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In the Clinic |

Lyme Disease

Linden T. Hu, MD
[+] Article, Author, and Disclosure Information

CME Objective: To review current evidence for prevention, diagnosis, and treatment of Lyme disease.

Funding Source: American College of Physicians.

Disclosures: Dr. Hu, ACP Contributing Author, has disclosed the following conflicts of interests: Consultancy: Abzyme; Grants/Grants Pending: Mass Biologics and Sanofi; Royalties: Up to Date. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0012.

Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.

With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians.

In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.

Ann Intern Med. 2016;164(9):ITC65-ITC80. doi:10.7326/AITC201605030
© 2016 American College of Physicians
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This issue provides a clinical overview of Lyme disease, focusing on prevention, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.


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Posted on June 8, 2016
Daniel Weiss MD, CDE, FACP
Your Diabetes Endocrine Nutrition Group,Inc.
Conflict of Interest: None Declared
In May, the incidence of vector-borne disease increases markedly as more Americans spend time outdoors. Therefore Dr. Hu’s review on Lyme disease is opportune (In the Clinic May 3, 2016). However Hu provides little new information to help clinicians with decision-making, and repeats outdated dogma.

First Hu claims that ticks need to be attached for 24 hours for Borrelia burgdorferi to be transmitted. Yet the minimum attachment time for transmission has never been demonstrated1. As Hu states, many patients with Lyme are unaware of having been bitten.

Second, the recommendation to use a single dose doxycycline for prophylaxis after a tick bite contradicts the evidence that supports treatments of 20 days or longer2.

Third, resolution of erythema migrans is not a demonstration of treatment success. The eruption resolves on its own, increasing clinical confusion about disease duration and resolution.

Fourth, the fundamental challenge in Lyme disease is the lack of a gold standard to rule out infection or to prove cure. Hu states that diagnostic tests for Lyme have high false positivity, yet chronic infection with Borrelia burgdorferi leads to immune depression and hypogammaglobulinemia3. Indeed there is substantial evidence of high rates of false negative serologic tests for Lyme. Lyme patients and their physicians must recognize that serologic tests alone neither prove nor disprove infection. In contrast a positive culture is very compelling evidence of active infection. A reliable culture method is commercially available, but not widely used4.

Fifth, this absence of a gold standard for diagnosis and cure is a fundamental obstacle to progress against this disease. Confused clinical definitions and circular reasoning often equate the disappearance of erythema migrans with the resolution of disease, leading to erratic reporting. For example, Hu published a review in JAMA one week before the Annals article. In JAMA he estimated that 90% of patients with Lyme have erythema migrans 5. In the Annals, his estimate was 70%.

Lastly, treatment guidelines described by Hu contradict those posted on the National Guideline Clearinghouse. Older CDC guidelines do not meet modern standards of proof and are misleading. Patients and clinicians should be referred to the only evidence-based guidelines currently available2. Reviews that obfuscate and mislead do not help the more than 300,000 people who will contract Lyme disease in the U.S. this year, or the millions already suffering with complications of this infection.


1. Cook, M. J. Lyme borreliosis: a review of data on transmission time after tick attachment. Int J Gen Med 8, 1–8 (2015).
2. Cameron, D. J., Johnson, L. B. & Mahoney, E. L. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Review of Anti-Infective Therapy 1–33 (2014). doi:10.1586/14787210.2014.940900
3. Berndtson, K. Review of evidence for immune evasion and persistent infection in Lyme disease. Int J Gen Med 6, 291–306 (2013).
4. Sapi, E. et al. Improved culture conditions for the growth and detection of Borrelia from human serum. Int J Med Sci 10, 362–376 (2013).
5. Sanchez, E., Vannier, E., Wormser, G. P. & Hu, L. T. Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. JAMA 315, 1767–1777 (2016).

Author's Response
Posted on June 24, 2016
Linden T. Hu, MD
Conflict of Interest: None Declared
Thank you Dr. Weiss for your comments on the In the Clinic article on Lyme Disease(1). I will try to address your points individually below:
1. I completely agree that there has never been a study that demonstrates the transmission time from an infected tick to a human. Estimates for the time of attachment needed to transmit infection are extrapolations from animal studies that may or may not accurately reflect human transmission. And as stated, studies of the efficacy of removal of feeding ticks before 24-48 hours at preventing disease have been mixed. However, there is little downside risk to early removal of attached ticks.
2. Recommendations for consideration of single dose doxycycline prophylaxis are based on results of a randomized controlled trial (2). It is not unusual for recommendations for prophylaxis and treatment of disease to differ.
3. I agree that resolution of erythema migrans alone is not sufficient to establish treatment success. In the majority of treatment studies, resolution of erythema migrans was not used as the sole criteria for success of therapy. Most studies also compared time to resolution, need for retreatment and development of late sequelae.
4. As was stated in the article, there are currently no tests available that offer “proof of cure” and that serologic testing cannot distinguish between active and treated infection. While there are known causes of false negative serologic testing, immune depression and hypogammaglobulinemia are not thought to be related to B. burgdorferi infection. I do fully endorse the statement that serologic tests alone neither prove nor disprove infection. The culture method cited by Dr. Weiss has not been independently validated and substantial questions have been raised about the results(3).
5. It is agreed that better definitions and diagnostic tests are needed in the controversial area involving patients with persistent symptoms after treatment for Lyme disease.
6. The guidelines posted in the National Guideline Clearinghouse are from the International Lyme and Associated Diseases Society (ILADS) and have not been endorsed by the National Guidelines Clearinghouse or other major medical societies. While I fully agree that there is a need for higher quality data regarding the treatment of many aspects of Lyme disease, the presented recommendations are up to date based on currently available information.
1. Hu LT. Lyme Disease. Ann Intern Med. 2016;164(9):ITC65-ITC80.
2. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKenna D, et al. Prophylaxis with single-dose doxycycline for the prevention of Lyme disease after an Ixodes scapularis tick bite. New England Journal of Medicine. 2001;345(2):79-84.
3. Johnson BJ, Pilgard MA, Russell TM. Assessment of new culture method for detection of Borrelia species from serum of lyme disease patients. J Clin Microbiol. 2014;52(3):721-4.

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