Comments from “The Patient -Centered Care Advocacy Group”

Inadequacy of tick- bite prophylaxis recommendations:

The IDSA recommendation for prophylaxis of Lyme disease are based on a study published in the New England Journal of Medicine in 2001.[i]

The study evaluated the efficacy of a single dose of doxycycline for preventing Lyme disease after a tick bite. Endpoints in the study included erythema migrans (EM), isolation of Borrelia burgdorferi in culture, or seroconversion. The study design was randomized, double-blind, and involved over 450 subjects. The end points used to determine if subjects were infected with B. burgdorferi and developed Lyme disease are shown below:

“The primary end point was the development of erythema migrans at the site of the tick bite. Erythema migrans occurring at a different site from that of the identified tick bite and laboratory evidence of B. burgdorferi infection in the absence of erythema migrans were analyzed as secondary end points. Seroconversion was defined as a change from a negative result on ELISA to an equivocal or positive result in association with the presence of IgM bands on immunoblotting that met the recommended criteria for seropositivity.”

The conclusion of this study that the prophylaxis “prevented Lyme disease” is inadequately supported by the data presented in the paper. The study design is based on “end points” for Lyme disease which rule out subjects who did not develop an EM rash or seroconvert during the 6-week study period. As noted in the HHS Tick-Borne Disease Working Group 2018 report to Congress[ii], the clinical observations of acute viral-like illness without EM, disseminated EMs, asymptomatic seroconversion, and febrile episodes are, in fact, symptoms associated with Borrelia burgdorferi infection (Lyme disease), and in some cases these symptoms may not occur for weeks to months after infection.

CDC surveillance data from 1992-2006 documented that 31% of surveillance cases lacked an EM rash.[iii] Patient-derived data from the MyLymeData patient registry (a project by LymeDisease.org)[iv] noted that only 34% of 3,903 patients recalled having an EM rash. More commonly reported early symptoms were flu-like symptoms (64%) and severe headache or stiff neck (44%).

In a comprehensive study of the pathobiology of infection with B. burgdorferi in outbred non-human primates (NHPs), the rate of EM in NHPs infected by nymph tick bite and confirmed to be infected by culture or PCR, was only 10%. It is noted by the NHP researchers that more than half of infected NHPs do not develop any erythematous rash (personal communication with the study authors) following infection. NHP studies convincingly demonstrate that the macaque model most closely resembles human borreliosis and provides the best experimental model to study Lyme disease.[v] In this animal model, the rate of association between EM and B. burgdorferi infection is low.

Since the association between EM and B. burgdorferi infection (Lyme disease) is quite low (40-70%), the number of subjects who developed Lyme disease cannot be determined from the data. The data shows only that there was a statistical difference in the rate of EM, but not Lyme disease, between the prophylaxis and placebo groups.

In a study which evaluated existing diagnostic tests for a “definitive diagnosis” of Lyme disease, the sensitivity of ELISA during the acute phase of infection is less than 50%.[vi] Subjects in the single dose prophylaxis study were therefore equally likely to have Lyme disease, whether the ELISA was positive or negative.

As noted in the HHS Tick Borne Disease Working Group report to Congress, seroconversion, defined by the study authors as “a change from a negative result on ELISA to an equivocal or positive result in association with the presence of IgM bands on immunoblotting,” may not occur during the first 4-6 weeks of infection. It was also noted that treatment of B. burgdorferi infection with an antibiotic, prophylactic or otherwise, is shown to prevent seroconversion, and that a proportion of people infected with B. burgdorferi do not seroconvert at all. As this study ended at 6 weeks, subjects who were infected but did not seroconvert or develop symptoms for weeks to months post infection, would not have been considered to have Lyme disease.

In Table 3 of the NEJM article, three subjects—one in the treatment group and two in the placebo group—had nonspecific symptoms and evidence of B. burgdorferi infection (secondary endpoints of the study). It should be noted for these characteristics – nonspecific symptoms and seroconversion – there appears to be no statistical difference between the treatment and placebo groups, which indicates that the prophylaxis does not prevent Lyme disease.

Since neither the primary or secondary end points used in this study will identify subjects with Lyme disease, the conclusion that the single dose prophylaxis prevents Lyme disease is invalid.

As detailed in Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease, published by the International Lyme and Associated Diseases Society (ILADS) in 2014,[vii] the quality of the evidence supporting the use of a single 200 mg dose of doxycycline following a tick bite is very low, implying that the true effectiveness of this prophylaxis is likely to be substantially different from the effectiveness rate reported in the NEJM article.

Instead, ILADS makes the following recommendation: “Clinicians should promptly offer antibiotic prophylaxis for known Ixodes tick bites in which there is evidence of tick feeding, regardless of the degree of tick engorgement or the infection rate in the local tick population. The preferred regimen is 100–200 mg of doxycycline, twice daily for 20 days.”

Finally, in the Discussion section of the NEJM article that is used to support the recommendation that a single dose doxycycline prophylaxis prevents Lyme disease, the authors note, “The efficacy rate found in our study should be interpreted cautiously, however, because of the relatively small number of subjects in whom Lyme disease developed and the resultant wide 95 percent confidence interval (25 to 98 percent).” They also concluded that “Our results contrast with those of previous studies,^6-8 which showed no clear protection attributable to antimicrobial prophylaxis given after a tick bite.”

Since there is contrasting evidence showing that antimicrobial prophylaxis does not prevent Lyme disease, the recommendation should be removed until such time that an unbiased study on tick bite prophylaxis can be completed.

Nadelman R, Nowakowski J, Fish 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. doi:10.1056/nejm200107123450201 https://www.ncbi.nlm.nih.gov/pubmed/11450675

[ii] 2018 Report to Congress by the Tick Borne Disease Working Group.
www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/index.html

[iii] Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease–United States, 1992-2006. MMWR SurveillSumm. 2008;57(10):1–9. www.ncbi.nlm.nih.gov/pubmed/18830214

[iv]MyLymeData https://www.lymedisease.org/mylymedata-lyme-disease-research

[v] Embers ME, Hasenkampf NR, Jacobs MB, Tardo AC, Doyle-Meyers LA, Philipp MT, et al. Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS ONE 12(12): e0189071. https://doi.org/10.1371/journal.pone.0189071

[vi] Coulter P, Lema C, Flayhart D, et al. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol. 2005;43(10):5080–5084. doi:10.1128/JCM.43.10.5080-5084.2005 https://www.ncbi.nlm.nih.gov/pubmed/16207966

[vii] 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 Ther. 2014;12(9):1103–1135. doi:10.1586/14787210.2014.940900 https://www.ncbi.nlm.nih.gov/pubmed/25077519

[i] Nadelman R, Nowakowski J, Fish 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. doi:10.1056/nejm200107123450201 https://www.ncbi.nlm.nih.gov/pubmed/11450675

[ii] 2018 Report to Congress by the Tick Borne Disease Working Group.
www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/index.html

[iii] Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease–United States, 1992-2006. MMWR SurveillSumm. 2008;57(10):1–9. www.ncbi.nlm.nih.gov/pubmed/18830214

[iv]MyLymeData https://www.lymedisease.org/mylymedata-lyme-disease-research

[ii] 2018 Report to Congress by the Tick Borne Disease Working Group.
www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/index.html

[iii] Bacon RM, Kugeler KJ, Mead PS. Surveillance for Lyme disease–United States, 1992-2006. MMWR SurveillSumm. 2008;57(10):1–9. www.ncbi.nlm.nih.gov/pubmed/18830214

[iv]MyLymeData https://www.lymedisease.org/mylymedata-lyme-disease-research

Bruce Alan Fries, President

Lyme Disease Guidelines: www.lymediseaseguidelines.org is your site for guideline response. Devoted to transparency in Lyme diagnosis and treatment Guidelines