aid Advances in Infectious Diseases 2164-2656 2164-2648 Scientific Research Publishing 10.4236/aid.2026.161005 aid-149133 Article Medicine Healthcare Persistent Borrelia Infection in Chronic Lyme Disease: A Review of the Medical Literature 0000-0003-2149-8517 Stricker Raphael B. 1 2 0000-0002-5531-6032 Fesler Melissa C. 1 0000-0003-4513-2106 Johnson Lorraine 2 Union Square Medical Associates, San Francisco, USA LymeDisease.org, San Diego, USA

The authors have no conflicts to declare.

 08 03 2026 03 2026 16 01 73 87 09 12 2025 23 01 2026 26 01 2026 © 2026 by the authors and Scientific Research Publishing Inc. 2026 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ). https://doi.org/10.4236/aid.2026.161005

Chronic Lyme disease (CLD) remains a controversial illness. The controversy is based on a profound disagreement over the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, and the ability of this persistent infection to cause chronic symptoms in patients who are untreated or undertreated for the spirochetal disease. Based on a review of the medical literature, we identified 56 studies confirming B. burgdorferipersistence. In this article, we summarize evidence from animal models and human studies that support persistent spirochetal infection as the cause of CLD. Specifically, direct and functional testing using culture, histology and xenodiagnosis has shown viable organisms following antibiotic therapy, and the potential role of cysts (L-forms) and biofilms in this process is examined. Future studies are required to investigate the mechanism of persistent infection in CLD.

 Lyme Disease <i>Borrelia burgdorferi</i> Cysts Biofilms Animal Models Persistence Chronic Lyme Disease Post-Treatment Lyme Disease 1. Introduction

More than 500,000 new cases of Lyme disease are diagnosed each year in the USA, making it the most common vector-borne disease of North America [1][2]. If the acute spirochetal infection is not adequately addressed due to variable symptoms, poor diagnostic test sensitivity and a lack of clinical biomarkers, patients may develop chronic Lyme disease (CLD), which remains a controversial illness [3]. At the heart of this controversy lies a profound disagreement over the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, and the ability of this persistent infection to cause chronic symptoms in patients who are untreated or undertreated for the spirochetal disease. CLD constitutes a significant health care burden, costing the US healthcare system nearly 1.3 billion dollars annually [4].

CLD is a multisystem illness with diverse musculoskeletal, neuropsychiatric and/or cardiovascular manifestations [3]. The disease is associated with pathogenic members of the Borrelia spirochete complex often in combination with other tickborne disease (TBD) pathogens. To qualify for the diagnosis of CLD, patients must have Lyme-compatible symptoms and signs that are either consistently or variably present for six or more months. Two subcategories of CLD include untreated chronic Lyme disease (CLD-U) and chronic Lyme disease following a limited course of antibiotic treatment (CLD-T), as defined elsewhere [3].

Although some earlier infectious disease articles maintain that there is no “credible scientific evidence” for persistent infection with B. burgdorferifollowing 2 - 4 weeks of antibiotic therapy [5], a number of animal and human studies provide evidence for persistent infection as a cause of chronic symptoms in Lyme disease patients, thereby contradicting the earlier infectious disease point of view [1][6] (Table A1 and Table A2). Alternative explanations for persistent symptoms in CLD include infection-induced immune dysfunction, inflammation due to persistent bacteria, bacterial “debris” and genetic and other mechanisms [7].

Unfortunately, the CLD controversy often results in misdiagnosis, inadequate treatment, and medical gaslighting that contribute to patient suffering and persistent infection [6][8]. The failure to recognize persistent infection as a cause of CLD has a detrimental health impact on patients and society because these patients are often denied antibiotic treatment that may restore their health. These patients have worse quality of life than many other chronic disease conditions, including diabetes, multiple sclerosis, congestive heart failure, and arthritis [6].

This literature review presents the evidence for persistent infection with B. burgdorferiand provides a resource for academics and clinicians who require further validation for CLD.

 2. Methods

We conducted a review of the medical literature to identify studies demonstrating persistent Borreliainfection in both animal models and humans. Two data bases (PubMed and Google Scholar) were searched using key words such as Borrelia, B. burgdorferi, Lyme disease, chronic, persistent, and infection. The literature was reviewed and categorized based on whether the subjects were animal or human and subcategories were created based on animal type. Animal studies were included if direct or functional testing techniques for B. burgdorferiwere used, including culture, histology, xenodiagnosis, polymerase chain reaction (PCR) and/or RNA in-situ hybridization. Antibiotic therapy was not a requirement for this group, and length and sites of infection were noted. Human studies were only included if direct detection of Borreliasequences or organisms was noted using culture, histology, xenodiagnosis, PCR and/or fluorescent in situ hybridization (FISH) following antibiotic treatment.

 3. Results

We identified 24 animal studies (13 rodent, 2 canine, 7 monkey, and 2 horse) and 32 human studies supporting persistence of Borreliainfection (Table A1 and Table A2). Borreliawas identified in various sample sites from 60 days to 46 months following infection. Persistent detection of Borreliasequences following antibiotic treatment was found in 13 of 24 animal studies and 31 of 32 human studies. In 10 animal studies and 25 human studies viable spirochetes were demonstrated by culture, histology and/or xenodiagnosis following antibiotic treatment. The primary methods used to identify Borrelia in the animal and human studies included culture (13 animal, 15 human), histology (18 animal, 11 human), xenodiagnosis (4 animal, 1 human), and PCR (15 animal, 12 human). Additional modes of detection can be found in Table A1 and Table A2. Detection of Borrelia organisms was described in 21 (88%) animal studies and 26 (81%) human studies. The remaining studies only used PCR for molecular detection of spirochete sequences.

 4. Discussion

After performing a literature review, we identified 56 studies showing that B. burgdorferiwas detectable in longterm culture (Table A1 and Table A2). Viable spirochetes were identified by culture, histology and/or xenodiagnosis following antibiotic treatment in 10 animal studies and 25 human studies, demonstrating that live organisms can persist following this treatment. These findings contradict the earlier contention that the Lyme spirochete cannot survive antibiotics. Further evidence for evasion of the immune response and antibiotic therapy is described below.

A monkey study by Embers et al. published in 2012 provides the best animal evidence for persistent infection as a mechanism for CLD [9]. The study was conceived as an animal counterpart to the human trial by Klempner et al. that was published in 2001 [10], and the monkeys were treated with a regimen of intravenous ceftriaxone followed by oral doxycycline that was identical to the protocol used in the human trial. The results of this study showed that three-quarters of the monkeys failed treatment, and these animals had evidence of persistent infection in various tissues at necropsy using culture, immunofluorescence and PCR techniques [9]. Equally important, the study showed that 25% of treated monkeys cleared their infection, thereby demonstrating antibiotic efficacy in some animals. This finding contradicts the negative treatment results reported by Klempner et al. in humans to support the conclusion that antibiotics are not effective in treating patients with persistent Lyme disease symptoms [11]. In short, Embers was able to demonstrate persistence using an invasive approach (necropsy) that could not be used in human clinical trials [9][12].

In another study, Bockenstedt et al. presented a mouse model of B. burgdorferiinfection that on the surface appears to contradict the monkey study [13]. Following infection, the mice were treated with subcutaneous ceftriaxone or doxycycline administered in drinking water. The authors arrive at the conclusion that non-infectious spirochetal “debris” gets deposited around the joints of these mice, and instead of being cleared by the reticuloendothelial system this “debris” is responsible for persistent inflammation in mouse tissues [13]. The “debris”, which contained both DNA and protein particles, could not be cultured, transmitted to other mice via ear transplants or to ticks that were allowed to feed on the mice (xenodiagnosis).

This novel hypothesis of non-infectious persistence of B. burgdorferi“debris” including the presence of DNA contradicts previous experimental results. For example, Malawista et al. showed that B. burgdorferiDNA is rapidly cleared from culture-negative ear and bladder tissues of mice following prompt antibiotic treatment [14], and Lazarus et al. demonstrated that DNA from dead spirochetes is routinely cleared from mouse skin within several hours [15]. The “debris” hypothesis fails to explain persistence of viable spirochetes in culture, histology and xenodiagnosis experiments following antibiotic therapy. Furthermore, the study methods of Bockenstedt et al. may have been insufficient to rule out persistent spirochetal forms of B. burgdorferi, since ear transplants are often negative following antibiotic treatment, and using an insufficient number of animals for xenodiagnosis may fail to demonstrate transmissible infection [16][17]. Of greater importance, there appear to be two alternative mechanisms of B. burgdorferipersistence that merit consideration in these mice: the persistence of cysts (L-forms) and the inability to detect spirochetes in biofilms.

In a commentary on the mouse study, Alan Barbour proposed the alternative hypothesis that cell-wall deficient cysts (L-forms) may be responsible for B. burgdorferipersistence in these animals [18]. He noted that these cystic structures, which Bockenstedt et al. observed in their infected animals, have been described as a persister mechanism employed by many bacteria, including B.burgdorferi[19]-[27]. Bockenstedt et al. claim that these are not true cysts because they form too fast, appearing in minutes rather than hours or days. However, Brorson and Brorson have demonstrated that cysts of B. burgdorferimay develop in minutes under appropriate culture conditions [28]. Thus the observation of Bockenstedt et al. supports B. burgdorfericyst formation in their mouse model, and this cyst formation appears to be a better explanation for spirochetal persistence compared to the “debris” that the authors postulate.

As noted above, the methods employed by Bockenstedt et al. may not have been sufficient to exclude other persistent spirochetal forms such as cysts (L-forms) in their animals. Persistent viable organisms also may have been hidden in biofilms, the adherent polysaccharide-based matrices that protect bacteria against the host immune system and antibiotic therapy [1]. Biofilms of B. burgdorferihave been demonstrated in vitro by Sapi et al. [29]. These biofilms may take the form of “debris” on intravital microscopy, and they may contain organisms that are non-cultivable but still viable and prone to reactivation [29]-[31]. Biofilms of B. burgdorferiwould also be consistent with the “amber hypothesis” proposed as a mechanism of persistent Lyme disease symptoms due to “introduction into the joint space of non-viable spirochetes or spirochetal debris enmeshed in a host-derived fibrinous or collagenous matrix” [32]. Like the “debris” hypothesis, the “amber” hypothesis fails to explain live Borrelia persistence after antibiotic therapy. Persister spirochetes in biofilms could explain the experimental results of Bockenstedt et al. and would offer a more plausible explanation than the “debris” and “amber” hypotheses for the reasons outlined above.

Recently McClune et al. presented evidence that B. burgdorferipeptidoglycan (PG) can persist in synovial fluid after murine infection and may cause symptoms compatible with CLD [33]. McCausland et al. demonstrated unusual properties of the spirochete-derived PG that allow it to persist in mouse liver for weeks [34]. Although these observations may support the “debris” hypothesis of CLD, they do not rule out persistent B. burgdorferiinfection in cysts (L-forms) and biofilms. Further work is needed to examine the relationship between PG-induced inflammation and persistent spirochete infection in CLD.

Like most aspects of Lyme disease, the role of cysts (L-forms) and biofilms in persistent B. burgdorferiinfection has been controversial [1][30][35]. These spirochetal forms are resistant to common antibiotics due to reduced metabolic activity or protective matrices. Whether CLD arises from persisting spirochetal forms hidden in biofilms (as suggested by the monkey studies of Embers et al. and the work of Sapi et al.) or from cell wall-deficient cysts (L-forms) of B. burgdorferi(as suggested by the mouse study observations of Bockenstedt et al. and the interpretation of Barbour), persisting forms of bacteria require treatment. To date the treatment options for these bacterial persisters are extremely limited, but their recognition dictates a more aggressive approach to eradication of Lyme disease using combination antibiotic therapy modeled on treatment regimens for tuberculosis and HIV disease [2]. The fact that B. burgdorferishares cyst (L-form) properties, biofilm configurations and resistance genes with pathogenic mycobacteria supports the need for this therapeutic approach [36][37]. It remains to be seen which forms of B. burgdorferiare the true culprits in CLD and which treatments are most efficacious in clearing infection from patients [38]-[48].

 5. Strengths and Limitations

The strengths of this review lie in the demonstration of longterm Borreliainfection in animal models and persistent infection following antibiotic therapy in animals and humans. Although various detection techniques were used, the culture, histology and xenodiagnosis testing identified viable spirochetes that persisted for long periods in animal models and survived antibiotics in animal and human cases. Although conventional PCR is a useful detection method, it can only detect fragments of the spirochete, leaving the door open for the “debris” hypothesis. Overall, this review confirms that Borreliacan persist despite treatment, but the exact mechanism for this observation remains to be determined. Although this study was not a systematic review of the literature, we sought to include as many studies as possible that demonstrate viable Borreliapersistence through direct detection techniques following antibiotic therapy. Future more robust reviews are required to strengthen the level of evidence for the conclusions drawn from this study.

 6. Conclusion

In this article, we summarize evidence from animal models and human studies that support persistent spirochetal infection as the cause of CLD. Specifically, direct and functional testing using culture, histology and xenodiagnosis has shown viable organisms following antibiotic therapy, and the role of cysts (L-forms) and biofilms in this process is highlighted. Determining the mechanism behind Borreliapersistence may hold the key to development of targeted treatments for CLD.

 Authors’ Contributions

Raphael B. Stricker, Melissa C. Fesler and Lorraine Johnson meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). All authors made substantial contributions to the conception, design and revisions of the current article and were involved in the analysis and interpretation of data. All authors have approved the final version.

 Acknowledgements

The authors thank Joseph Burrascano, Michael Cook, Christine Green, Steven Harris, Erica Lehman, Ken Liegner, Marianne Middelveen, Eva Sapi, John Scott, Jyotsna Shah, Carl Tuttle, Karen Vanderhoof-Forschner and Edward Winger for helpful discussion. This article is dedicated to the memory of Pat Smith and Alan MacDonald.

 Appendix

Table A1. Evidence for persistent infection in animal models of Lyme disease*.

*PCR, polymerase chain reaction; LN, lymph node; ISH, in situ hybridization, **Time from initial infection to final positive testing point. †Detectable B.burgdorferi following antibiotic treatment.

 Table A1 References

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2. Duray PH, Johnson RC. The histopathology of experimentally infected hamsters with the Lyme disease spirochete, Borreliaburgdorferi. ProcSocExpBiolMed. 1986; 181: 263-9.

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9. Bockenstedt LK, Mao J, Hodzic E, Barthold SW, Fish D. Detection of attenuated, noninfectious spirochetes in Borreliaburgdorferi-infected mice after antibiotic treatment. JInfectDis. 2002; 186: 1430-7.

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Table A2. Evidence for persistent human infection following treatment of Lyme disease*†.

Study/Year/Reference Study Origin Persistence of B. burgdorferi Shown by Sample Source
Weber et al. , 1988 1 Europe Histology Brain, liver (Autopsy)**
Schmidli et al. , 1988 2 Europe Culture Synovial Fluid
Cimmino et al. , 1989 3 Europe Histology Spleen
Preac-Mursic et al. , 1989 4 Europe Culture Skin Bx, CSF
Pfister et al. , 1991 5 Europe Culture CSF
Strle et al. , 1993 6 Europe Culture Skin Bx
Preac-Mursic et al. , 1993 7 Europe Culture Iris Bx
Haupl et al. , 1993 8 Europe Culture Ligament Bx
Strle et al. , 1996 9 Europe Culture Skin Bx
Preac-Mursic et al. , 1996 10 Europe Culture Skin Bx, CSF
Oksi et al. , 1996 11 Europe Culture CSF
PCR Brain Bx
PCR Brain (Autopsy)
Priem et al. , 1998 12 Europe PCR Synovial Bx/Fluid
Oksi et al. , 1999 13 Europe Culture, PCR Blood
Breier et al. , 2001 14 Europe Culture Skin Bx
Hunfeld et al. , 2005 15 Europe Culture Skin Bx
Svecova et al. , 2008 16 Europe PCR Blood
Hudson et al. , 1998 17 Australia Culture, PCR Skin Bx
Steere et al. , 1988 18 USA Histology Synovial Bx
Kirsch et al. , 1988 19 USA Histology LN (Autopsy)
Liegner et al. , 1993 20 USA Histology Skin Bx
PCR Blood
Battafarano et al. , 1993 21 USA Histology, PCR Synovial Bx/Fluid
Chancellor et al. , 1993 22 USA Histology Bladder Bx
Nocton et al. , 1994 23 USA PCR Synovial Fluid
Shadick et al. , 1994 24 USA Histology Brain (Autopsy)
Masters et al. , 1994 25 USA Culture Blood
Lawrence et al. , 1995 26 USA PCR CSF
Bayer et al. , 1996 27 USA PCR Urine
Nocton et al. , 1996 28 USA PCR CSF
Marques et al. , 2014 29 USA Xenodiagnosis Tick***
Middelveen et al. , 2018 30 USA Culture, Histology Blood, Genital
PCR Secretions, Skin
Sapi et al. , 2019 31 USA PCR, Histology, FISH, Confocal microscopy Liver, Heart, Kidney, Brain (Autopsy)
Bransfield et al. , 2024 32 USA Histology, FISH Pancreas, Heart, Brain (Autopsy)

†Adapted from Stricker RB, Johnson L. Lyme disease: the next decade. InfectDrugResist. 2011; 4:1-9. *Except for case of Weber etal. (see below), all patients received a minimum of 10 days of antibiotic therapy. PCR, polymerase chain reaction; Bx, biopsy; CSF, cerebrospinal fluid; LN, lymph node. FISH, fluorescent in-situ hybridization; **Mother treated with antibiotics for one week during pregnancy; newborn died; ***B.burgdorferi DNA recovered from ticks fed on human Lyme patients.

 Table A2 References

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8. Haupl T, Hahn G, Rittig M, Krause A, Schoerner C, Schonherr U, Kalden JR, Burmester GR. Persistence of Borreliaburgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis. ArthritisRheum. 1993; 36: 1621-6.

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