy treatment with no active ingredient.
• A large European trial found the same for an extra 12 weeks of antibiotics [7].

The current guideline from the IDSA, the American Academy of Neurology and the American College of Rheumatology therefore advises against more antibiotics for lasting, non-specific symptoms. The exception is when there is objective evidence of a new infection or failed treatment [1].

You may also see the term “chronic Lyme disease”. Some groups use it more broadly, for example the International Lyme and Associated Diseases Society (ILADS). It includes people who would not meet the PTLDS definition [3]. The term is disputed. This article focuses on PTLDS because it is the best-defined group.

How does Dr Shoemaker explain illness after Lyme disease?

Expert opinion Dr Shoemaker’s view is set out most fully in the 2018 consensus statement on diagnosing CIRS, written by his group [8]. A consensus statement is a document in which a group of experts agrees on a common position. It is not a study.

These steps are Dr Shoemaker’s model, not proven fact. In more detail, the statement says:

• Post-Lyme illness is a type of CIRS. The group calls it CIRS-PLS (post-Lyme syndrome). It is one of four routes into CIRS that the statement recognises. The others are water-damaged buildings, cyanobacteria blooms (toxic blue-green algae) and ciguatera fish poisoning [8].
• It shares the CIRS findings: low MSH, high TGF-β1, raised C3a and C4a (pieces of the complement system, part of the innate immune system), an abnormal visual contrast sensitivity (VCS) test and certain changes on brain MRI. Raised C3a is described as more typical after Lyme disease than after mould exposure [8].
• It has its own genetic susceptibility. The statement links the HLA-DR haplotypes 15-6-51, 16-5-51, 4-3-53 and 11-3-52B to Lyme-related CIRS. A haplotype is a set of gene variants inherited together (see HLA genes) [8].
• CIRS treatment brought the markers back towards normal. A table of laboratory values from Dr Shoemaker’s private practice shows inflammatory markers that stayed abnormal after antibiotics. After CIRS treatment they came closer to the values of healthy controls [8].
• Patients first reacted badly to binders. Binders are medicines that bind toxins in the gut. When post-Lyme patients took cholestyramine after antibiotics, many got worse, not better. The group calls this “intensification” and links it to a surge in MMP-9, an inflammation marker [8]. This experience shaped the later, stepwise Shoemaker protocol.

The idea that Borrelia makes a biotoxin is central to this model. The consensus statement bases it on a 1998 patent filing by two Lyme researchers [8]. A patent filing is a legal document, not a published study.

What has Dr Shoemaker actually published on Lyme disease?

In the peer-reviewed research listed in PubMed, the main database of medical research, we found two studies by Dr Shoemaker on Lyme disease.

1. A 2006 trial in 25 patients with both Lyme disease and Babesia infection One small study Babesia is a parasite that ticks can also spread. The patients were still ill and had abnormal VCS results after earlier treatment. All of them took cholestyramine. The trial first compared the antiparasitic drug atovaquone with placebo, then gave both drugs to everyone. After 12 weeks, 5 patients had no symptoms and 16 had clearly fewer symptoms [9].

Two limits matter. Every patient took cholestyramine, so the trial cannot show what cholestyramine itself did. And the patients had a second infection, so the results do not apply directly to illness after Lyme disease in general.

2. A 2008 study of complement markers in early Lyme disease One small study C3a and C4a were raised in all 31 patients with Lyme disease seen within 96 hours of a tick bite. They were rarely raised in tick-bitten people without Lyme disease or in healthy controls [10]. This study is about diagnosing the new infection, not about long-term illness.

The bigger claim, that post-Lyme illness is CIRS, rests on the consensus statement and the practice data in it. The statement appeared in Internal Medicine Review, a journal not listed in PubMed. Its claims about post-Lyme illness have not been checked in an independent, controlled study [8]. In a controlled study, people who get a treatment are compared with a similar group who do not.

How does this differ from the mainstream view?

Both views agree that symptoms after Lyme disease are real and involve the immune system. They disagree on almost everything else.

• Toxin or not. Mainstream researchers note that the Borrelia genome, its full set of genes, does not seem to code for any known toxins. So they put the symptoms down mainly to the body’s own immune response [3]. The CIRS model calls Borrelia a source of biotoxins [8].
• Gene-activity findings. An independent study followed 29 Lyme patients for six months. It found a pattern of gene activity that lasted after treatment. But the pattern was the same in patients who had recovered and in those who still had symptoms [11]. Dr Shoemaker’s group cites this study as support for hidden, ongoing illness [8]. It can just as well be read as showing that the pattern does not explain who stays ill.
• Testing. Mainstream guidelines rely on clinical findings and antibody tests [1]. The CIRS approach adds a panel of inflammation markers, HLA gene typing and the VCS test. Independent studies have not validated any of them for PTLDS.
• Treatment. Mainstream care supports the patient and treats the symptoms. There is no approved drug treatment for PTLDS [3]. The CIRS approach uses the Shoemaker protocol, whose evidence comes mainly from the doctors who use it [12].

Lyme disease and CIRS compared

	Post-treatment Lyme disease syndrome (mainstream)	Post-Lyme CIRS (Shoemaker group)
What it is	Lasting symptoms after treated Lyme disease; cause unknown [2, 3]	Long-term inflammation of the innate immune system, triggered by Lyme disease [8]
Key symptoms	Fatigue, widespread pain, problems with thinking [2, 4]	The same, plus the wider CIRS symptom list (e.g. light sensitivity, thirst, numbness) [8]
Diagnosis	Clinical definition; no test confirms it [3]	Symptoms, history, VCS, CIRS laboratory markers, HLA typing [8]
Role of toxins	No known Borrelia toxin [3]	A Borrelia biotoxin is assumed [8]
Treatment	Supportive care; extra antibiotics not recommended [1, 6, 7]	Stepwise Shoemaker protocol after antibiotics [8]
Evidence base	Well studied Several cohort studies and randomised trials from many groups [3–7]	Expert opinion Consensus statement and private-practice data from one group; two small related studies [8–10]

Could mould be the real problem after Lyme disease?

Sometimes, perhaps. The Shoemaker approach asks about every possible biotoxin exposure, not only the one the patient already suspects. One person can have more than one [8].

Someone who never recovered from Lyme disease may also live or work in a water-damaged building. The symptoms of the two are hard to tell apart.

Not studied Nobody has studied how often this happens. But it is a question you can answer, because buildings can be inspected. See what triggers CIRS for the full list of triggers.

What should I do if I have not recovered from Lyme disease?

How strong is the evidence?

Well studied For PTLDS itself, the evidence is fairly solid. Well-designed cohort studies, which follow groups of people over time, show that it exists and how it affects people [4, 5]. Randomised trials show that long antibiotic courses do not help [6, 7]. Its cause is not known.

Expert opinion For the idea that post-Lyme illness is CIRS, the evidence is thin. It rests on:

• one group’s consensus statement,
• practice data that have not been published as a study,
• the group’s clinical experience [8], and
• two small related studies that do not test the idea directly [9, 10].

The proposed HLA haplotypes, the claimed Borrelia toxin and the benefit of CIRS treatment after Lyme disease have not been tested in independent, controlled studies. We found no such studies in October 2026. Dr Shoemaker’s work is based on patients in the United States. So we do not know how well his model fits borreliosis in Finland and the rest of Europe.

That does not make the idea wrong. It means it is a hypothesis that some doctors work with. Anyone who is offered it deserves to know how little it has been tested. To read more about the other triggers and how they connect, start with biotoxins and CIRS.

Remember these

Test yourself: Can you explain why the antibiotic trials matter for people who are still ill? And what kind of study would be needed to show that post-Lyme illness is CIRS?

What next?

• Read how CIRS is diagnosed.
• Read what triggers CIRS.
• Find out more about biotoxins and CIRS.

References

1. Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical practice guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 guidelines for the prevention, diagnosis and treatment of Lyme disease. Clin Infect Dis. 2021;72(1):e1–e48. PubMed
2. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089–1134. PubMed
3. Rebman AW, Aucott JN. Post-treatment Lyme disease as a model for persistent symptoms in Lyme disease. Front Med (Lausanne). 2020;7:57. PubMed
4. Rebman AW, Bechtold KT, Yang T, et al. The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment Lyme disease syndrome. Front Med (Lausanne). 2017;4:224. PubMed
5. Aucott JN, Yang T, Yoon I, Powell D, Geller SA, Rebman AW. Risk of post-treatment Lyme disease in patients with ideally-treated early Lyme disease: a prospective cohort study. Int J Infect Dis. 2022;116:230–237. PubMed
6. Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med. 2001;345(2):85–92. PubMed
7. Berende A, ter Hofstede HJ, Vos FJ, et al. Randomized trial of longer-term therapy for symptoms attributed to Lyme disease. N Engl J Med. 2016;374(13):1209–1220. PubMed
8. Shoemaker R, Johnson K, Jim L, et al. Diagnostic process for chronic inflammatory response syndrome (CIRS): a consensus statement report of the Consensus Committee of Surviving Mold. Internal Medicine Review. 2018;4(5):1–47. PDF
9. Shoemaker RC, Hudnell HK, House DE, Van Kempen A, Pakes GE; COL40155 Study Team. Atovaquone plus cholestyramine in patients coinfected with Babesia microti and Borrelia burgdorferi refractory to other treatment. Adv Ther. 2006;23(1):1–11. PubMed
10. Shoemaker RC, Giclas PC, Crowder C, House D, Glovsky MM. Complement split products C3a and C4a are early markers of acute Lyme disease in tick bite patients in the United States. Int Arch Allergy Immunol. 2008;146(3):255–261. PubMed
11. Bouquet J, Soloski MJ, Swei A, et al. Longitudinal transcriptome analysis reveals a sustained differential gene expression signature in patients treated for acute Lyme disease. mBio. 2016;7(1):e00100-16. PubMed
12. Dooley M, Vukelic A, Jim L. Chronic inflammatory response syndrome: a review of the evidence of clinical efficacy of treatment. Ann Med Surg (Lond). 2024;86(12):7248–7254. PubMed