Misinformation About Lyme Disease
Bacteria produce only two types of toxins: endotoxins, which are non-secreted lipopolysaccharides (LPSs) that make up a large part of the cell wall of gram-negative bacteria; and, exotoxins that are secreted by some gram-positive bacteria and a few strains of gram-negative bacteria.
At one time, Borrelia burgdorferi, was thought to possess an endotoxin since a product isolated from B. burgdorferi was reported to be pyrogenic for rabbits, mitogenic for human mononuclear cells and mouse spleen cells, capable of clotting limulus lysate (a diagnostic test for LPS), and cytotoxic for mouse macrophages; these are properties generally ascribed to bacterial LPS (1). However, subsequent studies revealed the absence of lipid A and other chemical structures characteristic of classic gram-negative endotoxins (2). Although B. burgdorferi does not produce an endotoxin, it does possess lipoproteins that interact with Toll-like receptors (TLRs) on the surface of mammalian cells that comprise the innate immune system, to cause them to release inflammatory products that result in tissue damage and some of the clinical manifestations of Lyme disease (3-9).
There is abundant evidence to show that treatment with a short course of oral antibiotics is likely to cure active infection by B. burgdorferi (10); however, it is possible that some biologically active lipoproteins from dead bacterial cells persist in host tissues for periods of time after the initial infection has been cured.
Although some claim that B. burgdorferi produces a potent neurotoxin, there is no published, peer-reviewed evidence indicating that B. burgdorferi is an exotoxin-producing bacterium. In fact, the genomic sequence data do not reveal the presence of genes that encode for either key structural elements of any known bacterial exotoxin, or components of a secretory apparatus required for the export and delivery of an exotoxin (11).
In view of these considerations, treatment regimens for Lyme disease based on the neutralization -- or removal by chelation-- of a yet-to-be-identified neurotoxin should be viewed with much skepticism; such quackery is not only likely to be a waste of time and money, but also has the potential to cause great harm. There is no clinical evidence to indicate that such treatments are safe or effective.
1. Beck, G., G.S. Habicht, J.L. Benach, and J.L. Coleman. 1985. Chemical and biological characterization of a lipopolysaccharide extracted from the Lyme disease spirochete, (Borrelia burgdorferi). J. Infect. Dis. 152: 108-117.
2. Takayama, K., R.J. Rothenberg, and A.G. Barbour. 1987. Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect. Immun. 55: 2311-2313.
3.Wooten, R.M. and J.J. Weis. 2001. Host-pathogen interactions promoting inflammatory Lyme arthritis: use of mouse models for dissection of disease processes. Current Opinion in Microbiol. 4: 274-279.
4. Aliprantis, A.O., R.B. Yang, M.R. Mark, et al. 1999. Cell activation and apoptosis by bacterial lipoproteins through Toll- like receptor-2. Science 285: 736-739.
5. Brightbill, H.D., D.H. Libraty. S.R. Krutzik, et al. Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285: 732-736.
6. Hirschfield, M., C.J. Kirschning, R. Schwandner. et al., 1999. Inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by Toll-like receptor-2. J. Immunol. 163: 2382-2386.
7. Lien, E., T.J. Sellati, A. Yoshimura, et al. 1999. Toll-like receptor- 2 functions as a pattern recognition receptor for diverse bacterial products. Chemistry 274: 33419-33425.
8. Ozinsky, A., D.M. Underhill, J.D. Fontenot, et al. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Nat. Acad. Sci. 97: 13766-13771.
9. Alexopoulou, L., V. Thomas, M. Schnare, et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi Osp A in humans and in TLR-1 and TLR-2 deficient mice. Nature Medicine 8: 878-884.
10. Wormser, G.P., R.J. Dattwyler, E.D. Shapiro, et al. 2006. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Disease Society of America. Clin. Infect. Dis. 43: 1089-1134.
11. Fraser, C., S. Casjens, W.M. Huang, et al. (1997). Genomic sequence of a Lyme disease spirochete, Borrelia burgdorferi. Nature 390: 580-586.
The Plum Island Animal Disease Center (PIADC), that is now managed by the U.S. Department of Agriculture, is dedicated to research on plant and large animal diseases likely to have a significant economic impact on the livestock and agricultural industries. Because of its isolation from the main land mass and stringent containment facilities, it is ideally suited for such work. In 1952, it was managed by the U.S. Army Chemical Corps as a component of its biological warfare program. However, when that program was abolished by a Presidential directive in 1969, it was transferred to the U.S. Department of Agriculture for its present use.
Some claim that Lyme disease was introduced into the northeastern region of the U.S. by a man-made strain of Borrelia burgdorferi that escaped from a high containment biological warfare laboratory on Plum Island. However, there is ample evidence to indicate that both Ixodes ticks and B. burgdorferi were present in the U.S. well before the Plum Island facility was ever established. An examination of museum specimens of Ixodes ticks showed that the presence of Lyme disease spirochetes in suitable arthropod vectors preceded -- by at least a generation -- the year (1982) when Lyme disease was first recognized as a distinct clinical entity in the U.S. (1, 2). More recent studies revealed that Ixodes ticks and B. burgdorferi were present in the northeastern and Midwestern regions of the U.S. in pre-colonial times and many thousands of years before European settlements were established in the U.S. (3). Lyme disease certainly existed in the U.S. long before anyone knew how to diagnose and treat it.
Although the per capita incidence of Lyme disease in the Northeastern United States is more than twice that in the Midwestern United States, the prevalence of B. burgdorferi in the tick vector is nearly identical in both regions. The disparity in the incidence of disease did not appear to be due to a disparity in human invasiveness since a genetic analysis revealed that B. burgdorferi population in the Northeast and Midwest shard a recent common ancestor. This suggests that substantial evolutionary divergence in human invasiveness has not occurred and that the disparity in the incidence of disease between the two regions may be due to animal ecology or human behavior (4).
Finally, the prehistoric remains of "The Ice Man"--more than 5,000 years old-- provide positive evidence of infection by Borrelia burgdorferi (http://ngm.nationalgeographic.com/2007/07/iceman/hall-text) .
1. Persing, DH, Telford, SR III, Rys, PN, Dodge, DE, White, TJ, Malawista, SE and Spielman, A. Detection of Borrelia burgdorferi DNA in museum specimens of Ixodes damimini ticks. Science 249: 1420-1423, 1990.
2. Burgdorfer, W, Barbour, AG, Hayes, SF, Benach, JL, Grunwaldt, E, and Davis, J.P. Lyme disease: a tick-borne spirochetosis? Science 216: 1317-1319,1982.
3. Hoen, AG, Margos, G, Bent, S.J. Duik-Wasser, MA, Barbour, A, Kurtenbach, K, and Fish, D. Phylogeography of Borrelia burgdorferi in the eastern United States reflects multiple independent Lyme disease emergence events. Proc. Natl. Acad. Sci. 106: 15013-15018, 2009.
4. Brisson, D., Vandermause, M.F., Meece, J.K., Reed, K.D. and Dykhuizen. Evolution of Northeastern and Midwestern Borrelia burgdorferi in the United States. Emerg. Infect. Dis. 16: 911-917, 2010.
This photo has been reproduced from the more detailed version of the Tick Map found on the Home Page of the ALDF website. It summarizes current information, from 2006 - 2008) on the incidence of infected Ixodes ticks, as well as reported cases of Lyme disease in the continental United States.
Note that no Ixodes scapularis or I. pacificus ticks are found in some States, and that there are several States in which I. scapularis or I. pacificus have been reported, but host-seeking nymphs -- the major transmitters of Lyme disease -- are extremely low as well as the prevalence of infection. Since Lyme disease is not a sexually transmitted disease and is transmitted to humans only by infected Ixodes ticks (see preceding articles in this section), it is not surprising that most (>95%) reported cases of Lyme disease occur in those States (the Northeastern and Upper Mid-Central States) where host-seeking nymphal I. scapularis ticks are abundant.
Ixodes ticks are not found in the Arizona, Colorado, Idaho, Montana, Nevada, North Dakota, Utah, and Wyoming. Consequently, it is reasonable for residents of those States with non-specific symptoms often associated with Lyme disease in the absence of positive serological tests conducted by validated standard procedures and possible exposure to Ixodes ticks from visits to endemic areasto consider other possibilities to explain their symptoms.
Although Amblyoma americanum ticks sometimes carry a strain of Borrelia called Borrelia lonestarii, there is no evidence to indicate that B. lonestarii produces disease in humans (1). Furthermore, A. americanum has not been shown to be a competent vector for B. burgdorferi, the spirochete that causes Lyme disease (2,3).
1. Wormser, G.P., Masters, E., Livedris, D. et al. "Microbiologic evaluation of patients from Missouri with erythema migrans." Clin, Infect. Dis. 40: 423-428, 2005.
2. Ledia, K.E., N.S. Zeidner, J.M. Riberio, et al. "Borreliacidal activity of saliva from the tick Amblyomma americanum. Med.Vet. Entomol. 19: 90-95, 2005.
3. Piesman, J., and C.M. Kapp. "Ability of the Lyme disease spirochete Borrelia burgdorferi to infect rodents and three species of human-biting ticks (blacklegged tick, American dog tick, lone star tick). J. Med. Entomol. 34: 451-456, 1997.
Some Lyme disease patient advocates claim that there is a causal relationship between amyotrophic lateral sclerosis (ALS) and Lyme 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. An examination 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; furthermore, the medical record of only 4 of these seropositive patients (0.97%) confirmed previous infection by Borrelia burgdorferi(1). In another larger study conducted in the U.S., more that 4,000 patients with ALS also were tested for Lyme disease; only 30 (<1%) were found to be positive based on the results of validated ELISA and Western Blot tests (2). Such a low incidence is comparable to the background incidence of positive tests in individuals without ALS in the population at large (3). 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 often used to treat Lyme disease with neurological symptoms, have been shown to possess profound neuroprotective effects that are independent of their antimicrobial properties (4). Clinical trials are now underway to determine if extended ceftriaxone therapy might be beneficial in the treatment of ALS (5). This in no way implies that ALS is due to a persistent infection that requires prolonged antibiotic therapy to cure, since the drug is being used solely to exploit its neuroprotective properties.
Unfortunately, these clinical trials were terminated because the results obtained failed to show that treatment with ceftriaxone provide a significant benefit in patients with ALS (6).
1. Qureshi, M, Bedlack, RS, and Cudkowicz, ME. Lyme disease serology in amyotrophic lateral sclerosis. Muscle and Nerve 40: 626-628, 2009.
2. The ALSUntangled Group. ALSUntangled update 1: investigating a bug (Lyme Disease) and a drug (Iplex) on behalf of people with ALS. Amyotrophic Lateral Sclerosis 10: 248-250, 2009.
3. Murphree, B, Kugeler, K, and Mead, P. Surveillance for Lyme disease, United States 1992-2006. www.cdc.gov/mmwr/PDF/ss/ss5710.pdf.
4. Rothstein, JD, Patel, S, Regan, MR et al. β-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73-77, 2005.
5. Clinical trials on the use of ceftriaxone in patients with ALS http://clinicaltrials.gov/ct2/results?term=ceftriaxone+and+ALS
The view that Lyme disease induces autism in children has been advanced by the Lyme-Induced Autism Foundation (LIAF) which claims that up to 90% of autistic children are infected with Borrelia (1). There are no published data to substantiate such a claim. Having a positive ELISA or Western Blot test is not proof of active infection; it might indicate the presence of antibodies that are the result of past infection with Borrelia burgdorferi, the causative agent of Lyme disease. Such antibodies may persist at low levels, months to years after the active infection has been cured by appropriate antibiotic therapy. In some persons, a positive ELISA or Western blot is due to a non-specific cross-reaction (i.e., a false positive test).
There are serious problems with the quality of the laboratory tests used to support the claim that a large percentage of autistic children are seropositive for Lyme disease. 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. Such criteria are at variance with those recommended by the CDC, thereby resulting in a significant number of false positive tests. Consequently, the unpublished results of the serological tests reported by the LIAF must be viewed with grave skepticism.
The results of two recent carefully conducted controlled studies completely refute the erroneous claim of the LIAF, namely, that Lyme disease induces autism in children (2,3).
It should also be noted that data on the prevalence of autism and Lyme disease (number of reported cases per 100,000 residents) for nine States (Al, AR, CO, GA, MD, MO, NC, PA, SC, and WI) for the years 2004 and 2006, provide no indication of an association between Lyme disease and autism (4,5). An analysis by Spearman's rank correlation test yields r values of 0.234 and 0.317 for the years 2004 and 2006, respectively. In this particular method of statistical analysis, r values must be at or very close to 1.0 to affirm a close association between Lyme disease and autism. Furthermore, the average age at which the first signs/symptoms of autism occur in children is lower than that of Lyme disease, and there is no evidence that autistic children are exposed to ticks at a greater frequency than normal children.
Since families with autistic children already suffer enormous financial and emotional burdens, they should not have their hopes needlessly raised by unproven speculations that are not supported by scientific evidence. It would be irresponsible and even harmful to treat autistic children with extended antibiotic therapy, as some physicians are already recommending and doing, in the absence of indisputable evidence of a persistent infection. 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.
2. "Serologic markers of Lyme disease in children with autism".
Ajamtan, M., Kosofsky, B.E., Wormser, G.P., Rajadhyalsha, A., and Alaedini, A.
JAMA 309: 1771-1772, 2013.
3. "Lack of serum antibodies against Borrelia burgdorferi in children with autism"
Burbelo, P.D., Swedo, S.E., Thurm, A., Bayal, A., Levin, A.E., Marques, A.,
and Iadorola, M.J.
Clinical Vaccine Immunology, May 2013, on-line ahead of print publication.
4. Autism and Developmental Disabilities Monitoring Network Report of 2009 (http://www.cdc.gov/ncbddd/autism/states/ADDMCommunityReport2009.pdf).
5. Reported Lyme Disease Cases by State, 1999-2008 (http://www.cdc.gov/ncidod/dvbid/lyme/ld_rptdLymeCasesbyState.htm
Although the agent of Lyme disease, Borrelia burgdorferi, is transmitted only by Ixodes ticks, the question of sexual transmission of Borrelia burgdorferi has been a matter of speculation in the public media because both B. burgdorferi and Treponema pallidum, the agent of syphilis, are spirochetes. They utilize skin as the point of entry to establish an infection; however, the similarity ends there. In the case of T. pallidum, syphilis spirochetes grow to abundance in moist scabs on superficial ulcers known as chancres, and syphilis spirochetes are transmitted by sexual contact through abrasions of the genital, anal or oral mucosa. By contrast, B. burgdorferi spirochetes are present only in sparse numbers in the deep inner layers of the skin; unlike Treponema, B. burgdorferi spirochetes cannot survive on the surface of the skin or genital mucosa. Lyme disease spirochetes enter the skin through a highly ordered process of metabolic changes in the spirochetes during feeding by its tick vector. There are no epidemiological or clinical data to support the sexual transmission of Lyme disease.
The biology of B. burgdorferi has been extensively investigated in the laboratory using several well-defined animal models under highly controlled conditions; it should be noted that in many of the animal models used, infection with B. burgdorferi commonly results in the wide-spread dissemination of spirochetes throughout the body and body fluids. 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. The CDC has no record of a single case of Lyme disease that has been sexually transmitted.
1. Barthold, S. W. 1991. Infectivity of Borrelia burgdorferi relative to route of inoculation and genotype in laboratory mice. J Infect Dis 163:419-420.
2. Moody, K. D., and S. W. Barthold. 1991. Relative infectivity of Borrelia burgdorferi in Lewis rats by various routes of inoculation. Am. J. Trop. Med. Hyg. 44:135-139.
3. Silver, R. M., L. M. Yang, R. A. Daynes, D. W. Branch, C. M. Salafia, and J. J. Weis. 1995. Fetal outcome of murine Lyme disease. Infect Immun 63:66-72.
4. Weis, J. J., L. Yang, K. PetriSeiler, and R. M. Silver. 1997. Pathological manifestations in murine Lyme disease: association with tissue invasion and spirochete persistence. Clin Infect Dis 25(suppl):S18-S24.
5. Woodrum, J. E., and J. H. Oliver. 1999. Investigation of venereal, transplacental, and contact transmission of the Lyme disease spirochete, Borrelia burgdorferi, in Syrian hamsters. J Parasitol 85:426-430.
Lyme disease affects the nervous system. This statement is both accurate and terrifying since, for many of us, damage to the brain is the most feared consequence of disease. However, when it comes to Lyme disease, much of this fear is misplaced. Lyme disease can affect the lining of the brain, a disorder known as meningitis. Other than causing fever and bad headaches, this form of meningitis is remarkably benign; nobody has ever died of it, and it has rarely -- if ever -- caused significant damage to any patient's brain. On extremely rare occasions, the infection can involve the brain or spinal cord, disorders that are now extraordinarily rare. Other patients can develop inflammation of various nerves, e.g., the nerves that control the muscles on one side of the face (Bell's palsy); this might occur in about 5% of untreated individuals. Other nerves can be affected, but even less frequently.
When considering these disorders, it is essential to recognize some key facts. First, the infection is highly responsive to antibiotics. Second, if the facial nerve has been severely damaged, there may be some residual weakness after treatment. However it is extraordinarily rare for there to be any permanent damage to the brain itself.
More importantly, there are many symptoms that occur in patients with Lyme disease and most other infections that may make one think there is a problem with the brain; however, that is not the case. Headaches, which are remarkably common in individuals with fever of any cause, are rarely due to a brain infection. Slowed thinking, with difficulty in concentrating, remembering or mentally focusing occurs to a greater or lesser extent in virtually everyone with an active inflammatory condition; however, it is almost never due to the disease affecting the brain itself. Rather, these are the effects of chemicals produced by the body in response to an infection or inflammation. These effects disappear as soon as the infection or inflammation resolves.
Since some patients with Lyme disease develop fatigue and thinking difficulties, some have suggested that these symptoms in isolation-- are strongly suggestive of this infection. However, this is misguided thinking. Studies have shown that symptoms such as these, which are severe enough to affect day-to-day functioning but are never due to nervous system disease, occur in over 2% of the population at large at any given time. In the U.S., this amounts to 6,000,000 people! Since there only about 30,000 cases of Lyme disease are reported each year, patients with Lyme disease obviously represent only a very tiny fraction of the total number of individuals with these symptoms.
There is a great deal of misunderstanding, among patients and doctors, about what laboratory test for the diagnosis of Lyme disease actually measure and what constitutes a positive test result.
The most common, widely used tests simply measure antibodies against the Lyme disease bacterium, Borrelia burgdorferi. Since antibodies are produced by the body's immune system to fight infection, detecting the presence of antibodies against bacteria or a virus is a good way to determine if someone has -- or had-- an infection. 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. Immunoglobulin M (IgM) develops first, during the first 7 to 10 days of infection; it is followed by the development of Immunoglobulin G (IgG), one to two weeks later. 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.
Why do we use IgM assays at all? It is because IgM is produced first. IgM can be found in people very early during infection, well before IgG antibody is produced. Within 1-2 weeks following the onset of infection, IgM antibodies to B. burgdorferi can be detected in the vast majority of infected individuals. However, after one month, IgG antibody responses predominate and there is no longer a need to depend on an unreliable assay based on the detection of IgM antibody. Thus, because of the limitations of IgM assays and the high rate of false positives, their use should be limited to the first month of infection; however, that frequently is not the case. 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 against B. burgdorferi. The two most common procedures are by ELISA and Western blot. An ELISA is carried out on a plastic plate and measures the amount of antibody that binds to one or more B. burgdorferi proteins (antigens). A Western blot is like a bar code. Different kinds of B. burgdorferi proteins are separated by size on a strip of special paper and the antibodies in the patient's blood bind specifically to the proteins on the paper. The binding antibodies are then colored and the bar code is read. People who have been infected with B. burgdorferi have antibodies against certain specific proteins, thereby resulting in a positive bar code. What constitutes a positive pattern was established by the CDC in collaboration with many experienced physician scientists from major research centers 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.
There are some who claim that several important proteins (e.g., OspA, OspB, and other B. burgdorferi proteins or antigens) were not 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. Although it is true that OspA and OspB antigens are indeed specific for B. burgdoreferi, these antigens are produced only when the bacterium is grown on artificial laboratory media or in the midgut of Ixodes ticks. Since these antigens are not -- or are only minimally produced -- during the course of a human infection, they are of little or no diagnostic value for human disease; the presence of other antibodies recommended in the CDC standard criteria predominate and thus are of greater relevance, as demonstrated by the results of thousands of comparative laboratory tests.
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 (http://igenex.com/Website) . Consequently, the results of their tests fall outside the range of standard practice and have a much greater rate of false positives than one would get using the CDC criteria.
The CDC is responsible for guiding physicians in the appropriate use of laboratory tests for the diagnosis of Lyme disease and other infectious diseases. The CDC has warned about nonstandard testing and the interpretation of laboratory test results using unvalidated criteria. This carries great weight among mainstream physicians, as well as scientists working at State public health laboratories. Thus, the CDC criteria remain the standard and other criteria are considered to be unvalidated and unacceptable.
As is the case for most serologic assays, Lyme disease serologic assays are not by themselves diagnostic. A diagnosis of Lyme disease can only be made in the presence of well defined objective clinical abnormalities 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. Simply demonstrating that someone has an immune response against B. burgdorefri does not mean that person is actively infected, or that any general symptoms have anything to do with B. burgdorferi infection. It also is important to realize that the immune system has memory. That means that an individual who makes a mature antibody response against any infecting bacterium or virus continues to have detectable antibodies in their blood. This is true for all infections, including Lyme disease. Thus, a positive test after someone has been treated is in fact normal and does not indicate on going infection.
There is no indeterminate designation in the CDC criteria. Also there is no separate CDC surveillance criteria for serologic assays. The lack of a positive serology in a patient without the clear objective abnormalities known to be associated with Lyme disease has a very high negative predictive value, indicating that patient does not have Lyme disease.
The CDC has issued the following statement which summarizes its views on the diagnosis of Lyme disease (LD):
A two-test approach for active disease and for previous infection using a sensitive enzyme immunoassay (EIA) or immunofluorescent assay (IFA) followed by a Western immunoblot is the algorithm of choice. All specimens positive or equivocal by a sensitive EIA or IFA should be tested by a standardized Western immunoblot. Specimens negative by a sensitive EIA or IFA need not be tested further. When Western immunoblot is used during the first 4 weeks of disease onset (early LD), both immunoglobulin M (IgM) and immunoglobulin G (IgG) procedures should be performed. A positive IgM test result alone is not recommended for use in determining active disease in persons with illness greater than 1 month's duration because the likelihood of a false-positive test result for a current infection is high for these persons. If a patient with suspected early LD has a negative serology, serologic evidence of infection is best obtained by the testing of paired acute- and convalescent-phase serum samples. Serum samples from persons with disseminated or late-stage LD almost always have a strong IgG response to Borrelia burgdorferi antigens.
Although Borrelia burgdorferi-like organisms have been observed in mosquitoes, horse flies, and deer flies in areas where Lyme disease is endemic, these organisms have not been cultured to verify their identity. Experiments attempting to transmit B. burgdorferi from infected to uninfected laboratory animals by mosquitoes have not been successful (1). Furthermore, epidemiological studies have shown that the date of onset for Lyme disease occurs in June, coincident with the peak abundance of nymphal Ixodes scapularis ticks, and not during August when mosquitoes and other biting files are at peak abundance (2). Despite findings of B. burgdorferi in other tick species such as the American dog tick (Dermacentor variabilis) and the lone star tick (Amblyomma americanum) in the field, laboratory transmission studies have confirmed that these tick species cannot transmit the infection to laboratory animals; thus, they are not competent vectors for Lyme disease (3). Both experimental and epidemiological studies have shown that Ixodes scapularis and Ixodes pacificus are the only tick species in North America that are capable of transmitting B. burgdorferi, the spirochete that causes Lyme disease, to humans. Please consult the Lyme Disease Risk Assessment Map on the home page of the ALDF website (www.aldf.com) for specific information on the incidence of Ixodes ticks as well as the numbers of reported cases of Lyme disease for individual States.
1. Magnarelli, LA, and Anderson, JF. J. Clin. Microbiol. 26: 1482-1486, 1988.
2. Falco, R.C., D.F. McKenna, T.J. Daniels, R.B. Nadelman, J. Nowakowski, D. Fish, and G.P. Wormser. Am. J. Epidemiol: 149: 771 -776, 1999.
3. Piesman, J. and Happ, CM. J. Med. Entomol. 34: 451-156, 1997.
The clear and simple answer is "no". According to Saunder's "Dictionary and Encyclopdeia of Laboratory Medicine and Technology", there are two definitions of the term "cyst". The first is used to describe any closed cavity or sac -- both normal and abnormal -- that is lined by epithelial cells, although in some locations, it may be lined by connective tissue or bone. The second 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, use of the term "cyst" with reference to B. burgdorferi or any other bacterium is incorrect. In most cases, the term is used to convey the false impression that, by forming "cysts", Borrelia are some how able to escape destruction by antibiotics and host immune defense mechanisms, so that they can establish a long-term persistent infection. Although some even advocate additional treatment with metronidazole to eliminate these "cysts" (1), there is no evidence that they have any clinical relevance.
Some investigators 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 antibiotics that influence cell wall formation. Such variants are of two types and differ only in the amount of residual cell wall material that they possess: spheroplasts, which still contain some remnants of cell wall material; and, protoplasts which are completely devoid of any cell wall material (2). 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 occurs, it occurs relatively early after antibiotic treatment, i.e., when the levels of antibiotic first begin to decline (2). Since neither variant is surrounded by a "cyst-like" protective structure, there is no reason to assume that they are any less permeable or susceptible to antibiotics than the original parental cell type. 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 (3,4,5).
1. Brorson, O, and Brorson, SH.. An in vitro study of the susceptibility of mobile and cystic forms of Borreli burgdorferi to metronidazole. APMIS 107: 566-576, 1999.
2. Allan, EJ, Hoischen, D, and Gumpert, Bacterial L-forms. J. Advan. Applied Microbiol. 68: 2-39, 2009.
3. Hodzic, E, Feng, S, Holden, K, et al.. Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Antimicrob. Agents Chemother. 52: 1728-1736, 2008.
4. Bockenstedt, LK, Mao, J, Hodzic, E et al. Detection of attenuated. Non-infectious spirochetes in Borrelia-burgdorferi - infected mice after antibiotic treatment. J. Infect. Dis. 186: 1430-1437, 2002.
5. Wormser, GP, and Schwartz, I. Antibiotic treatment of animals infected with Borrelia burgdorferi. Clin. Microbiol. Rev. 22: 387-395, 2009.
Several spirochetes have demonstrated the ability to cause transplacental infections in a variety of animals and in humans, especially the causative agent of syphilis (Trepanema pallidum) (1-7). Cases of congenital syphilis acquired from the mother are well documented and used to be relatively common. Although the Lyme disease bacteria (Borrelia burgdorferi) is also a spirochete, it differs from T. pallidum in several important ways including its genetics, transmission, clinical manifestations, and effects on the fetus. Unlike congenital syphilis, there is limited evidence that congenital Lyme disease occurs in humans.
Human pregnancy studies
Several published case series have assessed the relationship between Lyme disease in pregnant women and outcomes of the fetus. These included a retrospective investigation of 19 women with Lyme disease during pregnancy where infection with B. burgdorferi could not be directly implicated as the cause of any of the adverse outcomes that were noted (8). In a prospective report of 17 women who acquired Lyme disease during pregnancy, one woman had a spontaneous abortion with no evidence of an infection with B. burgdorferi on either stains or cultures of the fetal tissue, one woman had an infant with isolated syndactyly, and 15 women delivered normal infants with no clinical or serologic evidence of infection with B burgdorferi (9). A study of 105 women with erythema migrans during pregnancy found that 93 (88%) had healthy infants delivered at term, 6 (6%) delivered prematurely, and 2 (2%) had pregnancies that ended with a miscarriage (10). One of the preterm infants had cardiac abnormalities and 2 died shortly after birth. Four (4%) babies born at term had congenital anomalies, 1 with syndactyly and 3 with urologic abnormalities. Infection with B. burgdorferi could not be directly implicated as the cause of any of these adverse outcomes. The placentas were examined from 60 asymptomatic women who lived in an area endemic for Lyme disease and whose serology was either positive or equivocal for antibodies to B. burgdorferi (11). Three (5%) were found to contain spirochetes using Warthin-Starry silver stains while B. burgdorferi DNA was detected using PCR in 2 of the placentas that were tested, but all of these pregnancies had entirely normal outcomes. Finally, no association was found between exposure of 105 women to B. burgdorferi (either before conception or during pregnancy) and fetal death, prematurity, or congenital malformations (12).
[Note: This last sentence summarizes a study of 2,000 pregnant women of whom 15 had evidence of exposure to B. burgdorferi- either a past history of Lyme disease, seropositivity, or Lyme disease diagnosed during pregnancy]
Studies of children with possible congenital Lyme disease
Researchers compared 5,000 infants, half from an area in which Lyme disease was endemic and half as controls from an area without Lyme disease (13). They found no significant differences in the overall incidence of congenital malformations between the two groups. Although there was a statistically significant higher rate of cardiac malformations in the endemic area compared with the control area, there was no relationship between a cardiac malformation and either a clinical history or serologic evidence of Lyme disease.
No association was found between the presence of IgG antibodies to B. burgdorferi and congenital malformations in 421 infants whose cord blood was analyzed for B. burgdorferi antibody (14). In another study, of 12 infants born to women who were B. burgdorferi antibody positive at delivery, half had minor medical problems as neonates (15). Only one woman had a history consistent with Lyme disease during pregnancy and her infant had a ventricular septal defect. At follow-up evaluations approximately 9-17 months later, all of the children, except for the child with the cardiac defect, were entirely well, and none had serologic evidence of an infection with B. burgdorferi.
Transplacental transmission of B. burgdorferi in humans has been demonstrated in association with adverse fetal outcome in four case reports. The first report was of a 28-year old woman with untreated Lyme disease during the first trimester of pregnancy who gave birth at 35 weeks gestation to an infant with widespread cardiovascular abnormalities (16). This infant died during the first week of life and postmortem examination showed spirochetes morphologically compatible with B. burgdorferi in the infant's spleen, kidneys, and bone marrow, but not in the heart. In contrast to the mononuclear cell infiltrate and proliferation of fibroblasts usually seen with congenital syphilis (17), there was no evidence of inflammation, necrosis, or granuloma formation in this infant's heart or other organs. In a second report, a 24-year-old woman with untreated Lyme disease in the first trimester of pregnancy gave birth at term to a 2500-gram stillborn (18). B. burgdorferi was cultured from the liver, and spirochetes were seen in the heart, adrenal glands, liver, brain, and placenta with both immunofluorescent and silver stains. However, no evidence of inflammation was seen, and there were no abnormalities noted except for a small ventricular septal defect. The third report was a 37-year old woman who received penicillin orally for 1 week for erythema migrans during the first trimester of pregnancy and subsequently delivered a 3400-gram infant at term who died at 23 hours of age of what was believed to be "perinatal brain damage" (19). B. burgdorferi was identified in the newborn's brain using immunochromogenic staining with monoclonal antibodies. However, no significant inflammation or other abnormalities were found in any organ, including the brain, on postmortem examination. Finally, an otherwise healthy child who presented with multiple annular, erythematous lesions, fever, and generalized lymphadenopathy at 3 weeks of age, experienced these clinical findings recurrently throughout the first 3 years of life despite oral therapy with amoxicillin and josamycin (20). A skin biopsy revealed spirochetes by silver stain and was positive for B. burgdorferi by PCR assay. In addition, serologic studies were positive for infection with B. burgdorferi. The patient's mother had no history of either a tick bite or of Lyme disease, but she had been involved in outdoor activities in an endemic area and had a weakly positive serologic test for Lyme disease. No association between maternal Lyme disease and an adverse outcome of the pregnancy were described in several other case reports of pregnant women with either erythema migrans or neuroborreliosis who were treated with appropriate antimicrobial therapy at different stages of their pregnancy (21-24).
In a survey of neurologists in areas of the United States in which Lyme disease was endemic, none of the 162 pediatric and 37 adult neurologists who responded to the survey had ever seen a child whose mother had been diagnosed with Lyme disease during pregnancy (26). A retrospective case-control study was carried out in an area endemic for Lyme disease where 796 case children with congenital cardiac anomalies were compared with 704 control children without cardiac defects with respect to Lyme disease in their mothers either during or before the pregnancy (27). There was no association between congenital heart defects and either a tick bite or Lyme disease in the mothers either within 3 months of conception or during pregnancy.
In summary, even though Lyme disease is fairly common, there is little evidence that fetuses of pregnant women with Lyme disease are at increased risk of delivering a child either with congenital malformations or with congenital Lyme disease. Of course, if a pregnant woman develops Lyme disease, she should be treated appropriately, but she should also be reassured that there is little risk to her fetus.
1. Ingall, D, Dobson, SRM, and Musher, D. Syphilis. In, Remington, JS, Klein, JD, eds.. Infectious Diseases of the fetus and the Newborn Infant. 3rd ed. W,B. Saunders, --367-394, 1990.
2. Fuchs, PC, and Oyama, AA. Neonatal relapsing fever due to transplacental transmission of Borrelia. JAMA 208: 690-692, 1969.
3. Soghlan, JD, and Bain, AD. Leptospirosis in human pregnancy followed by the death of the foetus. Br. Med. J. 1: 228-230, 1969.
4. Lindsay, S, and Luke, IW. Fatal leptospirosis (Weil's disease) in a newborn infant. J. Pediatr. 34: 90-94, 1949.
5. Steenbarger, JR. Congenital tick-borne relapsing fever: report of a case with first documentation of transplacental transmission. Birth Defects Orig.Artic. Ser. 18: 39-45, 1982.
6. Yagupsky, P. and Moss, S. Neonatal Borrelia species infection (relapsing fever). Amer. J. Dis. Child 139: 74-76, 1985.
7. Lane, RS, Burgdorfer, W., Hayes, SF, et al. Isolation of a spirochete from the soft tick, Ornithodoros coriaceus : a possible agent of epizootic bovine abortion. Science 230: 85-87, 1985.
8. Markowitz, LE, Steere, AC, Benach, JL, et al. Lyme disease during pregnancy. JAMA 255: 3394-3396, 1986.
9. Ciesielski CA, Russell H, Johnson S, et al. Prospective study of pregnancy outcome in women with Lyme disease. Abstract 39. Twenty-Seventh International Conference of Antimicrobial Agents and Chemotherapy., New York, 1987.
10. Maraspin, V, Cimperman, J, Loric-Furlan, S. et al. Erythema migrans in pregnancy. Wien Klin. Wochenschr. 111: 933-940, 1999.
11. Figueroa, R., Bracero, LA, Aguero-Rosenfeld, M, et al. Confirmation of Borrelia burgdorferi spirochetes by polymerase chain reaction in placentas of women with reactive serology for Lyme antibodies. Gynecol. Obstet. Invest. 41: 240-243, 1996.
12. Strobino BA, Williams CL, Abid S, et al. Lyme disease and pregnancy outcome: a prospective study of two thousand prenatal patients. Am J Obstet Gynecol 169: 367-74, 1993
13. Williams, CL, Strobino, B, Weinstein, A., et al. Maternal Lyme disease and congenital malformations: a cord blood serosurvey in endemic and control areas. Paediatr. Perinat. Epidemiol. 9: 320-330, 1995.
14. Williams, CL, Benach, JL, Curran, AS, et al. Lyme disese during pregnancy: a blood cord serosurvey. Ann. NY Acad. Sci. 539: 504-506, 1988.
15. Nadal, D., Hunziker, UA, Bucher, HU, et al. Infants born to mothers with antibodies against Borrelia burgdorferi at delivery. Eur. J. Pediatr. 148: 426-427, 1989.
16. Schlesinger, PA, Duray, PH, Burke, BA, et al. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi. Ann. Intern. Med. 103: 67-68, 1985.
17. Oppenheimer, EH, and Hardy, JB. Congenital syphilis in the newborn infant: clinical and pathological observations in recent cases. Johns Hopkins Med. J. 129: 63-82, 1971.
18. MacDonald, AB, Benach, JL, and Burgdorfer, W. Still birth following maternal Lyme disease. NY State Med. J. 87: 615-616, 1987.
19. Weber, K, Bratzke, HJ, Neubert, U, et al. Borrelia burgdorferi in a newborn despite oral penicillin for Lyme borreliosis during pregnancy. Pediatr. Infect. Dis. J. 7: 286-289, 1988.
20. Trevisan, G., Stinco, G, and Cinco, M. Neonatal skin lesions due to spirochetal infection: a case of congenital Lyme borreliosis? Intl. J. Dematol. 36: 677-680, 1997.
21. Grandsaerd, MJ. Lyme borreliosis as a cause of facial palsy during pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol. 91: 99-100, 2000.
22. Mikkelson, AL, and Palle, C. Lyme disease during pregnancy. Acta Obstet. Gynecol. Scand. 6: 477-478, 1987.
23. Schaumann, R. Facial palsy caused by Borrelia infection in a twin pregnancy in an area of nonendemicity. Clin. Infect. Dis. 29: 955-956, 1999.
24. Scutzer, SE, Janniger, CK, and Schwartz, RA. Lyme disease during pregnancy. Cutis. 47: 267-268, 1991.
25. Stiernstedt, G. Lyme borreliosis during pregnancy. Scan. J. Infect. Dis. (suppl) 71: 99-100, 1990.
26. Gerber, MA, and Zalneraitis, EL. Childhood neurologic disorders and Lyme disease during pregnancy. Pediatr. Neurol. 11: 41-43, 1994.
27. Strobino, B, Abid, S, and Gewitz, M. Maternal Lyme disease and congenital heart disease: a case-control study in an endemic area. Amer. J. Obstet. Gynecol. 180: 711-716, 1999.
Is Lyme Disease a Lethal, Life-threatening Infection?
Although Lyme disease is not considered to be a lethal, life-threatening infection, there have been reports to the contrary in the lay press and on patient support websites. A recent study by the Centers for Disease Control and Prevention (CDC) of physician-diagnosed Lyme disease deaths, as recorded on death certificates and coded in NCHS death records issued in the U.S. from 1999 – 2003, was conducted to shed more light on this issue (1).
Approval to release death certificates for the study was obtained from all States except Idaho, Iowa, Louisiana, Maine, and Tennessee, which account for only about 1% of the total number of reported cases of Lyme disease. Lyme disease was reported to be an underlying cause of death on only 23 records. Since 96,068 cases of Lyme disease were reported to the CDC during the same study period (2), this suggests an extremely low calculated mortality rate that could be even lower if one considers the fact that: (a) the information on only 1 of the records that was completed properly was consistent with well-established clinical manifestations of Lyme disease; and, (b) the actual number of reported cases of Lyme disease may be underestimated.
Although it was not possible to review actual patient charts and medical histories as part of the study, the analysis of death records and death certificates did not reveal large numbers of reported deaths or a unique clinical syndrome potentially associated with Lyme disease that should be of great concern. Those persons whose deaths were attributed to Lyme disease have a similar age distribution to those who died of other causes, in contrast to the bimodal distribution of Lyme disease. Only one of the death certificates examined during the course of this analysis reported a clinical syndrome that was potentially consistent with known Lyme disease manifestations. In view of these considerations, there is no compelling evidence to indicate that Lyme disease is a fatal, life-threatening disease.
It should be noted that infection by Borrelia burgdorferi, the spirochete that causes Lyme disease in humans, produces an overwhelming disseminated infection (borreliosis) in white-footed mice, a natural host for this pathogen. However, such a pervasive infection does not impair the physical activity of infected mice in the least, nor does it result in death (3). Although several animals, including non-human primates, are susceptible to infection by B. burgdoreferi, it does not produce a lethal, life-threatening infection in any of the animal models of this infection studied.
1. Kugeler, K.J., Griffith, K.S., Gould, L.H., Kochancek, K., Delorey, M.J., Biggerstaff, B.J. and Mead, P.S. “A review of death certificates listing Lyme disease as an underlying or multiple cause of death in the United States”. Clin. Infect. Dis.52: 364-367, 2011.
2. "Summary of Notifiable Diseases -- United States, 2003",MMWR 52 (No. 54), 2005.
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 with such clinical problems were described in the 1980s, 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 to suggest they might be due to Lyme disease, even though this is probably the least likely explanation.
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 Lyme 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. 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 (1). 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, coupled with the clinical aspects of the patients illness, allows straightforward differentiation between these two disorders.
1. Klempner, M., Hu, L., Evans, J. et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N. Eng. J. Med. 345: 85-92, 2001.
The availability of sensitive and specific laboratory tests for the diagnosis of Lyme disease is essential not only to ensure prompt and effective treatment, but also to avoid the risks and substantial costs associated with the unnecessary and lengthy treatment of those who have been misdiagnosed. To this end, the 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.
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 (http://www.cdc.gov/mmwr/preview/mmwrhtml/00038469.htm). To avoid confusion, test results are recorded only as positive or negative, with no arbitrary degrees of positivity.
It has been recognized, since the early 1990s, that antibodies against the 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 (1, 2). At the time 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.
It is important to note that, unless recombinant OspA and OspB are used as ligands to develop these bands, one can not be sure that they are not due to reactivity against other proteins of similar molecular size that remain to be identified. Both the CDC and the 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; 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.
To consider including antibodies against OspA or OspB in a diagnostic test for Lyme disease is inconsistent with the basic biology of Borrelia burgdorferi. OspA and OspB, though certainly specific for Borrelia burgdorferi, are expressed primarily when B. burgdorferi is grown on artificial laboratory media or in the midgut of a tick, not during mammalian infection (3,4,5,6). This provides the rationale for the design of OspA-based vaccines (e.g., LYMErx) as transmission-blocking vaccines, rather than as vaccines that generate protective immunity in vivo as is the case for most conventional human or animal vaccines (6).
Obviously, only validated FDA-approved tests should be used for the diagnosis of Lyme disease. At present, there are 46 such tests (http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfivd/index.cfm). Both patients as well as physicians are strongly advised to examine this listing to ensure that any diagnostic test being considered for use is in fact FDA-approved.
Both the FDA and the CDC have issued warnings about both the use of nonstandard testing and evaluating the results of laboratory test using unvalidated criteria (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5405a6.htm). Such guidance is welcome and carries great weight among mainstream physicians, as well as scientists working at State public health laboratories.
1. Ma, B., Christen, B., Leung, D., and Vigo-Pelfrey, C. "Serodiagnosis of Lyme borreliosis by Western immunoblot: reactivity of various significant antibodies against Borrelia burgdorferi." J. Clin. Microbiol. 30: 370-376, 1992.
2. Dressler, F., Whalen, J.A., Reinhardt, B.N., and Steere, A.C. "Western blotting in the serodiagnosis of Lyme disease." J. Infect. Dis. 167: 392-400, 1993.
3. Schwan, T.G., and Piesman, J. "Temporal changes in outer surface proteins A and C of the Lyme disease-associated spirochete, Borrelia burgdorferi , during the chain of infection in ticks and mice." J. Clin. Microbiol. 38: 382-388, 2000.
4. Schwan, T.G., Piesman, J. Golde, W.T., Dolan, M.C., abd Rosa, P.A. Induction of outer surface protein on Borrelia burgdorferi during feeding. Proc. Natl. Acad. Sci. 92: 2909-2913, 1995.
5. deSilva, A.M., Telford, S.R., 3rd, Brunet, L.R., Barthold, S.W., and Fikrig, E. "Borrelia burgdorferi OspA is an arthropod-specific transmission blocking Lyme disease vaccine". J. Exp. Med. 183: 271-275, 1996.
6. Wang, G., Aguero-Rosenfeld, M.E., Wormser, G.P., and Schwartz, I. "Detection of Borrelia burgdorferi", in D.S. Samuels and J.D. Radolf , editors, "Borrelia : Molecular Biology, Host Interaction, and Pathogenesis", Caister Academic Press, Norfolk, UK, 2010, pp 443-466.
That certainly could be the case if you were correctly diagnosed with such an infection, in the first place, and it is responsive to the antibiotic used. However, in the absence of such a diagnosis, at least three other explanations are possible.
First, if another undiagnosed and unrelated infection that has nothing at all to do with Lyme disease is present (e.g., a urinary tract infection) and it is really the cause of the general symptoms experienced, its resolution by antibiotic therapy might then account for the relief of symptoms.
Second, in a large double-blinded, placebo-controlled study on the benefits of extended antibiotic therapy for the treatment of patients with persistent symptoms believed to be due to chronic Lyme disease, improvement was noted in 38% of the patients given placebo alone (1). Obviously, because of the magnitude of such a placebo effect, it is not possible to determine the beneficial effects of therapy for the treatment of chronic Lyme disease without conducting a placebo-controlled trial using adequate numbers of enrolled patients and appropriate statistical analysis. 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 (2). Testimonials, regardless of the numbers solicited, do not constitute proof of efficacy; for every patient who claims that a given therapeutic approach is beneficial, there may be just as many -- if not more -- who state that it is not.
Third, several antibiotics often used to treat Lyme disease, e.g., ceftriaxone and doxycycline, have significant neuroactive effects that can impact ones sense of well being (3,4). In fact, ceftriaxone, which appears to be the most potent in that regard, is now being tested in clinical trials for its efficacy in treating amylotropic lateral sclerosis or ALS (6). The anti-inflammatory and pain-relieving effects of tetracycline and its derivatives (doxycycline, minocycline, and tigecycline) are well known and have been studied extensively (7). So have the anti-inflammatory effects of macrolides such as erythromycin and azithromycin (8-11). Perhaps other drugs that are not antibiotics might work just as well -- or perhaps even better in this regard and not contribute to the emergence of new and more difficult to manage infections by antibiotic resistant strains of bacteria.
1. Klempner, M.S., Hu, L., Evans, J., et al. "Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease." New Eng. J. Med. 345: 85-92, 2001.
2. Kienle, G.S. and Kiene, H., "Placebo effect and placebo concept: a critical Methodological and conceptual analysis of reports on the magnitude of the placebo effect". Altern. Ther. Health Med. 2: 39-54, 1996.
3. Domercq, M. and Matute, C. "Neuroprotection by tetracyclines" Trends Pharmacol. Sci. 25: 609-612, 2004.
4. Rothstein, J.D., Patel, S., Regan, M.R. et al. "Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433: 73-77, 2005.
5. Clinical trials on the use of ceftriaxone in patients with ALS http://clinicaltrials.gov/ct2/results?term=ceftriaxone+and+ALS
6. Bastos, L.F.S., de Oliveira, A.C.P., Watkin, L.R. et al. "Tetracyclines and pain". Naunyn Schmiedebergs Arch. Pharmacol. 2012, Jan 27 [Epub ahead of print].
7. Tkalcevic, I., Bosnjak, B., Hrvacic, B. , et al. "Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice." Eur. J. Pharmacol. 539: 131-138, 2006.
8. Tamaoki, J., Kadota, J., and Takizawa, H. "Clinical implication of the immunomodulatory effects of macrolides". Amer. J. Med. 117: 5S-11S, 2004.
9. Sanz, M.J., Nabah, Y.N., Cerda-Nicolas, M., et al. Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression. British J. Pharmacol. 144: 190-201, 2005.
10. Sadreddini, S., Noshad, H., Molaeefard, M. et al. "A double blind, randomized, placebo-controlled study to evaluate the efficacy of erythromycin in patients with knee effusion due to osteoarthritis". Int. J. Rheum. Dis. 12: 44-51, 2009.