Research

Treatment Guidelines

Cameron DJ, Johnson LB, Maloney EL. Evidence Assessments and Guideline Recommendations in Lyme Disease: The Clinical Management of Known Tick Bites, Erythema Migrans Rashes and Persistent Disease. Expert Rev Anti Infect There. 2014 Sep;12(9):1103-1135. don:10.1586/14787210.2014.940900

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 Nov 1;43(9):1089-1134.

Centers for Disease Control and Prevention (CDC). Lyme Disease (Borrelia burgdorferi) 2022 Case Definition. Council of State and Territorial Epidemiologists (CSTE) Position Statement(s)

Maloney, Elizabeth L. “The management of Ixodes scapularis bites in the upper Midwest.” WMJ: Official Publication of the State Medical Society of Wisconsin 110.2 (2011): 78-81.

Tick Behavior and Exposure Prevention

Eisen, Rebecca J., and Lars Eisen. “The blacklegged tick, Ixodes scapularis: an increasing public health concern.” Trends in parasitology 34.4 (2018): 295-309.

Omodior, O., Luetke, M., Kianersi, S. et al. Predictors of Tick Exposure Risk-Reduction Behavior in Indiana. J Community Health 45, 862–870 (2020). https://doi.org/10.1007/s10900-020-00803-1

Omodior, Oghenekaro PhD, MPH; Kianersi, Sina DVM; Luetke, Maya MSPH. Prevalence of Risk and Protective Factors for Tick Exposure and Tick-Borne Disease Among Residents of Indiana. Journal of Public Health Management and Practice: November/December 2021 – Volume 27 – Issue 6 – p E210-E219 doi: 10.1097/PHH.0000000000001070

Chris Wojan, Thomas Thrasher, Evan Lacey, Keith Clay, Distribution, Dynamics, and Diversity of Questing Ticks in the Lower Midwest, Journal of Medical Entomology, Volume 59, Issue 1, January 2022, Pages 273–282, https://doi.org/10.1093/jme/tjab155

Micah B. Hahn, Catherine S. Jarnevich, Andrew J. Monaghan, Rebecca J. Eisen, Modeling the Geographic Distribution of Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae) in the Contiguous United States , Journal of Medical Entomology, Volume 53, Issue 5, September 2016, Pages 1176–1191, https://doi.org/10.1093/jme/tjw076

Rebecca J. Eisen, Lars Eisen, Charles B. Beard, County-Scale Distribution of Ixodes scapularis and Ixodes pacificus (Acari: Ixodidae) in the Continental United States , Journal of Medical Entomology, Volume 53, Issue 2, March 2016, Pages 349–386, https://doi.org/10.1093/jme/tjv237

Ticks as Transmitters (Vectors) of Disease

Schwartz AM, Hinckley AF, Mead PS, Hook SA, Kugeler KJ. Surveillance for Lyme Disease — United States, 2008–2015. MMWR Surveill Summ 2017;66(No. SS-22):1–12. DOI: http://dx.doi.org/10.15585/mmwr.ss6622a1

Ticks in Indiana Infected with Lyme Disease

https://www.in.gov/health/erc/zoonotic-and-vectorborne-epidemiology-entomology/maps-and-statistics/lyme-disease-tick-infection-maps/

Cook, Michael J. “Lyme borreliosis: a review of data on transmission time after tick attachment.” International journal of general medicine 8 (2015): 1.

Pathogen transmission in relation to duration of attachment by Ixodes scapularis ticks. Ticks Tick Borne Dis. Eisen L. 2018 Mar;9(3):535-542. doi: 10.1016/j.ttbdis.2018.01.002. Epub 2018 Jan 31. PMID: 29398603; PMCID: PMC5857464.

Tick-Borne Illnesses – Symptom severity and variability

Johnson, Lorraine, et al. “Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey.” PeerJ 2 (2014): e322.

Rebman, Alison W., et al. “The clinical, symptom, and quality-of-life characterization of a well-defined group of patients with posttreatment Lyme disease syndrome.” Frontiers in medicine (2017): 224.

Shor, Samuel. “Retrospective analysis of a cohort of internationally case defined chronic fatigue syndrome patients in a Lyme endemic area.” Bulletin of the IACFS/ME 18 (2011): 109-23.

Citera, Maryalice, Phyllis R. Freeman, and Richard I. Horowitz. “Empirical validation of the Horowitz multiple systemic infectious disease syndrome questionnaire for suspected Lyme disease.” International Journal of General Medicine 10 (2017): 249.

Nadelman RB, Nowakowski J, Forseter G, Goldberg NS, Bittker S, Cooper D, Aguero-Rosenfeld M, Wormser GP. The clinical spectrum of early Lyme borreliosis in patients with culture-confirmed erythema migrans. Am J Med. 1996 May;100(5):502-8. doi: 10.1016/s0002-9343(95)99915-9. PMID: 8644761.

Horowitz RI, Freeman PR. Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. Int J Gen Med. 2019 Feb 18;12:101-119. doi: 10.2147/IJGM.S193608. PMID: 30863136; PMCID: PMC6388746.

Duray, Paul Harrison, and Allen C. Steere. “The spectrum of organ and systems pathology in human Lyme disease.” Zentralblatt für Bakteriologie, Mikrobiologie und Hygiene. Series A: Medical Microbiology, Infectious Diseases, Virology, Parasitology 263.1-2 (1986): 169-178.

Lobraico, Jessika, et al. “New insights into stages of Lyme disease symptoms from a novel hospital-based registry.” Journal of Primary Care & Community Health 5.4 (2014): 284-287.

Systemic symptoms without erythema migrans as the presenting picture of early Lyme disease
Steere, Allen C et al. The American Journal of Medicine, Volume 114, Issue 1, 58 – 62

Diagnostic Considerations

Centers for Disease Control and Prevention (CDC). https://ndc.services.cdc.gov/case-definitions/lyme-disease-2017/. Council of State and Territorial Epidemiologists (CSTE) Position Statement(s)

Stricker RB, Lautin A, Burrascano JJ. Lyme disease: point/counterpoint. Expert Rev Anti Infect Ther. 2005 Apr;3(2):155-65. doi: 10.1586/14787210.3.2.155. PMID: 15918774.

Horn EJ, Dempsey G, Schotthoefer AM, Prisco ULMcArdle M, Gervasi SS, Golightly M, De Luca C, Evans M, Pritt BS, Theel ES, Iyer R, Liveris D, Wang G, Goldstein D, Schwartz I. 2020. The Lyme Disease Biobank: Characterization of 550 Patient and Control Samples from the East Coast and Upper Midwest of the United States. J Clin Microbiol 58:10.1128/jcm.00032-20. https://doi.org/10.1128/jcm.00032-20

Rudenko, Natasha, et al. “Isolation of live Borrelia burgdorferi sensu lato spirochaetes from patients with undefined disorders and symptoms not typical for Lyme borreliosis.” Clinical microbiology and infection 22.3 (2016): 267-e9.

Stricker, R. B., and L. Johnson. “Lyme disease diagnosis and treatment: lessons from the AIDS epidemic.” Minerva medica 101.6 (2010): 419-425.

Elsner, R. A., S. W. Barthold, and N. Baumgarth. “77: The immune system cannot generate immunological memory during infection with the Lyme disease agent B. burgdorfer.” Cytokine 63.3 (2013): 261.

Murphree Bacon, Rendi, Kiersten J. Kugeler, and Paul S. Mead. “Surveillance for Lyme disease–United States, 1992-2006.” (2008).

Horowitz, R. I., et al. “To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis.” Clinical Microbiology and Infection 24.2 (2018): 210.

Advances in Serodiagnostic Testing for Lyme Disease Are at Hand, Clinical Infectious Diseases, Branda et al. Volume 66, Issue 7, 1 April 2018, Pages 1133–1139, https://doi.org/10.1093/cid/cix943

Treatment Considerations
Jariwala, Neha, Erum Ilyas, and Herbert B. Allen. “Lyme disease: a bioethical morass.” J Clin Res Bioeth 7.1000288 (2016): 2.

Maloney, Elizabeth L. “The need for clinical judgment in the diagnosis and treatment of Lyme disease.” Journal of American Physicians and Surgeons 14.3 (2009): 82-89.

Johnson, Lorraine, Alexandra Aylward, and Raphael B. Stricker. “Healthcare access and burden of care for patients with Lyme disease: a large United States survey.” Health policy 102.1 (2011): 64-71.

Crowder, L. A., et al. “Lyme disease and post-treatment Lyme disease syndrome: the neglected disease in our own backyard.” Public Health 128.9 (2014): 784-791.

Garro, Aris C., et al. “Empiric antibiotics for children with suspected Lyme disease.” Ticks and Tick-borne Diseases 13.5 (2022): 101989.

DeLong, Allison K., et al. “Potential benefits of retreatment highlight the need for additional Lyme disease research.” The American Journal of Medicine 127.2 (2014): e9-e10.

Feder Jr, Henry M., et al. “Early Lyme disease: a flu-like illness without erythema migrans.” Pediatrics 91.2 (1993): 456-459.

Fallon, Brian A., et al. “Lyme borreliosis: Neuropsychiatric aspects and neuropathology.” Psychiatric Annals 36.2 (2006): 120.

Fallon, Brian A., et al. “A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.” Neurology 70.13 (2008): 992-1003.

Krupp, Lauren B., et al. “Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial.” Neurology 60.12 (2003): 1923-1930.

Cameron, D. “Severity of Lyme disease with persistent symptoms. Insights from a double-blind placebo-controlled clinical trial.” Minerva medica 99.5 (2008): 489-496.

Wahlberg, Peter, et al. “Treatment of late Lyme borreliosis.” Journal of Infection 29.3 (1994): 255-261.

Donta, Sam T. “Tetracycline therapy for chronic Lyme disease.” Clinical infectious diseases 25.Supplement_1 (1997): S52-S56.

Oksi, Jarmo, Jukka Nikoskelainen, and Matti K. Viljanen. “Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis.” European Journal of Clinical Microbiology and Infectious Diseases 17.10 (1998): 715-719.

Persistent Infection and Persistent Illness
Shor, Samuel, et al. “Chronic Lyme disease: An evidence-based definition by the ILADS Working Group.” Antibiotics 8.4 (2019): 269.

Aucott JN. Posttreatment Lyme disease syndrome. Infect Dis Clin North Am. 2015 Jun;29(2):309-23. doi: 10.1016/j.idc.2015.02.012. PMID: 25999226.

Cameron, Daniel J. “Proof that chronic Lyme disease exists.” Interdisciplinary Perspectives on Infectious Diseases 2010 (2010).

Maloney EL. Controversies in Persistent (Chronic) Lyme Disease. J Infus Nurs. 2016 Nov/Dec;39(6):369-375. doi: 10.1097/NAN.0000000000000195. PMID: 27755213; PMCID: PMC5102277.

Victoria Cairns, Jon Godwin, Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms, International Journal of Epidemiology, Volume 34, Issue 6, December 2005, Pages 1340–1345, https://doi.org/10.1093/ije/dyi129,

Sharma, Bijaya, et al. “Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells.” Antimicrobial agents and chemotherapy 59.8 (2015): 4616-4624.

Caskey, John R., and Monica E. Embers. “Persister development by Borrelia burgdorferi populations in vitro.” Antimicrobial agents and chemotherapy 59.10 (2015): 6288-6295.

Hodzic, Emir, et al. “Persistence of Borrelia burgdorferi following antibiotic treatment in mice.” Antimicrobial agents and chemotherapy 52.5 (2008): 1728-1736.

Barthold, Stephen W., et al. “Ineffectiveness of tigecycline against persistent Borrelia burgdorferi.” Antimicrobial agents and chemotherapy 54.2 (2010): 643-651.

Feng, Jie, et al. “Persister mechanisms in Borrelia burgdorferi: implications for improved intervention.” Emerging microbes & infections 4.1 (2015): 1-3.

Feng, Jie, et al. “Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library.” Emerging microbes & infections 3.1 (2014): 1-8.

Embers, Monica E., et al. “Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection.” PloS one 7.1 (2012): e29914.

Aslam, Bilal, et al. “Immune escape strategies of Borrelia burgdorferi.” Future Microbiology 12.13 (2017): 1219-1237.

Häupl, Thomas, et al. “Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 36.11 (1993): 1621-1626.

Zhang, Jing-Ren, et al. “Antigenic variation in Lyme disease borreliae by promiscuous recombination of VMP-like sequence cassettes.” Cell 89.2 (1997): 275-285.

Coutte, Loïc, et al. “Detailed analysis of sequence changes occurring during vlsE antigenic variation in the mouse model of Borrelia burgdorferi infection.” PLoS pathogens 5.2 (2009): e1000293.

Liang, Fang Ting, et al. “An immune evasion mechanism for spirochetal persistence in Lyme borreliosis.” The Journal of experimental medicine 195.4 (2002): 415-422.

Barbour, Alan G., et al. “Pathogen escape from host immunity by a genome program for antigenic variation.” Proceedings of the National Academy of Sciences 103.48 (2006): 18290-18295.

Schwan, Tom G., and Joseph Piesman. “Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi, during the chain of infection in ticks and mice.” Journal of clinical microbiology 38.1 (2000): 382-388.

David W. Dorward, Elizabeth R. Fischer, Diane M. Brooks. Invasion and Cytopathic Killing of Human Lymphocytes by Spirochetes Causing Lyme Disease, Clinical Infectious Diseases, Volume 25, Issue Supplement_1, July 1997, Pages S2–S8, https://doi.org/10.1086/516169

Sapi, Eva, et al. “Evaluation of in-vitro antibiotic susceptibility of different morphological forms of Borrelia burgdorferi.” Infection and drug resistance 4 (2011): 97.

Sapi, Eva, et al. “Characterization of biofilm formation by Borrelia burgdorferi in vitro.” PloS one 7.10 (2012): e48277.

Dunham-Ems, Star M., et al. “Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks.” The Journal of clinical investigation 119.12 (2009): 3652-3665

Stricker, Raphael B., Fesler, Melissa C., and Johnson, Lorraine. Persistent Borrelia Infection in Chronic Lyme Disease: A Review of the Medical Literature. Scientific Research. Advances in Infectious Diseases, Vol.No. 1, March 2026.

 

Lyme Disease in its varied forms and with involvement of multiple additional infections

Borrelia in Its Different Forms

Brorson, Ø., and Sverre-Henning Brorson. “Transformation of cystic forms of Borrelia burgdorferi to normal, mobile spirochetes.” Infection 25.4 (1997): 240-246.

Miklossy, Judith, et al. “Persisting atypical and cystic forms of Borrelia burgdorferiand local inflammation in Lyme neuroborreliosis.” Journal of neuroinflammation 5.1 (2008): 1-18.

Kersten, A., et al. “Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi.” Antimicrobial agents and chemotherapy 39.5 (1995): 1127-1133.

Al‐Robaiy, Samiya, et al. “Metamorphosis of Borrelia burgdorferi organisms–RNA, lipid and protein composition in context with the spirochetes’ shape.” Journal of basic microbiology 50.S1 (2010): S5-S17.

Duray, Paul H., et al. “Invasion of human tissue ex vivo by Borrelia burgdorferi.” Journal of Infectious Diseases 191.10 (2005): 1747-1754.

Alban, P. Scott, Paul W. Johnson, and David R. Nelson. “Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi.” Microbiology 146.1 (2000): 119-127.

Mursic, Vera Preac, et al. “Formation and cultivation ofBorrelia burgdorferi spheroplast-L-form variants.” Infection 24.3 (1996): 218-226.

David J. Civitello, Evelyn Rynkiewicz & Keith Clay (2010) Meta-Analysis of Co-Infections in Ticks, Israel Journal of Ecology & Evolution, 56:3-4, 417-431, DOI: 10.1560/IJEE.56.3-4.417

Tokarz, Rafal, et al. “Assessment of polymicrobial infections in ticks in New York state.” Vector-Borne and Zoonotic Diseases 10.3 (2010): 217-221.

Swanson, Stephen J., et al. “Coinfections acquired from Ixodes ticks.” Clinical microbiology reviews 19.4 (2006): 708-727.

Owen, David C. “Is Lyme disease always poly microbial?–The jigsaw hypothesis.” Medical hypotheses 67.4 (2006): 860-864.

 

Co-infections – TBRF

Talagrand-Reboul, Emilie, et al. “Relapsing fevers: neglected tick-borne diseases.” Frontiers in cellular and infection microbiology 8 (2018): 98.

Kingry, Luke C., et al. “Surveillance for and discovery of Borrelia species in US patients suspected of tickborne illness.” Clinical Infectious Diseases 66.12 (2018): 1864-1871.

 

Co-infections – Babesia

Schnittger, Leonhard, et al. “Babesia: a world emerging.” Infection, Genetics and Evolution 12.8 (2012): 1788-1809.

 

Co-infections – Bartonella

Reis, Caroline, et al. “Vector competence of the tick Ixodes ricinus for transmission of Bartonella birtlesii.” PLoS Neglected Tropical Diseases 5.5 (2011): e1186.

Maggi, Ricardo G., et al. “Bartonella spp. bacteremia and rheumatic symptoms in patients from Lyme disease–endemic region.” Emerging infectious diseases 18.5 (2012): 783.

 

Co-infections – Rickettsia

Biggs, Holly M., et al. “Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichiosis, and anaplasmosis—United States: A practical guide for health care and public health professionals.” Morbidity and Mortality Weekly Report: Recommendations and Reports 65.2 (2016): 1-44.

 

Co-infections – Mycoplasma

Sauteur, Patrick M. Meyer, et al. “The art and science of diagnosing Mycoplasma pneumoniae infection.” The Pediatric Infectious Disease Journal 37.11 (2018): 1192-1195.

Some of the Diagnoses which can be related to Tick-Borne Illnesses
Livengood, Jill A., and Robert D. Gilmore Jr. “Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.” Microbes and infection 8.14-15 (2006): 2832-2840.

Bransfield, Robert C. “Neuropsychiatric Lyme borreliosis: an overview with a focus on a specialty psychiatrist’s clinical practice.” Healthcare. Vol. 6. No. 3. MDPI, 2018.

Hájek, Tomáš, et al. “Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects.” American Journal of Psychiatry 159.2 (2002): 297-301.

Bransfield, Robert C., et al. “A clinical diagnostic system for late-stage neuropsychiatric Lyme Borreliosis based upon an analysis of 100 patients.” Healthcare. Vol. 8. No. 1. Multidisciplinary Digital Publishing Institute, 2020.

Bransfield, Robert C. “Suicide and Lyme and associated diseases.” Neuropsychiatric disease and treatment 13 (2017): 1575.

Shor, Samuel. “Retrospective analysis of a cohort of internationally case defined chronic fatigue syndrome patients in a Lyme endemic area.” Bulletin of the IACFS/ME 18 (2011): 109-23.

Brinar, Vesna V., and Mario Habek. “Rare infections mimicking MS.” Clinical neurology and Neurosurgery 112.7 (2010): 625-628.

Spirin, N. N., et al. “Differential aspects of multiple sclerosis and chronic borrelial encephalomyelitis.” Zhurnal Nevrologii i Psikhiatrii Imeni SS Korsakova 111.7 (2011): 8-12.

Pediatric Considerations
Nigrovic, Lise E., et al. “A minority of children diagnosed with Lyme disease recall a preceding tick bite.” Ticks and tick-borne diseases 10.3 (2019): 694-696.

Greenberg R. Infections and Childhood Psychiatric Disorders: Tick-Borne Illness and Bipolar; Disorder in Youth. Bipolar Disorder 2017. 3: 113.Doi: 10.4172?2472-1077.1000113

Tager, Felice A., et al. “A controlled study of cognitive deficits in children with chronic Lyme disease.” The Journal of neuropsychiatry and clinical neurosciences 13.4 (2001): 500-507.

Shea LJ. NYU Rusk Institute of Rehabilitative Medicine. The Neuropsychology of Lyme Disease: Challenges and Controversy in Lyme Disease and Tick Borne Illness Care Symposium. Mass General Hospital. Boston MA. Nov 9, 2013.

Baytunca, Muharrem Burak, Tugba Donuk, and Serpil Erermis. “Evaluation of a Neuropsychiatric Disorder: From PANDAS to PANS and CANS.” Turk Psikiyatri Dergisi 27.2 (2016).

Klein. Infectious Diseases of the Fetus and Newborn. Chapter by Gardner T. “Lyme Disease”. (1995) New York, NY. Remington-Saunders, p.447-528.

Bransfield, Robert C. “Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome.” (2009): 125-140.

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