Some Common Misconceptions About Lyme Disease

There is a lot of information regarding Lyme Disease available on the internet. In fact, there is a lot more misinformation than there is reliable information. Sifting through it all and deciding which is which can be a daunting task, especially for those without a background in medicine or science. For example the International Lyme and Associated Disease Society and American Lyme Disease Foundation may both appear to be reputable sites but only the latter is “The best private organization-based site that can be recommended to patients for education on Lyme disease” (Sood, 2002) What follows are some common misconceptions about Lyme Disease answered – from the American Lyme Disease Foundation site.

Are serological tests of any value in the diagnosis of Lyme disease?

This is an area where there is a great deal of misunderstanding among patients and even some doctors about what the tests for Lyme disease actually measure and what constitutes a positive result. The most common, widely used tests measure the body’s immune response (antibodies) to the bacterium responsible for Lyme disease, B. burgdorferi. Detection of antibodies is a good way of determining whether someone has – or had – an infection by a bacterium (or a virus).

Some of the confusion about Lyme disease testing is due to the fact that different types of antibodies are produced at various stages of the infection. The type of antibody produced changes as the immune response to infection matures. At the onset of infection, within the first 7 to 10 days, Immunoglobulin M (IgM) is produced first then one to two weeks later, Immunoglobulin G (IgG).

IgM is a less specific antibody that is quite a bit stickier than IgG. The stickiness of IgM makes tests that measure IgM less reliable and more likely to be falsely positive. So one asks the question, why do we test for IgM at all? Because it is produced first – so it is detectable in infected individuals within 1 to 2 weeks after the onset of infection. However, once IgG is produced a month after the initial infection it starts to predominate and we no longer need to rely on the less reliable IgM antibody for detection.

So, the use of IgM antibodies should be limited to the first month of infection, due to their rate of false-positives. A positive IgM test along with a negative IgG test after the first month of infection almost always results in a false positive test.

There are a number of different ways to measure antibodies to B. burgdorferi. As stated above the two most common procedures employed together in the two-tier testing method are the ELISA and Western blot. An ELISA (Enzyme-Linked ImmunoSorbent Assay) is carried out on a plastic plate with multiple wells and measures the amount of antibody that binds to one or more B. burgdorferi proteins (antigens). A Western blot uses gel electrophoresis to separate a sample of B. burgdorferi proteins, the antibodies in the patient’s blood bind specifically to the proteins, then the binding antibodies are coloured in a pattern that resembles a bar code.

People who have been infected with B. burgdorferi will have antibodies against certain specific proteins, resulting in a positive “bar code”. What constitutes a positive Western blot test ie. how many and which bands or “lines” of this “bar code” one must have to be considered positive to B. burgdorferi infection is the cause of some disagreement among some sections of the public. The CDC in collaboration with many experienced physician scientists from major research centres based on thousands of comparative tests as well as an extensive analysis of antibodies known to be both specific and characteristic of various stages of B. burgdorferi infection, all agreed upon how many and which bands there must be for a positive test to be made for B. burgdorferi infection.

There are some advocates who claim that several important proteins (e.g., OspA, OspB – outer surface proteins on the spirochete, and other B. burgdorferi proteins or antigens) were not (and should have been) included in the positive pattern established by the CDC. However, these proteins were initially considered for inclusion, but were rejected because they did not contribute significantly to diagnosis.

OspA and OspB antigens are specific for B. burgdorferi however they are only produced when the bacterium is grown on artificial laboratory media or in the midgut of Ixodes tick. Since these antigens are only minimally produced during human infection they are of little diagnostic use for the Western blot test.

In sharp contrast to the CDC standard criteria, some doctors and commercial laboratories (e.g. IGeneX) use or advocate non-standard criteria that have not been validated by rigorous comparative studies by the CDC and or FDA. Therefore such tests have a higher rate of false positives than one would get using the CDC criteria.

As is the case with most blood tests, diagnosis must be made in the presence of well defined objective clinical symptoms associated with Lyme disease. Because the presence of fatigue or vague aches and pains are too nonspecific, a positive serology in such individuals would have a very low positive predictive value.

What diagnostic tests and criteria are best for diagnosing Lyme disease?

It is essential for the timely diagnosis and effective treatment of Lyme disease, and preventing the costs and harm to those undergoing lengthy treatment who were misdiagnosed, that sensitive and specific laboratory tests for the diagnosis of Lyme disease are available. To this end, the US Centers for Disease Control and Prevention (CDC), in collaboration with investigators at various State Laboratories of Health and/or Lyme Disease Treatment Centers, have established clear and precise objective criteria for evaluating Western Immunoblots for the diagnosis of Lyme disease.

These criteria were validated based on an analysis of well-characterized specimens from patients known to have Lyme disease at different stages of development; they are designed to provide maximum sensitivity without compromising specificity. The CDC criteria have performed well, except in patients with the erythema migrans (EM) rash who have not been ill long enough to mount an antibody response (vide supra).

According to the CDC criteria, a positive IgM Western immunoblot requires the presence of 2 of the following 3 bands on the immunoblot pattern: 23 (also referred to as 24), 39, and 41 kDa. A positive IgG Western immunoblot requires the presence of 5 of the following 10 bands on the immunoblot pattern; 18, 23 (also referred to as 24), 28, 30, 39, 41, 45, 58, 66, and 93 kDa (CDC). To avoid confusion, test results are recorded only as positive or negative, with no arbitrary degrees of positivity.

Both the CDC and the US Food and Drug Administration (FDA) recommend that, because of the high potential for false positives, diagnostic tests based on the detection of IgM antibody are valid only when performed during the first 30 days of infection (when the IgM antibody is dominant); thereafter, it is more appropriate to use tests based on the detection of IgG antibody. The IgM antibody criteria were established to bridge the gap during early infection, until the development of an IgG antibody response.

It has been recognized, since the early 1990s, that antibodies against the outer surface proteins 31 kDA OspA and 34 kDa OspB protein bands are rarely detected in patients with Lyme disease. When found, they are usually detected in patients with long-standing Lyme arthritis and at a frequency much lower than that for antibodies against other more dominant proteins included in the CDC immunoblot criteria (Ma et al., 1992, Dressler et al., 1993).

When the CDC criteria were being developed, reactivity against both OspA and OspB were assessed to determine if adding them to the criteria would increase the sensitivity of the test. That was not the case. In those rare instances where antibodies against OspA and OspB were detected, specimens were judged to be positive due to the presence of antibodies against other bands also included in the criteria.

Obviously, only validated US FDA-approved tests should be used for the diagnosis of Lyme disease. At present, there are 46 such tests. Both the US FDA and the CDC have issued warnings about both the use of nonstandard testing and evaluating the results of laboratory test using unvalidated criteria. Such guidance is welcomed and carries great weight among mainstream physicians, as well as scientists working at State public health laboratories in the US.

Does Borrelia burgdorferi produce a neurotoxin?

Bacteria produce only two types of toxins: endotoxins and exotoxins. Endotoxins are lipopolysaccharides (LPSs) found on the outer cell wall of Gram-negative bacteria, and elicit strong immune responses in animals. Exotoxins are secreted by some Gram-positive bacteria and a few strains of Gram-negative bacteria.

At one time, B. burgdorferi, was thought to possess an endotoxin since a product isolated from B. burgdorferi was reported cause effects in a number of cases that are generally ascribed to LPSs (Beck et al., 1985). However, it was later revealed that B. burgdorferi does not produce a crucial component of LPS, Lipid A and other chemical structures characteristic of endotoxins (Takayama et al., 1987). Although B. burgdorferi does not produce an endotoxin it does produce lipoproteins that interact with the innate immune system of mammals to cause them to release inflammatory products that result in tissue damage and some of the signs and symptoms of Lyme disease (Wooten et al., 2001, Aliprantis et al., 1999, Brightbill, 1999, Hirschfeld et al., 1999, Lien et al., 1999, Ozinsky et al., 2000Alexopoulou et al., 2002).

Although there is every evidence a short course of oral antibiotics will likely cure an active infection with B. burgdorferi, it is possible some residual lipoproteins present in the host cells from dead bacterial cells for some time after the infection is cleared.

Some people claim that B. burgdorferi produces a potent neurotoxin. There is no published, peer-reviewed evidence to support the proposition that it produces an exotoxin. In fact the DNA of B. burgdorferi has been sequenced and there is no evidence of genes that encode for any key structural elements of any known bacterial exotoxin or secretory equipment the bacterium would need to deliver an exotoxin (Fraser et al., 1997).

In light of this information any treatments that advise one to neutralise or remove by “chelation” this as-yet-to-be-identified neurotoxin, should be viewed with much skepticism. Such treatments are not only a waste of time and money but can be potentially dangerous. There is no clinical evidence that they are either safe or effective.

Can Lyme disease be sexually transmitted?

There has been much speculation in the public media and the community about whether Lyme disease can be sexually transmitted. Despite the bacterial agent of Lyme disease, B. burgdorferi only being transferred by Ixodes ticks the source of the misconception is that both B. burgdorferi and Treponema pallidum, the agent of syphilis, are spirochetes. Both spirochetes establish infections via the skin but the similarity ends there.

The T. pallidum syphilis spirochetes grow to abundance in moist scabs on superficial ulcers known as chancres, and are transmitted by sexual contact through abrasions of the genital, anal or oral mucosa. However, unlike Treponema, B. burgdorferi spirochetes cannot survive on the surface of the skin or genital mucosa and are present only in sparse numbers in the deep inner layers of the skin.

The B. burgdorferi spirochetes can only enter the skin through highly ordered metabolic changes that occur during the feeding process of the ticks while attached. There are no epidemiological or clinical data to support the sexual transmission of Lyme disease. The CDC has no record of a single case of Lyme disease that has been sexually transmitted.

The biology of B. burgdorferi has been extensively investigated in the laboratory using several well-defined animal models under highly controlled conditions. The results of these studies provide no evidence of transmission by direct contact, transmission to the fetus from infected pregnant animals, and transmission by sexual contact (Barthold, 1991, Moody and Barthold, 1991, Silver et al., 1995, Weis et al., 1997, Woodrum and Oliver, 1999)

Does Lyme Disease cause Amyotrophic Lateral Sclerosis (ALS)?

Some Lyme disease advocates claim there is a causal relationship between Lyme disease and ALS (also called Motor Neurone Disease) simply because some patients with ALS appear to test positive in serological tests for Lyme disease. The results of recent clinical studies negate the validity of such a relationship (Qureshi et al., 2009). The study of 414 patients with ALS who also underwent validated serological tests for Lyme disease, showed that only 24 (5.8 %) were seropositive for Lyme disease. Of those, only 4 (0.97 %) were confirmed to have previous infection by B. burgdorferi from their medical histories.

Another much larger study in the US of over 4000 ALS patients found only 30 (<1%) were found to be positive based on the results of validated ELISA and Western Blot tests (ALS Untangled, 2009). Such incidence level is similar to that in the general population without ALS. Since these findings indicate that Lyme disease is rare in patients with ALS, there is no reason to believe that Lyme disease causes ALS.

It should be noted that several β-lactam antibiotics, including ceftriaxone are often used to treat Lyme disease with neurological symptoms, have been shown to posses neuroprotective properties not related to their antibiotic properties (Rothstein et al., 2005). Recent clinical trials of ceftriaxone in patients with ALS were terminated because the results obtained failed to show that treatment provided a significant benefit.

Are the signs and symptoms of Lyme disease identical to those of multiple sclerosis (MS)?

Rarely, and mostly in European patients, does Lyme disease cause inflammation in the central nervous system (CNS), i.e., the brain and/or spinal cord. Although the few patients in the US with such clinical problems were described in the 1980s (Halperin et al., 1989Halperin et al., 1990, Halperin, 1997), this appears to be an even rarer event today, since patients are usually diagnosed and treated for Lyme disease, well before there is significant involvement of the CNS.

When CNS involvement does occur, typical changes are noted on brain MRI scans; unfortunately, early descriptions of these findings led to several misconceptions. Non-specific abnormalities are seen frequently in brain MRI scans of otherwise healthy individuals, particularly those with high blood pressure, diabetes, migraine or even those who simply are over the age of 50. When such changes are seen, it has become commonplace for radiologists in the US to suggest they might be due to Lyme disease, even though this is probably the least likely explanation (American Lyme Disease Foundation).

It is important to note that the real brain and spinal cord abnormalities that rarely occur in CNS Lyme disease look much like those of any other form of brain inflammation, and can be confused with changes seen in multiple sclerosis (MS). Although the location of these abnormalities can differ somewhat between CNS Lyme disease and MS, this is not always helpful.

However, there are two characteristic features that can help one differentiate between MS and CNS Lyme disease. Typically, MS is a disease with relapses and remissions occurring over the course of years; such a pattern is not typical of CNS Lyme disease.

More helpful, though, are observations noted upon examination of the cerebrospinal fluid (CSF). In both MS and CNS Lyme, the spinal fluid shows inflammatory changes that include locally elevated concentrations of white blood cells, protein and antibodies; such changes were not noted in a large clinical study of patients with persistent symptoms and a history of Lyme disease (Klempner et al., 2001).

As with many other infections, when there is locally elevated antibody concentration in the spinal fluid because of an infection, the locally concentrated antibodies can readily be shown to be specific for the infecting organism, i.e. Borrelia burgdorferi, in the case of Lyme disease.

Although this measure of local production of anti-borrelial antibody may not be elevated in all cases of CNS Lyme disease, it should be elevated in any patient in whom there is an overall increase in spinal fluid antibodies, a finding that is universal in MS.

This is based on the fundamental observation, based on what is known as the blood-brain barrier, there is a partition or concentration differential between the antibodies made locally in the CNS (the cerebrospinal fluid) and the those present in the blood or general circulation. In the case of active infection of B. burgdorferi in the CNS, the concentration of antibodies for B. burgdorferi is higher in the CNS than in the blood.

In the case of Lyme disease without CNS involvement, antibodies for B. burgdorferi are present in the blood but absent in the CNS. With MS it is important to note there is a breakdown of the blood-brain barrier (Alvarez et al., 2011) so that the concentration of all antibodies in the blood and the CNS is essentially the same. Such a breakdown or disruption of the blood-brain barrier is not characteristic of Lyme disease. So to determine the difference between CNS Lyme disease and MS a differential of antibodies between the CNS and the blood must be detected.

This, coupled with the clinical aspects of the patients illness, allows straightforward differentiation between these two disorders. Schmutzhard discusses the means of differentiating the two illnesses (Schmutzhard, 2002).

Do Borrelia burgdorferi form cysts that protect them from being attacked and eliminated by antibiotics and host immune defense mechanisms?

The clear and simple answer is “no”. Saunder’s “Dictionary and Encyclopaedia of Laboratory Medicine and Technology”, there are two definitions of the term “cyst”.  The one relevant here is used to describe a stage in the life cycle of certain parasites (e.g., Echinococcus granulosus) during which they are enclosed within a protective sac called a hydatid cyst. Some bacteria (Bacillus and Clostridia species) – certainly not Borrelia burgdorferi – form protective structures called spores. However, no bacteria form cysts. Therefore the use of the term “cyst” with reference to Borrelia burgdorferi or any other bacterium is meaningless and incorrect.

In most cases the term “cyst” is used to leave the false impression that Borrelia burgdorferi can by forming “cysts” somehow evade destruction by antibiotics and the immune system’s defence mechanisms and establish a persistent and long-term infection. Some even advocate treating these “cyst” forms with metronidazole (Brorson and Brorson, 1999) despite there being no evidence there is any clinical relevance.

Some mistakenly use the term “cyst” to describe those structures (e.g. L-forms or “cell-wall deficient” variants) that are not part of the normal growth cycle of Borrelia, but which are formed after exposure to certain antibiotics that influence cell wall formation. Such variants are of two types that differ in the amount of residual cell-wall material they contain: spheroplasts and protoplasts. The former, spheroplasts still contain some remnants of cell wall material, whereas the latter, protoplasts are completely devoid of any cell wall material (Allan et al., 2009). Both types may be stable or unstable, depending on their capacity to revert to the original parental cell type when placed in an antibiotic- free environment. If reversion to the parent cell occurs it does so relatively early in the antibiotic treatment i.e. when the antibiotic levels first begin to decline (Allan et al., 2009).

Since neither variant is surrounded by a “cyst-like” protective structure there is no reason to believe they would be any less permeable or susceptible to antibiotics than the parent cell. In most cases, these structures have not been characterized with respect to B. burgdorferi and then only with regard to their morphology. No well-controlled functional or physiological studies have been conducted to demonstrate that they are relevant to human disease. Two studies show that such residual structures may exist in mice after treatment for B. burgdorferi infection. However, these forms are not cultivable, not virulent, and eventually are eliminated by host defense mechanisms without causing disease (Hozdic et al., 2008, Bockenstedt et al., 2002, Wormser and Schwartz 2009, Pavia and Wormser, 2014).

Two extensive and systematic literature searches were performed to identify studies in which round morphologic variants of B. burgdorferi were described in situ in human clinical specimens. It was not possible to ascribe any pathogenic role for any morphological variant of B. burgdorferi in either typical Lyme disease or in what is often labelled as chronic Lyme disease. Thus there is no clinical literature evidence for the treatment of different cell types of B. burgdorferi (Lantos et al., 2014).

Some patients who believe that they have chronic Lyme disease claim that prolonged treatment with antibiotics relieves their symptoms and makes them feel better. Does this mean that these beneficial effects must be due to the elimination of a chronic borrelial infection?

This could very well be the case if they have been correctly diagnosed with a bacterial infection that responds to the antibiotics being used. However, in the absence of such a diagnosis, there are at least three possible alternative explanations.

First, if another undiagnosed and unrelated infection that has nothing at all to do with Lyme disease is present and it is really the cause of the general symptoms experienced, and it is cleared up by antibiotics then that might account for relief of the symptoms.

Second, the placebo effect. In a large double-blinded, placebo-controlled study of the benefits of extended antibiotic therapy for the treatment of patients with persistent symptoms believed to be due to chronic Lyme disease, symptom improvement was noted in 38% of the patients given placebo alone (Klempner et al., 2001). It is generally accepted that 35% of patients with any of a wide variety of disorders can be treated successfully with placebo alone, and that cure rates of 70% – 100% have been reported in some studies (Kienle and Kiene, 1996). Positive testimonials, regardless of the number do not constitute scientific evidence, because for every patient who claimed a particular therapy was beneficial there will be just as many, if not more who will state the exact opposite.

Third, the non-antibiotic effects of antibiotics. Several antibiotics often used to treat Lyme disease, e.g., ceftriaxone and doxycycline, have significant neuroactive effects that can impact ones sense of wellbeing (Domercq and Matute, 2004,  Rothstein et al., 2005). In fact, ceftriaxone, which appears to be the most potent in that regard, was until recently being trialled as a treatment for ALS. The anti-inflammatory and pain-relieving effects of tetracycline (Ivetic Tkalcevic, 2006, Bastos et al., 2012) and its derivatives (doxycycline, minocycline, and tigecycline) and macrolides such as erythromycin and azithromycin (Tamaoki et al., 2004, Sanz et al., 2005, Kobayashi et al., 2013) are well known and have been studied extensively. Perhaps other drugs that are not antibiotics might work just as well – or perhaps even better and not contribute to the emergence of new and difficult to treat infections by antibiotic resistant strains of bacteria that the overuse of antibiotics is causing across the world.

Does Lyme disease cause autism in children?

The view that Lyme disease induces autism in children was advanced by the Lyme-Induced Autism Foundation (LIAF) which claims that up to 90% of autistic children are infected with Borrelia. There are no published data to substantiate such a claim. First, the actual data upon which the claim is based have never been published in a peer reviewed scientific journal; this casts doubts on their accuracy. Second, there has been no independent confirmation to establish that the results are valid and reproducible. Third, in many cases, it appears that non-standard criteria were used to interpret the Western blots that were used to support an association between Lyme disease and autism.

In fact recent results of two carefully conducted controlled studies completely refute the erroneous claim of the LIAF, namely, that Lyme disease induces autism in children (Ajamian et al., 2013, Burbelo et al., 2013). The work by Ajamian et al. was written up in TheScientist.com.

Relative recent statistical analyses of the prevalences of autism and Lyme disease in several US states in 2004 and 2006 found no significant correlation between the two (Autism and Developmental Disabilities Monitoring Network Report of 2009Reported Lyme Disease Cases by State). Furthermore, the average age at which autism symptoms/signs occur is much lower than that of Lyme disease and there is no evidence that autistic children are more exposed to ticks than the general population of children.

Since families of children with autism are already under financial and emotional burdens, they should not have the hopes needlessly raised by quacks who propose to and are currently prescribing long-term antibiotic treatments to vulnerable children with no scientific evidence to back them. Neither the National Institutes of Health nor the Autism Science Foundation, which fund almost all of the research on autism and have developed many promising and successful approaches for treating autism, have any evidence to support a link between Lyme disease and autism.

At time of writing, the website of LIAF was offline.

Does Lyme disease play a significant role in the aetiology (cause) of Alzheimer’s disease?

Several researchers have claimed a role of Borrelia in the aetiology of Alzheimer’s disease (MacDonald and Miranda, 1987, Miklossy, 1993, Miklossy et al., 1994). These claims were made on the basis of visual identification of Borrelia in autopsy brain tissue of deceased Alzheimer’s patients by silver staining and culturing in artificial media. However these results have never been reproduced or confirmed independently. In fact attempts to do so, lead to quite the opposite conclusions (Pappolla et al., 1989, Gutacker et al., 1998, Marques et al., 2000).

In the article by Marques et al. the very sensitive technique polymerase chain reaction (PCR) assay designed to amplify a Borrelia -specific DNA target sequence present in all B. burgdorferi sensu lato known to cause disease in humans was used to analyse brain specimens of 15 Alzheimer’s patients and 15 age-matched and sex-matched controls. No evidence for the presence of Borrelia was found in the Alzheimer’s patients.

In another report, a research group (Krut et al., 2013) examined the cerebrospinal fluid (CSF) biomarker profile for Alzheimer’s disease and compared it to that for several central nervous system (CNS) infectious diseases, including Lyme neuroborreliosis. The results revealed distinctly different pathological pathways in Alzheimer’s disease and Lyme neuroborreliosis.

If there were a significant role of Borrelia in Alzheimer’s, one would expect there to be a direct relationship between the incidence of Lyme disease and deaths due to Alzheimer’s disease. Just such an analysis was done using the numbers of deaths attributed to Alzheimer’s disease in 13 States compared with the highest reported number of cases of Lyme disease, for the years 2002 – 2011 (O’Day and Catalano, 2014). The results obtained revealed no correlation.

Alzheimer’s disease, the most common form of dementia, places an enormous personal and financial burden on patients, their families and other loved ones. Current treatment options are limited, and only serve to lessen the impact of the illness’ symptoms. Suggesting the patient’s symptoms are due to Lyme disease invariably leads to extended antibiotic therapy and with the prolonged and unconventional regimens recommended by some are used, this substantially places the patient at risk of serious side effects. If the goal of treatment of what is currently an incurable disease is the maximum preservation of dignity and quality of life, this hardly seems justifiable.

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Websites And Links

Centers for Disease Control and Prevention (CDC) page on Lyme Disease

American Lyme Disease Foundation

Infectious Diseases Society of America

University of Sydney’s Tick Borne Diseases Unit

US National Institute of Health

US National Institute of Allergy and Infectious Diseases (Lyme Disease Page)

Books

Institute of Medicine (US) Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington (DC): National Academies Press (US); 2011. Available from: http://www.ncbi.nlm.nih.gov/books/NBK57020/

Lyme Disease: the Great Controversy Halperin, J.J., Baker, P., and Wormser, G.P. In, “Lyme Disease: An Evidence-based Approach”(American Lyme Disease Foundation) (Link to Chapter 17 pdf)

Wang, G. (2015). Chapter 104 – Borrelia burgdorferi and other Borrelia species, Molecular Medical Microbiology (Second Edition), Pages 1867–1909, Elsevier Ltd.

Radolf, J. D., et al. (2010). Lyme disease in humans, Caister Academic Press.

Journal Articles

Halperin, J. J. “Nervous system Lyme disease, chronic Lyme disease, and none of the above.” Acta Neurol Belg, 2016, 116(1): 1-6.

Lantos, P. M. “Chronic Lyme disease.” Infect Dis Clin North Am, 2015, 29(2): 325-340.

Aucott, J. N. “Posttreatment Lyme disease syndrome.” Infect Dis Clin North Am, 2015, 29(2): 309-323.

Mayne, P. J. “Clinical determinants of Lyme borreliosis, babesiosis, bartonellosis, anaplasmosis, and ehrlichiosis in an Australian cohort.” Int J Gen Med, 2015, 8: 15-26.

Gofton, A. W., et al. “Inhibition of the endosymbiont “Candidatus Midichloria mitochondrii” during 16S rRNA gene profiling reveals potential pathogens in Ixodes ticks from Australia.” Parasit Vectors, 2015, 8: 345.

Gofton, A. W., et al. “Bacterial profiling reveals novel “Ca. Neoehrlichia”, Ehrlichia, and Anaplasma species in Australian human-biting ticks.” PLoS One, 2015, 10(12): e0145449/0145441-e0145449/0145416.

Patrick, D. M., et al. “Lyme Disease Diagnosed by Alternative Methods: A Phenotype Similar to That of Chronic Fatigue Syndrome.” Clin Infect Dis, 2015.

Ostfeld, R. S. and J. L. Brunner. “Climate change and Ixodes tick-borne diseases of humans.” Philos Trans R Soc Lond B Biol Sci, 2015, 370(1665).

Aguero-Rosenfeld, M. E. and G. P. Wormser. “Lyme disease: diagnostic issues and controversies.” Expert Rev. Mol. Diagn., 2015, 15(1): 1-4.

Halperin, J. J. “Chronic Lyme disease: misconceptions and challenges for patient management.” Infect Drug Resist, 2015, 8: 119-128.

Borchers, A. T., et al. “Lyme disease: a rigorous review of diagnostic criteria and treatment.” J Autoimmun, 2015, 57: 82-115.

Mayne, P., et al. “Evidence for Ixodes holocyclus (Acarina: Ixodidae) as a Vector for Human Lyme Borreliosis Infection in Australia.” J Insect Sci, 2014, 14(1).

Lantos, P. M. and G. P. Wormser. “Chronic coinfections in patients diagnosed with chronic lyme disease: a systematic review.” Am J Med, 2014, 127(11): 1105-1110.

DeBiasi, R. L. “A concise critical analysis of serologic testing for the diagnosis of lyme disease.” Curr Infect Dis Rep, 2014, 16(12): 450.

Brissette, C. A. and R. A. Gaultney. “That’s my story, and I’m sticking to it–an update on B. burgdorferi adhesins.” Front Cell Infect Microbiol, 2014, 4: 41.

Groshong, A. M. and J. S. Blevins. “Insights into the biology of Borrelia burgdorferi gained through the application of molecular genetics.” Adv. Appl. Microbiol., 2014, 86: 41-143.

Lantos, P. M., et al. “A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease.” Clin Infect Dis, 2014, 58(5): 663-671.

Pavia, C. S. and G. P. Wormser. “Culture of the entire mouse to determine whether cultivable Borrelia burgdorferi persists in infected mice treated with a five-day course of ceftriaxone.” Antimicrob. Agents Chemother., 2014, 58(11): 6701-6703, 6704 pp.

O’Day, D. H. and A. Catalano. “A lack of correlation between the incidence of lyme disease and deaths due to Alzheimer’s disease.” J Alzheimers Dis, 2014, 42(1): 115-118.

Strle, K., et al. “Elevated Levels of IL-23 in a Subset of Patients With Post-Lyme Disease Symptoms Following Erythema Migrans.” Clin. Infect. Dis., 2014, 58(3): 372-380.

Halperin, J. J., et al. “Common misconceptions about Lyme disease.” Am J Med, 2013, 126(3): 264.e261-267.

Klempner, M. S., et al. “Treatment trials for post-Lyme disease symptoms revisited.” Am J Med, 2013, 126(8): 665-669.

Kobayashi, Y., et al. “A novel macrolide solithromycin exerts superior anti-inflammatory effect via NF-κB inhibition.” J Pharmacol Exp Ther, 2013, 345(1): 76-84.

Ajamian, M., et al. “Serologic markers of lyme disease in children with autism.” JAMA, J. Am. Med. Assoc., 2013, 309(17): 1771-1772.

Burbelo, P. D., et al. “Lack of serum antibodies against Borrelia burgdorferi in children with autism.” Clin. Vaccine Immunol., 2013, 20(7): 1092-1093.

Krut, J. J., et al. “Cerebrospinal fluid Alzheimer’s biomarker profiles in CNS infections.” J. Neurol., 2013, 260(2): 620-626.

Barbour, A. “Remains of infection.J. Clin. Invest., 2012, 122(7): 2344-2346.

Bockenstedt, L. K., et al. “Spirochete antigens persist near cartilage after murine Lyme borreliosis therapy.J. Clin. Invest., 2012, 122(7): 2652-2660.

Embers, M. E., et al. “Persistence of Borrelia burgdorferi in rhesus macaques following antibiotic treatment of disseminated infection.PLoS One, 2012, 7(1): e29914.

Huyshe-Shires, S. “Lyme disease antiscience.” Lancet Infect Dis, 2012, 12(5): 361; author reply 362-363.

Perronne, C. “Lyme disease antiscience.” Lancet Infect Dis, 2012, 12(5): 361-362; author reply 362-363.

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