On 2017 Mar 15, Sin Hang Lee commented:

Correspondence submitted to Nat.Rev.Dis.Primers

In their recent Primer [Lyme borreliosis. Nat. Rev. Dis. Primers 2, 16091 (2016)] Allen Steere and colleagues described Lyme borreliosis as an important emerging infectious disease [1]. The authors assert that the natural history of untreated Lyme borreliosis can be divided into stages 1, 2 and 3, and that the early stage 1 infections can be treated successfully with a 10–14 day course of antibiotics. However, the authors also stated that demonstration of borrelial infection by laboratory testing is required for reliable diagnosis of Lyme borreliosis, with the exception of erythema migrans and that serodiagnostic tests are insensitive during the first several weeks of infection. If not treated early, “within days to weeks, the strains of B. burgdorferi in the United States commonly disseminate from the site of the tick bite to other regions of the body”. In other words, the authors have affirmed that if reliably diagnosed at the early stage of the infection, Lyme borreliosis can be cured with timely, appropriate antibiotics to prevent deep tissue damage along with its associated clinical manifestations resulting from host immune response to various spirochetal products or components. In the Outlook Diagnostic tests section of the article, the authors failed to mention the fact that currently the diagnosis of emerging infectious diseases largely depends on finding evidence of the causative agent in the host by nucleic acid-based tests [2], not serodiagnostic tests which usually turn positive only during convalescence. The authors seem to advise the medical practitioners to not treat Lyme disease patients until the proliferating spirochetes in the host have elicited certain immune responses which can be confirmed by serologic tests. Such practice should not be accepted or continued for obvious reasons.

The authors stated “After being deposited in the skin, B. burgdorferi usually multiplies locally before spreading through tissues and into the blood or lymphatic system, which facilitates migration to distant sites.”. This statement acknowledges that spirochetemia is an early phase in the pathogenesis of Lyme borreliosis. But under the section of Diagnostic tests, polymerase chain reaction (PCR) test was only mentioned for synovial fluid of patients in late Lyme arthritis and for cerebrospinal fluid (CSF) of late neuroborreliosis. To refute the usefulness of DNA test for Lyme disease diagnosis, the authors cited a study which showed borrelial DNA was detected in synovial fluid of Lyme arthritis patients containing moribund or dead spirochetes [3]. However, the authors failed to discuss the significance of detection of borrelial DNA in the diagnosis of spirochetemia. The authors failed to acknowledge that even the finding of moribund or dead borrelial cells circulating in the blood is diagnostic of an active infection. Free foreign DNA is degraded and eliminated from the mammalian host’s blood within 48 hours [4]. Detection of any borrelial DNA validated by DNA sequencing is indicative of a recent presence of spirochetes, dead or alive, in the circulating blood which is evidence of an active infection beyond a reasonable doubt.

It seems unfortunate for many current Lyme disease patients that Lyme arthritis was described before the era of Sanger sequencing and PCR [5]. If Lyme borreliosis were discovered as an emerging infectious disease today, Lyme disease would probably be routinely diagnosed using a highly accurate nucleic acid amplification test, as reiterated by Dr. Tom Frieden, director of the Centers for Disease Control and Prevention (CDC) for Zika virus infection [6], or by the European Centre for Disease Prevention and Control for the case definition of Ebola virus infection [7]. Now there is evidence that clinical “Lyme disease” in the United States may be caused by B. miyamotoi [8-10], co-infection of B. burgdorferi and B. miyamotoi [9], a novel CDC strain (GenBank ID# KM052618) of unnamed borrelia [10], and a novel strain of B. burgdorferi with two homeologous 16S rRNA genes [11]. The Lyme disease patients infected with these less common strains of borreliae may have negative or non-diagnostic two-tiered serology test results. Neither erythema migrans nor serologic test is reliable for the diagnosis of Lyme disease. In one summer, the emergency room of a small hospital in Connecticut saw 7 DNA sequencing-proven B. burgdorferi spirochetemic patients. Only three of them (3/7) had a skin lesion and only one (1/7) had a positive two-tiered serologic Lyme test [12].

After a 40-year delay, the medical establishment should begin to diagnose “Lyme disease” as an emerging infectious disease by implementing nucleic acid-based diagnostic tests in the Lyme disease-endemic areas. A national proficiency test program to survey the competency of diagnostic laboratories in detecting various pathogenic borrelia species is urgently needed for stimulating diagnostic innovation. We should treat the borrelial infection of “Lyme disease” to reduce its autoimmune consequences, just like treating streptococcal infection early to reduce the incidence of rheumatic heart disease in the past.

Allen Steere and colleagues have written a prescription to treat Lyme borreliosis in their lengthy article raising numerous questions [1], but paid little attention to the issue of how to select the patients at the right time for the most effective treatment. For the physicians managing current and future Lyme disease patients, a sensitive and no-false positive molecular diagnostic test is a priority, also the most important issue for the patients that Allen Steere and his colleagues have simply glossed over.

Conflict of Interest: Sin Hang Lee is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests for community hospital laboratories.

References 1. Steere, A.C. et al. Lyme borreliosis. Nat. Rev. Dis. Primers 2,16091 (2016). 2. Olano, J.P. & Walker, D.H. Diagnosing emerging and reemerging infectious diseases: the pivotal role of the pathologist. Arch. Pathol. Lab. Med. 135, 83-91 (2011). 3. Li, X. et al. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or Lyme arthritis. Arthritis Rheum. 63, 2238–2247 (2011). 4. Schubbert, R. et al. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sci. U. S. A. 94, 961-966 (1997). 5. Steere, A. C. et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities. Arthritis Rheum. 20, 7–17 (1977). 6. Frieden T. Transcript for CDC Telebriefing: Zika Update. https://www.cdc.gov/media/releases/2016/t0617-zika.html (2016) 7. ECDC. Ebola virus disease case definition for reporting in EU. http://ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/EVDcasedefinition/Pages/default.aspx#sthash.LvKojQGu.wf5kwZDT.dpuf (2016 last accessed) 8. Jobe, D.A. et al. Borrelia miyamotoi Infection in Patients from Upper Midwestern United States, 2014-2015. Emerg. Infect. Dis. 22, 1471-1473 (2016). 9. Lee, S.H. et al. Detection of borreliae in archived sera from patients with clinically suspect Lyme disease. Int. J. Mol. Sci. 15, 4284-4298 (2014). 10. Lee, S.H. et al. DNA sequencing diagnosis of off-season spirochetemia with low bacterial density in Borrelia burgdorferi and Borrelia miyamotoi infections. Int. J. Mol. Sci. 15, 11364-11386 (2014). 11. Lee, S.H. Lyme disease caused by Borrelia burgdorferi with two homeologous 16S rRNA genes: a case report. Int. Med. Case Rep. J. 9,101-106 (2016). 12. Lee, S.H. et al. Early Lyme disease with spirochetemia - diagnosed by DNA sequencing. BMC Res. Notes. 3, 273 (2010).

On 2016 Dec 28, Marcia Herman-giddens commented:

While there are many aspects of this review paper by Steere, et al, which beg for comment, I focus on the erythema migrans rash (EM). Steere, et al, state that “erythema migrans is the presenting manifestation of Lyme borreliosis in ~80% of patients in the United States” based on their 2003 paper. It is unclear from that paper exactly how this figure was obtained. As far as I know, there has never been a well-designed study to examine this issue.

I was pleased to see Figure 5 showing photographs of EM rashes with their more accurate solid red appearance. Research has shown that, contrary to popular belief (likely because of the promotion of the so-called ‘target or bull’s-eye’ type of lesion), most EMs are solid red. As stated by Shapiro in 2014 in the NEJM, “Although reputed to have a bull’s-eye appearance, approximately two thirds of single erythema migrans lesions either are uniformly erythematous or have enhanced central erythema without clearing around it.” Later, some may have central clearing. The CDC estimates “70-80%” of Lyme disease patients have an EM rash and call the picture on their webpage “classic” even though it shows a bull’s-eye or target type lesion.

One outcome of this misrepresentation as a bull’s eye or target lesion, is that patients with the more common solid EM rash may not present to their medical provider in a timely manner thinking that it does not represent possible Lyme disease. I know of several cases where this happened and the patients went on to develop late Lyme disease. Aucott et al, in their 2012 paper, “Bull’s-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans,” found that many of the general public participants were familiar with the classic target-type erythema migrans lesion but only 20.5% could correctly identify the nonclassic erythema migrans. In addition, many health care providers are not well trained in the recognition of EM rashes. In a case series by Aucott et al. in 2009, among Lyme disease patients presenting with a rash, the diagnosis of EM was initially missed by providers in 23%.

The well-known lack of sensitivity in the recommended two-tier test for diagnosis of Lyme disease in early infections and the probability that many EM rashes are misdiagnosed or missed, especially among people living alone or when the rash occurs in the hairline, etc. contribute to the lack of accurate data on the incidence of EM rashes following infection with B. burgdorferi. These factors and others affect the collection of accurate data on the proportion of patients newly infected with B. burgdorferi who do develop erythema migrans and suggest that the true incidence is likely lower than 70-80%.

Steere et al. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090. doi: 10.1038/nrdp.2016.90. Steere AC, Sikand VK. The presenting manifestations of Lyme disease and the outcomes of treatment. New England Journal of Medicine. 2003 Jun 12;348(24):2472-4. Shapiro ED. Lyme disease. New England Journal of Medicine. 2014 May 1;370(18):1724-31. www.cdc.gov/lyme/signs_symptoms/ Aucott JN, Crowder LA, Yedlin V, Kortte KB. Bull’s-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans. Dermatology research and practice. 2012 Oct 24;2012. Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infectious Diseases. 2009 Jun 1;9(1):1.

On 2016 Dec 25, Raphael Stricker commented:

Lyme Primer is Obsolete (Part 1)

Raphael B. Stricker, Union Square Medical Associates, San Francisco, CA; Lorraine Johnson, LymeDisease.org, Chico, CA. rstricker@usmamed.com; lbjohnson@lymedisease.org

The Lyme primer by Steere and colleagues presents an overview of the epidemiology, pathogenesis, diagnosis and treatment of Lyme disease. The authors adhere to the dogma and opinions of the Infectious Diseases Society of America (IDSA), and as a result the primer showcases the schizoid nature of the IDSA view of Lyme disease: while the pathogenesis of the disease is highly complex and worthy of a formidable infectious agent, the epidemiology, diagnosis and treatment of the disease is ridiculously simple and rather banal ("hard to catch and easy to cure"). As a result, the primer propagates the myths and misinformation about Lyme disease that have made the IDSA view obsolete and contributed to the unchecked spread of the tickborne disease epidemic around the world. The following points address significant flaws and deficiencies in the primer, with appropriate references.

There are two standards of care for Lyme disease. One is based on the guidelines of IDSA (Reference 101 in the primer) and the other is based on the guidelines of the International Lyme and Associated Diseases Society (ILADS) (1). The primer adheres to the IDSA guidelines, which are based largely on "expert opinion" (2,3) and were recently delisted by the National Guideline Clearinghouse (NGC) because they are obsolete and fail to meet methodological quality standards for guideline development set forth by the Institute of Medicine (IOM) (1). The NGC recognizes the ILADS guidelines, which were developed using the GRADE methodology endorsed by the IOM (1). Much of the clinical information in the primer is refuted by the ILADS guidelines, as outlined below.

In the Abstract, the primer states that "All manifestations of the infection can usually be treated successfully with appropriate antibiotic regimens, but the disease may be followed by post-infectious sequelae in some patients." Current evidence from "big data" analysis indicates that 36-63% of patients treated with IDSA-recommended short-course antibiotics may fail this therapy (4-6). The concept of "post-infectious sequelae" ignores the extensive literature on persistent Borrelia burgdorferi (Bb) infection despite antibiotic treatment (1,7).

The primer states that "Infection through alternate modes of transmission, including transfusion, sexual contact, semen, urine, or breast milk, has not been demonstrated." This is a very strong statement that ignores growing evidence of other modes of Bb transmission, especially via pregnancy and sexual contact (8-10). The primer states that Borrelia does not produce its own matrix degrading proteases. This statement ignores the description of a Bb aggrecanase that plays a role in tissue invasion by the spirochete and probably facilitates chronic infection as well (11,12).

Neurological syndromes associated with Bb infection are considered "controversial" by IDSA proponents because only hard neurological signs (Bell's palsy, meningoencephalitis) are accepted as significant by that group. In contrast, many Lyme patients have only soft neurological signs (cognitive and memory problems, severe fatigue, neuropathy), and these features of chronic Lyme disease are ignored by the primer authors despite supportive literature (13,14). The concept that neurological and cardiac involvement in Lyme disease resolves spontaneously, even without treatment, promotes a pet IDSA theme that Lyme disease is a trivial illness. This concept is not supported by recent literature that has documented cardiac deaths in untreated patients (15).

The primer repeats the discredited view that Lyme testing is "virtually 100%" positive after 4-8 weeks of untreated infection. This unreferenced statement ignores the fact that two-tier testing for persistent Bb infection has poor sensitivity (46%) despite excellent specificity (99%) (16,17). The studies that allegedly show high sensitivity of two tier testing used circular reasoning to arrive at this conclusion: patients were chosen because they had positive Lyme tests, and then they had positive Lyme tests (18). Thus the primer propagates one of the biggest myths about Lyme disease diagnosis instead of acknowledging the dreadful state of 30-year-old Lyme serology and the need for better testing, such as companion and molecular diagnostics.

On 2016 Dec 25, Raphael Stricker commented:

Lyme Primer is Obsolete (Part 2)

Raphael B. Stricker, Union Square Medical Associates, San Francisco, CA; Lorraine Johnson, LymeDisease.org, Chico, CA. rstricker@usmamed.com; lbjohnson@lymedisease.org

The primer states that a tick must usually be attached for more than 24 hours to transmit Bb, and that a single 200 mg dose of doxycycline can prevent transmission of Bb. The former statement is not supported by recent literature, especially when coinfecting agents are transmitted along with Bb (19). The latter statement is based on a flimsy study that has been attacked repeatedly for its many flaws (1).

The statement that there has been no evidence of Bb drug resistance ignores studies showing that resistance may occur (20-22). The issue of cyst forms that evade the immune system and antibiotic therapy is also ignored (6,23), and the primer disregards recent literature on antibiotic-tolerant persister organisms in Lyme disease (24-26). Once again the primer propagates the IDSA theme that Lyme disease is a trivial infection, with statements about quality of life after short-course treatment such as this: "Regardless of the disease manifestation, most patients with Lyme borreliosis respond well to antibiotic therapy and experience complete recovery." This statement whitewashes the significant morbidity associated with chronic Lyme disease symptoms (4,5). Approximately 42% of respondents in a survey of over 3,000 patients reported that they stopped working as a result of Lyme disease (with 24% reporting that they received disability as a result of chronic Lyme disease), while 25% reported having to reduce their work hours or change the nature of their work due to Lyme disease (4,5).

The unreferenced statement that two weeks of antibiotics cures Lyme carditis is not supported by the literature (1). The primer has limited the discussion of longer antibiotic treatment for post-treatment Lyme disease to studies by Klempner et al. and Berende et al. The authors ignore the positive studies of Krupp et al. and Fallon et al. showing benefit of longer antibiotic treatment, and they avoid discussion of the deep flaws in the negative Lyme treatment trials that lacked the size and power to yield meaningful results (27,28).

The primer calls the LYMErix(R) Lyme vaccine that was withdrawn from the market "safe and efficacious" and the authors blame Lyme advocacy groups for the vaccine failure. This mantra of "blaming the victims" has become a familiar excuse for the failed vaccine, which generated a class action lawsuit based on its lack of safety (29,30). Until vaccine developers come to grips with the very real potential hazards of Lyme vaccine constructs, a successful Lyme vaccine will remain out of reach.

Under "competing interests", there is no disclaimer by Paul Mead, who is an employee of the Centers for Disease Control and Prevention (CDC). Does this mean that Mead represents the CDC in endorsing this slanted and obsolete view of Lyme disease? If that is the case, it is disturbing that a government agency is shirking its responsibility to lead the battle against tickborne disease and instead endorses a regressive viewpoint that stunts science and harms patients.

References 1. Cameron et al, Expert Rev Anti Infect Ther. 2014;12:1103-35. 2. Johnson & Stricker, Philos Ethics Human Med 2010;5:9. 3. Johnson & Stricker, Clin Infect Dis. 2010;51:1108-9. 4. Johnson et al, Health Policy 2011;102:64- 71. 5. Johnson et al, PeerJ 2014;2:e322; DOI 10.7717/peerj.322. 6. Adrion et al, PLoS ONE 2015;10:e0116767. 7. Stricker & Johnson, Infect Drug Resist 2011:4:1-9. 8. Wright & Nielsen, Am J Vet Res. 1990;51:1980-7. 9. MacDonald, Rheum Dis Clin NA. 1989;15:657-677. 10. Stricker & Middelveen, Expert Rev Anti-Infect Ther. 2015;13:1303-6. 11. Russell and Johnson, Mol Microbiol. 2013;90:228-40. 12. Stricker & Johnson, Front Cell Infect Microbiol. 2013;3:40. 13. Cairns & Godwin, Int J Epidemiol. 2005;34:1340-5. 14. Fallon et al, Neurobiol Dis. 2010;37:534-41. 15. Muehlenbachs et al, Am J Pathol. 2016;186:1195-205. 16. Ang et al, Eur J Clin Microbiol Infect Dis. 2011;30:1027-32. 17. Stricker & Johnson, Minerva Med. 2010;101:419-25. 18. Stricker/PMC, Comment on Cook & Puri, Int J Gen Med. 2016;9:427-40. 19. Cook, Int J Gen Med. 2014;8:1-8. 20. Terekhova et al, Antimicrob Agents Chemother. 2002;46:3637-40. 21. Galbraith et al, Antimicrob Agents Chemother. 2005;49:4354-7. 22. Hunfeld & Brade, Wien Klin Wochenschr. 2006;118:659-68. 23. Merilainen et al, Microbiology. 2015;161:516-27. 24. Feng et al, Emerg Microbes Infect. 2014;3:e49. 25. Sharma et al, Antimicrob Agents Chemother. 2015;59:4616-24. 26. Hodzic, Bosn J Basic Med Sci. 2015;15:1-13. 27. Delong et al, Contemp Clin Trials 2012;33:1132-42. 28. Stricker/PMC, Comment on Berende et al, N Engl J Med. 2016;374:1209-20. 29. Marks, Int J Risk Saf Med. 2011;23:89-96. 30. Stricker & Johnson, Lancet Infect Dis. 2014;14:12. Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2016 Dec 20, Sin Hang Lee commented:

None

On 2016 Dec 20, Sin Hang Lee commented:

None

On 2016 Dec 25, Raphael Stricker commented:

Lyme Primer is Obsolete (Part 2)

Raphael B. Stricker, Union Square Medical Associates, San Francisco, CA; Lorraine Johnson, LymeDisease.org, Chico, CA. rstricker@usmamed.com; lbjohnson@lymedisease.org

The primer states that a tick must usually be attached for more than 24 hours to transmit Bb, and that a single 200 mg dose of doxycycline can prevent transmission of Bb. The former statement is not supported by recent literature, especially when coinfecting agents are transmitted along with Bb (19). The latter statement is based on a flimsy study that has been attacked repeatedly for its many flaws (1).

The statement that there has been no evidence of Bb drug resistance ignores studies showing that resistance may occur (20-22). The issue of cyst forms that evade the immune system and antibiotic therapy is also ignored (6,23), and the primer disregards recent literature on antibiotic-tolerant persister organisms in Lyme disease (24-26). Once again the primer propagates the IDSA theme that Lyme disease is a trivial infection, with statements about quality of life after short-course treatment such as this: "Regardless of the disease manifestation, most patients with Lyme borreliosis respond well to antibiotic therapy and experience complete recovery." This statement whitewashes the significant morbidity associated with chronic Lyme disease symptoms (4,5). Approximately 42% of respondents in a survey of over 3,000 patients reported that they stopped working as a result of Lyme disease (with 24% reporting that they received disability as a result of chronic Lyme disease), while 25% reported having to reduce their work hours or change the nature of their work due to Lyme disease (4,5).

The unreferenced statement that two weeks of antibiotics cures Lyme carditis is not supported by the literature (1). The primer has limited the discussion of longer antibiotic treatment for post-treatment Lyme disease to studies by Klempner et al. and Berende et al. The authors ignore the positive studies of Krupp et al. and Fallon et al. showing benefit of longer antibiotic treatment, and they avoid discussion of the deep flaws in the negative Lyme treatment trials that lacked the size and power to yield meaningful results (27,28).

The primer calls the LYMErix(R) Lyme vaccine that was withdrawn from the market "safe and efficacious" and the authors blame Lyme advocacy groups for the vaccine failure. This mantra of "blaming the victims" has become a familiar excuse for the failed vaccine, which generated a class action lawsuit based on its lack of safety (29,30). Until vaccine developers come to grips with the very real potential hazards of Lyme vaccine constructs, a successful Lyme vaccine will remain out of reach.

Under "competing interests", there is no disclaimer by Paul Mead, who is an employee of the Centers for Disease Control and Prevention (CDC). Does this mean that Mead represents the CDC in endorsing this slanted and obsolete view of Lyme disease? If that is the case, it is disturbing that a government agency is shirking its responsibility to lead the battle against tickborne disease and instead endorses a regressive viewpoint that stunts science and harms patients.

References 1. Cameron et al, Expert Rev Anti Infect Ther. 2014;12:1103-35. 2. Johnson & Stricker, Philos Ethics Human Med 2010;5:9. 3. Johnson & Stricker, Clin Infect Dis. 2010;51:1108-9. 4. Johnson et al, Health Policy 2011;102:64- 71. 5. Johnson et al, PeerJ 2014;2:e322; DOI 10.7717/peerj.322. 6. Adrion et al, PLoS ONE 2015;10:e0116767. 7. Stricker & Johnson, Infect Drug Resist 2011:4:1-9. 8. Wright & Nielsen, Am J Vet Res. 1990;51:1980-7. 9. MacDonald, Rheum Dis Clin NA. 1989;15:657-677. 10. Stricker & Middelveen, Expert Rev Anti-Infect Ther. 2015;13:1303-6. 11. Russell and Johnson, Mol Microbiol. 2013;90:228-40. 12. Stricker & Johnson, Front Cell Infect Microbiol. 2013;3:40. 13. Cairns & Godwin, Int J Epidemiol. 2005;34:1340-5. 14. Fallon et al, Neurobiol Dis. 2010;37:534-41. 15. Muehlenbachs et al, Am J Pathol. 2016;186:1195-205. 16. Ang et al, Eur J Clin Microbiol Infect Dis. 2011;30:1027-32. 17. Stricker & Johnson, Minerva Med. 2010;101:419-25. 18. Stricker/PMC, Comment on Cook & Puri, Int J Gen Med. 2016;9:427-40. 19. Cook, Int J Gen Med. 2014;8:1-8. 20. Terekhova et al, Antimicrob Agents Chemother. 2002;46:3637-40. 21. Galbraith et al, Antimicrob Agents Chemother. 2005;49:4354-7. 22. Hunfeld & Brade, Wien Klin Wochenschr. 2006;118:659-68. 23. Merilainen et al, Microbiology. 2015;161:516-27. 24. Feng et al, Emerg Microbes Infect. 2014;3:e49. 25. Sharma et al, Antimicrob Agents Chemother. 2015;59:4616-24. 26. Hodzic, Bosn J Basic Med Sci. 2015;15:1-13. 27. Delong et al, Contemp Clin Trials 2012;33:1132-42. 28. Stricker/PMC, Comment on Berende et al, N Engl J Med. 2016;374:1209-20. 29. Marks, Int J Risk Saf Med. 2011;23:89-96. 30. Stricker & Johnson, Lancet Infect Dis. 2014;14:12. Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2016 Dec 25, Raphael Stricker commented:

Lyme Primer is Obsolete (Part 1)

Raphael B. Stricker, Union Square Medical Associates, San Francisco, CA; Lorraine Johnson, LymeDisease.org, Chico, CA. rstricker@usmamed.com; lbjohnson@lymedisease.org

The Lyme primer by Steere and colleagues presents an overview of the epidemiology, pathogenesis, diagnosis and treatment of Lyme disease. The authors adhere to the dogma and opinions of the Infectious Diseases Society of America (IDSA), and as a result the primer showcases the schizoid nature of the IDSA view of Lyme disease: while the pathogenesis of the disease is highly complex and worthy of a formidable infectious agent, the epidemiology, diagnosis and treatment of the disease is ridiculously simple and rather banal ("hard to catch and easy to cure"). As a result, the primer propagates the myths and misinformation about Lyme disease that have made the IDSA view obsolete and contributed to the unchecked spread of the tickborne disease epidemic around the world. The following points address significant flaws and deficiencies in the primer, with appropriate references.

There are two standards of care for Lyme disease. One is based on the guidelines of IDSA (Reference 101 in the primer) and the other is based on the guidelines of the International Lyme and Associated Diseases Society (ILADS) (1). The primer adheres to the IDSA guidelines, which are based largely on "expert opinion" (2,3) and were recently delisted by the National Guideline Clearinghouse (NGC) because they are obsolete and fail to meet methodological quality standards for guideline development set forth by the Institute of Medicine (IOM) (1). The NGC recognizes the ILADS guidelines, which were developed using the GRADE methodology endorsed by the IOM (1). Much of the clinical information in the primer is refuted by the ILADS guidelines, as outlined below.

In the Abstract, the primer states that "All manifestations of the infection can usually be treated successfully with appropriate antibiotic regimens, but the disease may be followed by post-infectious sequelae in some patients." Current evidence from "big data" analysis indicates that 36-63% of patients treated with IDSA-recommended short-course antibiotics may fail this therapy (4-6). The concept of "post-infectious sequelae" ignores the extensive literature on persistent Borrelia burgdorferi (Bb) infection despite antibiotic treatment (1,7).

The primer states that "Infection through alternate modes of transmission, including transfusion, sexual contact, semen, urine, or breast milk, has not been demonstrated." This is a very strong statement that ignores growing evidence of other modes of Bb transmission, especially via pregnancy and sexual contact (8-10). The primer states that Borrelia does not produce its own matrix degrading proteases. This statement ignores the description of a Bb aggrecanase that plays a role in tissue invasion by the spirochete and probably facilitates chronic infection as well (11,12).

Neurological syndromes associated with Bb infection are considered "controversial" by IDSA proponents because only hard neurological signs (Bell's palsy, meningoencephalitis) are accepted as significant by that group. In contrast, many Lyme patients have only soft neurological signs (cognitive and memory problems, severe fatigue, neuropathy), and these features of chronic Lyme disease are ignored by the primer authors despite supportive literature (13,14). The concept that neurological and cardiac involvement in Lyme disease resolves spontaneously, even without treatment, promotes a pet IDSA theme that Lyme disease is a trivial illness. This concept is not supported by recent literature that has documented cardiac deaths in untreated patients (15).

The primer repeats the discredited view that Lyme testing is "virtually 100%" positive after 4-8 weeks of untreated infection. This unreferenced statement ignores the fact that two-tier testing for persistent Bb infection has poor sensitivity (46%) despite excellent specificity (99%) (16,17). The studies that allegedly show high sensitivity of two tier testing used circular reasoning to arrive at this conclusion: patients were chosen because they had positive Lyme tests, and then they had positive Lyme tests (18). Thus the primer propagates one of the biggest myths about Lyme disease diagnosis instead of acknowledging the dreadful state of 30-year-old Lyme serology and the need for better testing, such as companion and molecular diagnostics.

On 2016 Dec 28, Marcia Herman-giddens commented:

While there are many aspects of this review paper by Steere, et al, which beg for comment, I focus on the erythema migrans rash (EM). Steere, et al, state that “erythema migrans is the presenting manifestation of Lyme borreliosis in ~80% of patients in the United States” based on their 2003 paper. It is unclear from that paper exactly how this figure was obtained. As far as I know, there has never been a well-designed study to examine this issue.

I was pleased to see Figure 5 showing photographs of EM rashes with their more accurate solid red appearance. Research has shown that, contrary to popular belief (likely because of the promotion of the so-called ‘target or bull’s-eye’ type of lesion), most EMs are solid red. As stated by Shapiro in 2014 in the NEJM, “Although reputed to have a bull’s-eye appearance, approximately two thirds of single erythema migrans lesions either are uniformly erythematous or have enhanced central erythema without clearing around it.” Later, some may have central clearing. The CDC estimates “70-80%” of Lyme disease patients have an EM rash and call the picture on their webpage “classic” even though it shows a bull’s-eye or target type lesion.

One outcome of this misrepresentation as a bull’s eye or target lesion, is that patients with the more common solid EM rash may not present to their medical provider in a timely manner thinking that it does not represent possible Lyme disease. I know of several cases where this happened and the patients went on to develop late Lyme disease. Aucott et al, in their 2012 paper, “Bull’s-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans,” found that many of the general public participants were familiar with the classic target-type erythema migrans lesion but only 20.5% could correctly identify the nonclassic erythema migrans. In addition, many health care providers are not well trained in the recognition of EM rashes. In a case series by Aucott et al. in 2009, among Lyme disease patients presenting with a rash, the diagnosis of EM was initially missed by providers in 23%.

The well-known lack of sensitivity in the recommended two-tier test for diagnosis of Lyme disease in early infections and the probability that many EM rashes are misdiagnosed or missed, especially among people living alone or when the rash occurs in the hairline, etc. contribute to the lack of accurate data on the incidence of EM rashes following infection with B. burgdorferi. These factors and others affect the collection of accurate data on the proportion of patients newly infected with B. burgdorferi who do develop erythema migrans and suggest that the true incidence is likely lower than 70-80%.

Steere et al. Lyme borreliosis. Nat Rev Dis Primers. 2016 Dec 15;2:16090. doi: 10.1038/nrdp.2016.90. Steere AC, Sikand VK. The presenting manifestations of Lyme disease and the outcomes of treatment. New England Journal of Medicine. 2003 Jun 12;348(24):2472-4. Shapiro ED. Lyme disease. New England Journal of Medicine. 2014 May 1;370(18):1724-31. www.cdc.gov/lyme/signs_symptoms/ Aucott JN, Crowder LA, Yedlin V, Kortte KB. Bull’s-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans. Dermatology research and practice. 2012 Oct 24;2012. Aucott J, Morrison C, Munoz B, Rowe PC, Schwarzwalder A, West SK. Diagnostic challenges of early Lyme disease: lessons from a community case series. BMC Infectious Diseases. 2009 Jun 1;9(1):1.

On 2017 Mar 15, Sin Hang Lee commented:

Correspondence submitted to Nat.Rev.Dis.Primers

In their recent Primer [Lyme borreliosis. Nat. Rev. Dis. Primers 2, 16091 (2016)] Allen Steere and colleagues described Lyme borreliosis as an important emerging infectious disease [1]. The authors assert that the natural history of untreated Lyme borreliosis can be divided into stages 1, 2 and 3, and that the early stage 1 infections can be treated successfully with a 10–14 day course of antibiotics. However, the authors also stated that demonstration of borrelial infection by laboratory testing is required for reliable diagnosis of Lyme borreliosis, with the exception of erythema migrans and that serodiagnostic tests are insensitive during the first several weeks of infection. If not treated early, “within days to weeks, the strains of B. burgdorferi in the United States commonly disseminate from the site of the tick bite to other regions of the body”. In other words, the authors have affirmed that if reliably diagnosed at the early stage of the infection, Lyme borreliosis can be cured with timely, appropriate antibiotics to prevent deep tissue damage along with its associated clinical manifestations resulting from host immune response to various spirochetal products or components. In the Outlook Diagnostic tests section of the article, the authors failed to mention the fact that currently the diagnosis of emerging infectious diseases largely depends on finding evidence of the causative agent in the host by nucleic acid-based tests [2], not serodiagnostic tests which usually turn positive only during convalescence. The authors seem to advise the medical practitioners to not treat Lyme disease patients until the proliferating spirochetes in the host have elicited certain immune responses which can be confirmed by serologic tests. Such practice should not be accepted or continued for obvious reasons.

The authors stated “After being deposited in the skin, B. burgdorferi usually multiplies locally before spreading through tissues and into the blood or lymphatic system, which facilitates migration to distant sites.”. This statement acknowledges that spirochetemia is an early phase in the pathogenesis of Lyme borreliosis. But under the section of Diagnostic tests, polymerase chain reaction (PCR) test was only mentioned for synovial fluid of patients in late Lyme arthritis and for cerebrospinal fluid (CSF) of late neuroborreliosis. To refute the usefulness of DNA test for Lyme disease diagnosis, the authors cited a study which showed borrelial DNA was detected in synovial fluid of Lyme arthritis patients containing moribund or dead spirochetes [3]. However, the authors failed to discuss the significance of detection of borrelial DNA in the diagnosis of spirochetemia. The authors failed to acknowledge that even the finding of moribund or dead borrelial cells circulating in the blood is diagnostic of an active infection. Free foreign DNA is degraded and eliminated from the mammalian host’s blood within 48 hours [4]. Detection of any borrelial DNA validated by DNA sequencing is indicative of a recent presence of spirochetes, dead or alive, in the circulating blood which is evidence of an active infection beyond a reasonable doubt.

It seems unfortunate for many current Lyme disease patients that Lyme arthritis was described before the era of Sanger sequencing and PCR [5]. If Lyme borreliosis were discovered as an emerging infectious disease today, Lyme disease would probably be routinely diagnosed using a highly accurate nucleic acid amplification test, as reiterated by Dr. Tom Frieden, director of the Centers for Disease Control and Prevention (CDC) for Zika virus infection [6], or by the European Centre for Disease Prevention and Control for the case definition of Ebola virus infection [7]. Now there is evidence that clinical “Lyme disease” in the United States may be caused by B. miyamotoi [8-10], co-infection of B. burgdorferi and B. miyamotoi [9], a novel CDC strain (GenBank ID# KM052618) of unnamed borrelia [10], and a novel strain of B. burgdorferi with two homeologous 16S rRNA genes [11]. The Lyme disease patients infected with these less common strains of borreliae may have negative or non-diagnostic two-tiered serology test results. Neither erythema migrans nor serologic test is reliable for the diagnosis of Lyme disease. In one summer, the emergency room of a small hospital in Connecticut saw 7 DNA sequencing-proven B. burgdorferi spirochetemic patients. Only three of them (3/7) had a skin lesion and only one (1/7) had a positive two-tiered serologic Lyme test [12].

After a 40-year delay, the medical establishment should begin to diagnose “Lyme disease” as an emerging infectious disease by implementing nucleic acid-based diagnostic tests in the Lyme disease-endemic areas. A national proficiency test program to survey the competency of diagnostic laboratories in detecting various pathogenic borrelia species is urgently needed for stimulating diagnostic innovation. We should treat the borrelial infection of “Lyme disease” to reduce its autoimmune consequences, just like treating streptococcal infection early to reduce the incidence of rheumatic heart disease in the past.

Allen Steere and colleagues have written a prescription to treat Lyme borreliosis in their lengthy article raising numerous questions [1], but paid little attention to the issue of how to select the patients at the right time for the most effective treatment. For the physicians managing current and future Lyme disease patients, a sensitive and no-false positive molecular diagnostic test is a priority, also the most important issue for the patients that Allen Steere and his colleagues have simply glossed over.

Conflict of Interest: Sin Hang Lee is the director of Milford Molecular Diagnostics Laboratory specialized in developing DNA sequencing-based diagnostic tests for community hospital laboratories.

References 1. Steere, A.C. et al. Lyme borreliosis. Nat. Rev. Dis. Primers 2,16091 (2016). 2. Olano, J.P. & Walker, D.H. Diagnosing emerging and reemerging infectious diseases: the pivotal role of the pathologist. Arch. Pathol. Lab. Med. 135, 83-91 (2011). 3. Li, X. et al. Burden and viability of Borrelia burgdorferi in skin and joints of patients with erythema migrans or Lyme arthritis. Arthritis Rheum. 63, 2238–2247 (2011). 4. Schubbert, R. et al. Foreign (M13) DNA ingested by mice reaches peripheral leukocytes, spleen, and liver via the intestinal wall mucosa and can be covalently linked to mouse DNA. Proc. Natl. Acad. Sci. U. S. A. 94, 961-966 (1997). 5. Steere, A. C. et al. Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities. Arthritis Rheum. 20, 7–17 (1977). 6. Frieden T. Transcript for CDC Telebriefing: Zika Update. https://www.cdc.gov/media/releases/2016/t0617-zika.html (2016) 7. ECDC. Ebola virus disease case definition for reporting in EU. http://ecdc.europa.eu/en/healthtopics/ebola_marburg_fevers/EVDcasedefinition/Pages/default.aspx#sthash.LvKojQGu.wf5kwZDT.dpuf (2016 last accessed) 8. Jobe, D.A. et al. Borrelia miyamotoi Infection in Patients from Upper Midwestern United States, 2014-2015. Emerg. Infect. Dis. 22, 1471-1473 (2016). 9. Lee, S.H. et al. Detection of borreliae in archived sera from patients with clinically suspect Lyme disease. Int. J. Mol. Sci. 15, 4284-4298 (2014). 10. Lee, S.H. et al. DNA sequencing diagnosis of off-season spirochetemia with low bacterial density in Borrelia burgdorferi and Borrelia miyamotoi infections. Int. J. Mol. Sci. 15, 11364-11386 (2014). 11. Lee, S.H. Lyme disease caused by Borrelia burgdorferi with two homeologous 16S rRNA genes: a case report. Int. Med. Case Rep. J. 9,101-106 (2016). 12. Lee, S.H. et al. Early Lyme disease with spirochetemia - diagnosed by DNA sequencing. BMC Res. Notes. 3, 273 (2010).