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Common bullseye rash pattern associated with Lyme Disease.
'Lyme disease', or 'borreliosis', is an emerging infectious disease caused by spirochete bacteria from the genus ''Borrelia''. Sherris Medical Microbiology, Ryan KJ, Ray CG (editors), , , McGraw Hill, 2004, The vector for the infection is typically the bite of an infected black-legged or deer tick, however other carriers (including other ticks in the ''Ixodes'' genus) have been implicated in disease transmission. Baron's Medical Microbiology ''(Baron S ''et al'', eds.), Johnson RC, , , Univ of Texas Medical Branch, 1996, ''Borrelia burgdorferi'' is the predominant cause of Lyme disease in the U.S.; Lyme disease in Europe is more often caused by ''Borrelia afzelii'' or ''Borrelia garinii''.
The disease varies widely in its presentation, which may include a rash and flu-like symptoms in its initial stage, followed by the possibility of musculoskeletal, arthritic, neurologic, psychiatric and cardiac manifestations. In most cases of Lyme disease, symptoms can be eliminated with antibiotics, especially if treatment is begun early in the course of illness. Delayed or inadequate treatment may often lead to "late stage" Lyme disease that is disabling and difficult to treat. Amid controversy over diagnosis, testing and treatment, two different standards of care for Lyme disease have emerged.[1][2]
Signs and Symptoms
Characterisitc "bulls-eye"-like rash caused by Lyme disease.
The acute phase of Lyme disease infection is a characteristic reddish "bulls-eye" rash, with accompanying fever, malaise, and musculoskeletal pain (arthralgia or myalgia). The characteristic reddish "bull's-eye" rash (known as ''erythema chronicum migrans'') may be seen in up to 80% of early stage Lyme disease patients,[3] appearing anywhere from one day to a month after a tick bite.[4] The rash does not represent an allergic reaction to the bite, but rather a skin infection with the Lyme bacteria, ''Borrelia burgodferi'' sensu lato.
The incubation period from infection to the onset of symptoms is usually 1–2 weeks, but can be much shorter (days), or much longer (months to years). Symptoms most often occur from May through September because the nymphal stage of the tick is responsible for most cases.[5] Asymptomatic infection exists, but is uncommon.[6]
Other, less common findings in acute Lyme disease include cardiac manifestations (up to 10% of patients may have cardiac manifestations including heart block and palpitations[7]), neurologic symptoms (neuroborreliosis may occur in up to 18%7), as well as simple altered mental status as the sole presenting symptom has been reported in early neuroborreliosis.[8]
Chronic symptoms
Untreated or persistent cases may progress to a chronic form most commonly characterized by meningoencephalitis, cardiac inflammation (myocarditis), and frank arthritis. It should be noted, however, that chronic Lyme disease can have a multitude of symptoms affecting numerous physiological systems: the symptoms appear heterogeneous in the affected population, which may be due to innate immunity or variations in ''Borrelia'' bacteria. Late symptoms of Lyme disease can appear months or years after initial infection and often progress in cumulative fashion over time. Neuropsychiatric symptoms often develop much later in the disease progession, much like tertiary neurosyphilis.
In addition to the acute symptoms, chronic Lyme disease can be manifested by a wide-range of neurological disorders, either
central or peripheral, including encephalitis or encephalomyelitis, muscle twitching, polyneuropathy or paresthesia, and vestibular symptoms or other otolaryngologic symptoms[9][10], among others. Neuropsychiatric disturbances can occur (possibly from a low-level encephalitis), which may lead to symptoms of memory loss, sleep disturbances, or changes in mood or affect.[11]
Cause
Main articles: Lyme disease microbiology
''Borrelia'' bacteria, the causative agent of Lyme disease. Magnified 400 times.
Lyme disease is caused by Gram-negative spirochetal bacteria from the genus ''Borrelia''. At least 37 ''Borrelia'' species have been described, 12 of which are Lyme related. The ''Borrelia'' species known to cause Lyme disease are collectively known as ''Borrelia burgdorferi'' sensu lato, and have been found to have greater strain diversity than previously estimated.[12]
Until recently it was thought that only three genospecies caused Lyme disease: ''B. burgdorferi'' sensu stricto (predominant in North America, but also in Europe), ''B. afzelii'', and ''B. garinii'' (both predominant in Eurasia). However, newly discovered genospecies have also been found to cause disease in humans.
Transmission
''Ixodes scapularis'', the primary vector of Lyme disease in eastern North America.
Hard-bodied ticks of the genus ''Ixodes'' are the primary vectors of Lyme disease. In Europe, ''Ixodes ricinus'' (known commonly as the sheep tick, castor bean tick, or European castor bean tick) is the transmitter. In North America, ''Ixodes scapularis'' (black-legged tick or deer tick) has been identified as the key to the disease's spread on the east coast, while on the west coast the primary vector is ''Ixodes pacificus'' (Western black-legged tick). The majority of infections are caused by ticks in the nymph stage, as adult ticks do not become infected through feeding.[13] Another possible vector is ''Amblyomma americanum'' (Lone Star tick),[14] which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well. Unfortunately, only about 20% of persons infected with Lyme disease by the deer tick are aware of having had any tick bite,[15] making early detection difficult in the absence of a rash.
While Lyme spirochetes have been found in insects other than ticks,[16] reports of actual infectious transmission appear to be rare.[17] Sexual transmission has been anecdotally reported; Lyme spirochetes have been found in semen[18] and breast milk,[19] however transmission of the spirochete by these routes is not known to occur. Lyme Disease: Questions and Answers Steere AC
Congenital transmission of Lyme disease can occur from an infected mother to fetus through the placenta during pregnancy, however prompt antibiotic treatment appears to prevent fetal harm.[20]
Diagnosis
Due to the difficulty in culturing ''Borrelia'' bacteria in the laboratory, diagnosis of Lyme disease is typically based on the clinical exam findings and a history of exposure to endemic Lyme areas. The EM rash, which does not occur in all cases, is considered sufficient to establish a diagnosis of Lyme disease even when serologies are negative.[21][22] Serological testing can be useful, but is not diagnostic.
Clinicians who diagnose strictly based on the U.S. Centers for Disease Control (CDC) Case Definition for Lyme are in error, as the CDC explicitly states that this definition is intended for surveillance purposes only, and is "not intended to be used in clinical diagnosis."[23][24]
Importantly, virtually no controlled studies of late lyme encephalopathy have been performed, and the CDC diagnostic criteria were not formulated for use on this entity. Once lyme disease is well established in the brain, it can occur as a very disabling diffuse encephalopathy which however is difficult to diagnose using standard serological or intrathecal testing for reasons outlined below. Lyme is a deep tissue infection and by the time encephalopathy is established, few if any CFS antibodies can be detetected, and PCR is unreliable. Seronegative disease can occur for the same reason that this phenomenon occurs in neurosyphilis, with incomplete or intercurrent antibiotic treatment abrogating the serum antibody response, but not eliminating the infection.
It is in this context that advanced imaging studies like SPECT or PET can provide objective evidence of global brain dysfunction. Resort is often made to neuropsychological testing, but a normal result does not rule out the illness, which can be very subtle and manifest as a disabling mood disorder accompanied by massive and debilitating fatigue, with few objective signs.
Diagnosis of late-stage Lyme disease it is often difficult due to the multi-faceted appearance which can mimic symptoms of many other diseases. For this reason Lyme has often been called the new "great imitator".[25] Lyme disease may be misdiagnosed as Multiple sclerosis, rheumatoid arthritis, fibromyalgia, chronic fatigue syndrome (CFS), or other autoimmune and neurodegenerative diseases.
Serology
The serological laboratory tests most widely available and employed are the Western blot and ELISA. A two-tiered protocol is recommended by the CDC: the more sensitive ELISA is performed first, if it is positive or equivocal, the more specific Western blot is run. The reliability of testing in diagnosis remains controversial, however studies show the Western blot IgM has a specificity of 94–96% for patients with clicnial symptoms of early Lyme disease.[26][27]
Erroneous test results have been widely reported in both early and late stages of the disease. These errors can be caused by several factors, including antibody cross-reactions from other infections including Epstein-Barr virus and cytomegalovirus,[28] as well as herpes simplex virus.[29]
Polymerase chain reaction (PCR) tests for Lyme disease have also been developed to detect the genetic material (DNA) of the Lyme disease spirochete. PCR tests are rarely susceptible to false-positive results but can often show false-negative results, and the overall reliability of PCR in this role remains unclear. With the exception of PCR, there is no currently practical means for detection of the presence of the organism, as serologic studies only test for antibodies of ''Borrelia''. High titers of either immunoglobulin G (IgG) or immunoglobulin M (IgM) antibodies to ''Borrelia'' antigens indicate disease, but lower titers can be misleading. The IgM antibodies may remain after the initial infection, and IgG antibodies may remain for years.[30]
Western blot, ELISA and PCR can be performed by either blood test via venipuncture or cerebral spinal fluid (CSF) via lumbar puncture. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive, reportedly CSF yields positive results in only 10-30% of patients cultured. The diagnosis of neurologic infection by ''Borrelia'' should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses.[31]
New techniques for clinical evaluation if ''Borrelia'' infection are under investigation, including ''Lymphocyte transformation tests'' [32] and ''focus floating microscopy''.[33] New research indicates chemokine CXCL13 may also be a possible marker for neuroborreliosis.[34]
Imaging
Single photon emission computed tomography (SPECT) imaging has been used to look for cerebral hypoperfusion indicative of Lyme encephalitis in the patient,[35] however SPECT is not a diagnostic tool in and of itself, but may be a useful method of determining brain function.
In Lyme patients cerebral hypoperfusion of frontal subcortical and cortical structures has been reported.[36] In about 70% of chronic Lyme disease patients with cognitive symptoms, brain SPECT scans typically reveal a pattern of global hypoperfusion in a heterogeneous distribution through the white matter.[37] This pattern is not definite or specific for Lyme disease per se, as it can also be seen in other central nervous system (CNS) syndromes such as HIV encephalopathy, viral encephalopathy, chronic cocaine use, and vasculitides. However, most of these syndromes can be ruled out easily through standard serologic testing and careful patient history taking.
The presence of global cerebral hypoperfusion deficits on SPECT in the presence of characteristic neuropsychiatric features should dramatically raise the index of suspicion for lyme encephalopathy among patients who have traveled to or inhabit endemic areas, regardless of patient recall of tick bite. Late disease can occur many years after initial infection, and the average time from symptom onset to diagnosis in these patients is about 4 years due to the CDC and infectious disease community's efforts to cover-up the illness. Because seronegative disease can occur, and because CFS testing is often normal, lyme encephalopathy often becomes a diagnosis of exclusion: once all other possibilities are ruled out, LE becomes ruled in. Although the abberrant SPECT patterns are caused by cerebral vaculitis, a vasculitide, brain biopsy is not commonly performed for these cases as opposed to other types of cerebral vasculitis.
Abnormal magnetic resonance imaging (MRI) findings are often seen in both early and late Lyme disease. MRI scans among patients with neurologic Lyme disease may demonstrate punctated white matter lesions on T2-weighted images, similar to those seen in demyelinating or inflammatory disorders such as multiple sclerosis, systemic lupus erythematosus (SLE), or cerebrovascular disease.[38] Cerebral atrophy and brainstem neoplasm has been indicated with Lyme infection as well.[39]
Diffuse white matter pathology can disrupt these ubiquitous gray matter connections and could account for deficits in attention, memory, visuospatial ability, complex cognition, and emotional status. White matter disease may have a greater potential for recovery than gray matter disease, perhaps because neuronal loss is less common. Spontaneous remission can occur in multiple sclerosis, and resolution of MRI white matter hyperintensities, after antibiotic treatment, has been observed in Lyme disease.[40]
Prevention
The currently recommended prevention involves avoiding areas in which ticks are found; this can reduce the probability of contracting Lyme disease. Other good prevention practices include wearing clothing that covers the entire body when in a wooded area; using mosquito/tick repellent; after exposure to wooded areas, checking all parts of the body (including hair) and clothing for ticks.
For clothing, you should wear long-sleeve shirts and pants that are tucked into socks or boots. One should also wear light-colored clothing so that you can see the tick on you before it attaches itself.
However, a more effective, community wide method of preventing Lyme disease is a reduction in numbers of the primary host on which the deer tick depends.
Management of host animals
Lyme and all other deer-tick borne diseases can be prevented on a regional level by reducing the deer population that the ticks depend on for reproductive success. This has been effectively demonstrated in the communities of Monhegan, Maine[41] and in Mumford Cove, CT.[42]. The black-legged or deer tick (''Ixodes scapularis'') is dependent on the white-tailed deer for successful reproduction.
By reducing the deer population back to healthy levels of 8 to 10 per square mile (from the current levels of 60 or more deer per square mile in the areas of the country with the highest Lyme disease rates) the tick numbers can be brought down to very low levels, too few to spread Lyme and other tick-borne diseases.[43]
Vaccination
A vaccine against a North American strain of the spirochetal bacteria was available between 1998 and 2002 by GlaxoSmithKline (GSK) called Lymerix and was based on the outer surface protein A (Osp-A) of ''Borrelia''. Osp-A causes creation of antibodies from the body's immune system to attack that protein. When taking it off the market, GSK cited poor sales, need for frequent boosters, the high price of the vaccine, and exclusion of children. Some people believe that the actual reason was that the vaccine was neither safe nor effective. A group of patients who took Lymerix developed arthritis, muscle pain and other troubling symptoms after vaccination. Class-action litigation against GSK followed. Cassidy v. SmithKline Beecham, No. 99-10423 (Ct. Common Pleas, PA state court) (common settlement case).[44]
It was later learned that patients with the genetic allele HLA-DR4 were susceptible to T-cell cross-reactivity between epitopes of OspA and lymphocyte function-associated antigen in these patients causing an autoimmune reaction.[45]
New vaccines are being researched using outer surface protein C (Osp-C) and glycolipoprotein as methods of immunization.[46][47]
Removal of ticks
Main articles: Tick#Removal
Many urban legends exist about the proper and effective method to remove a tick. Complete removal of the tick head is important; if the head is not completely removed, local infection of bite location may result. JAMA patient page. Lyme disease, Zeller JL, Burke AE, Glass RM, , , JAMA, 2007
Treatment
Antibiotics are the primary treatment for Lyme disease. Penicillin was first demonstrated by researchers to be useful against ''Borrellia'' in the 1950s; today the antibiotics of choice are doxycycline, amoxicillin and ceftriaxone. Macrolide antibiotics are also used.
Persons who remove attached ticks should be monitored closely for signs and symptoms of tick-borne diseases for up to 30 days. A three day course of doxycycline therapy may be considered for deer tick bites when the tick has been on the person for at least 12 hours. Patients should report any Erythema migrans over the subsequent two to six weeks. If there should be suspicion of disease, then a course of Doxycycline should be immediately given for ten days without awaiting serology tests which only yield positive results after an interval of one to two months.
In later stages, the bacteria disseminate throughout the body and may cross the blood-brain barrier, making the infection more difficult to treat. Late diagnosed Lyme is treated with oral or IV antibiotics, frequently ceftriaxone, 2 grams per day, for a minimum of four weeks. Minocycline is also indicated for neuroborreliosis for its ability to cross the blood-brain barrier.[48][49]
Antibiotic treatment controversy
With little research conducted specifically on treatment for late/chronic Lyme disease, particularly lyme encephalopathy, treatment remains controversial. Currently there are two sets of peer-reviewed published guidelines in the United States; the International Lyme and Associated Diseases Society (ILADS)[50] advocates extended courses of antibiotics for chronic Lyme patients in light of evidence of persistent infection, while the Infectious Diseases Society of America[51] does not recognize chronic infection and recommends no treatment for persistent symptoms. Double-blind, placebo-controlled trials of long-term antibiotics for chronic Lyme have produced mixed results.
A controversial new guideline developed by the American Academy of Neurology, finds conventionally recommended courses of antibiotics are highly effective for treating nervous system Lyme disease. They find no compelling evidence that prolonged treatment with antibiotics has any benefit in treating symptoms that persist following standard therapy. The guideline is endorsed by the Infectious Diseases Society of America (IDSA). However, these guidelines refer mostly to early acute lyme neuroborreliosis, as there is a paucity of studies on late lyme encephalopathy and parenchymal CNS disease. The guideline leader was John J. Halperin and was co-written by Gary Worsmer and Eugene Shapiro, neither of whom are neurologists. Halperin, Worsmer and Shapiro were all co-authors of the IDSA Lyme guidelines released in 2006 by the Journal of Clinical Infectious Diseases. There is significant disagreement with this guideline (www.ilads.org).
The latest double blind, randomized, placebo-controlled multicenter clincal study, done in Finland, results indicated that oral adjunct antibiotics were not justified in the treatment of patients with disseminated Lyme borreliosis who initially received intravenous antibiotics for 3 weeks. The researchers noted the clinical outcome of said patients should not be evaluated at the completion of intravenous antibiotic treatment but rather 6-12 months afterwards. In patients with chronic post-treatment symptoms, persistent positive levels of antibodies did not seem to provide any useful information for further care of the patient.[52]
Antibiotic-resistant therapies
Antibiotic treatment is the central pillar in the management of Lyme disease. In the late stages of borreliosis, symptoms may persist despite extensive and repeated antibiotic treatment.[53][54] Lyme arthritis which is antibiotic resistant may be treated with hydroxychloroquine or methotrexate.[55] Experimental data is consensual on the deleterious consequences of systemic corticosteroid therapy. Corticosteroids are not indicated in Lyme disease.[56]
Antibiotic refractory patients with neuropathic pain responded well to gabapentin monotherapy with residual pain after intravenous ceftriaxone treatment in a pilot study.[57] The immunomodulating, neuroprotective and anti-inflammatory potential of minocycline may be helpful in late/chronic Lyme disease with neurological or other inflammatory manifestations. Minocycline is used in other neurodegenerative and inflammatory disorders such as multiple sclerosis, Parkinsons, Huntingtons disease, rheumatoid arthritis (RA) and ALS.[58]
Alternative therapies
A number of other alternative therapies have been suggested, though clinical trials have not been conducted. For example, the use of hyperbaric oxygen therapy (which is used conventionally to treat a number of other conditions), as an adjunct to antibiotics for Lyme has been discussed.[59] Though there are no published data from clinical trials to support its use, preliminary results using a mouse model suggest its effectiveness against ''B. burgdorferi'' both in vitro and in vivo. Current and novel therapies for Lyme disease., Pavia C, , , Expert Opin Investig Drugs, 2003 Anecdotal clinical research has shown potential for the antifungal azole medications such as diflucan in the treatment of Lyme, but has yet to be repeated in a controlled study or postulated a developed hypothetical model for its use.[60]
Alternative medicine approaches include bee venom because it contains the peptide melittin, which has been shown to exert inhibitory effects on Lyme bacteria in vitro;[61] no clinical trials of this treatment have been carried out, however.
Prognosis
For early cases, prompt treatment is usually curative.[62] However, the severity and treatment of Lyme disease may be complicated due to late diagnosis, failure of antibiotic treatment, simultaneous infection with other tick-borne diseases including ehrlichiosis, babesiosis, and bartonella, and immune suppression in the patient.
A meta-analysis published in 2005 found that some patients with Lyme disease have fatigue, joint and/or muscle pain, and neurocognitive symptoms persisting for years despite antibiotic treatment.[63] Patients with late Stage Lyme disease have been shown to experience a level of physical disability equivalent to that seen in congestive heart failure.[64]
Though rare, Lyme disease can be fatal.[65][66][67][68]The first CDC recognized death from Lyme disease was Amanda Schmidt, age 11.[69]
Ecology
Urbanization and other anthropogenic factors can be implicated in the spread of the Lyme disease into the human population. In many areas, expansion of suburban neighborhoods has led to the gradual deforestation of surrounding wooded areas and increasing "border" contact between humans and tick-dense areas. Human expansion has also resulted in a gradual reduction of the predators that normally hunt deer as well as mice, chipmunks and other small rodents -- the primary reservoirs for Lyme disease. As a consequence of increased human contact with host and vector, the likelihood of transmission to Lyme residents has greatly increased.[70][71] Researchers are also investigating possible links between global warming and the spread of vector-borne diseases including Lyme disease.[72]
The deer tick (''Ixodes scapularis'', the primary vector in the northeastern U.S.) has a two-year life cycle, first progressing from larva to nymph, and then from nymph to adult. The tick feeds only once at each stage. In the fall, large acorn forests attract deer as well as mice, chipmunks and other small rodents infected with ''B. burgdorferi''. During the following spring, the ticks lay their eggs. The rodent population then "booms." Tick eggs hatch into larvae, which feed on the rodents; thus the larvae acquire infection from the rodents. (Note: At this stage, it is proposed that tick infestation may be controlled using acaricides (miticide).
Adult ticks may also transmit disease to humans. After feeding, female adult ticks lay their eggs on the ground, and the cycle is complete. On the west coast, Lyme disease is spread by the western black-legged tick (''Ixodes pacificus''), which has a different life cycle.
The risk of acquiring Lyme disease does not depend on the existence of a local deer population, as is commonly assumed. New research suggests that eliminating deer from smaller areas (less than 2.5 ha or 6.2 acres) may in fact lead to an increase in tick density and the rise of "tick-borne disease hotspots".[73]
Epidemiology
Lyme disease is the most common tick-borne disease in North America and Europe, and one of the fastest-growing infectious diseases in the United States. Of cases reported to the United States Center for Disease Control (CDC), the ratio of Lyme disease infection is 7.9 cases for every 100,000 persons. In the ten states where Lyme disease is most common, the average was 31.6 cases for every 100,000 persons for the year 2005.[74]
Although Lyme disease has now been reported in 49 of 50 states in the U.S, about 99% of all reported cases are confined to just five geographic areas (New England, Mid-Atlantic, East-North Central, South Atlantic, and West North-Central). Charts and tables for Lyme disease statistics in the U.S. can be found at the CDC website.
The number of reported cases of the disease have been increasing, as are endemic regions in North America. For example, it had previously been thought that ''B. burgdorferi'' sensu lato couldn't be maintained in an enzootic cycle in California because it was assumed the large lizard population would dilute the prevalence of ''B. burgdorferi'' in local tick populations, but this has since been proven false as lizards are now known carriers of ticks in North America, Europe and North Africa. Indeed, the DNA of ''Borrelia'' has been detected in lizards, indicating that they can be infected.[75]
While ''B. burgdorferi'' is most associated with deer tick and the white tailed mouse, ''Borrelia afzelii'' is most frequently detected in rodent-feeding vector ticks, ''Borrelia garinii'' and ''Borrelia valaisiana'' appear to be associated with birds. Both rodents and birds are competent reservoir hosts for ''B. burgdorferi'' sensu stricto. The resistance of a genospecies of Lyme disease spirochetes to the bacteriolytic activities of the alternative complement pathway of various host species may determine its reservoir host association.
In Europe, cases of ''B. burgdorferi'' sensu lato infected ticks are found predominantly in Norway, Netherlands, Germany, France, Italy, Slovenia and Poland, but have been isolated in almost every country on the continent. Lyme disease statistics for Europe can be found at Eurosurveillance website.
''B. burgdorferi'' sensu lato infested ticks are being found more frequently in Japan, as well as in Northwest China and far eastern Russia.[76][77] ''Borrelia'' has been isolated in Mongolia as well.[78]
In South America tick-borne disease recognition and occurrence is rising. Ticks carrying ''B. burgdorferi'' sensu lato, as well as canine and human tick-borne disease, have been reported widely in Brazil, but the subspecies of ''Borrelia'' has not yet been defined.[79] The first reported case of Lyme disease in Brazil was made in 1993 in Sao Paulo.[80] ''B. burgdorferi'' sensu stricto antigens in patients have been identified in Colombia and in Bolivia.
In Northern Africa ''B. burgdorferi'' sensu lato has been identified in Morocco, Algeria, Egypt and Tunisia.[81][82][83]
In Western and sub-Saharan Africa, tick-borne relapsing fever was first identified by the British physicians Joseph Dutton and John Todd in 1905. ''Borrelia'' in the manifestation of Lyme disease in this region is presently unknown but evidence indicates that Lyme disease may occur in humans in sub-Saharan Africa. The abundance of hosts and tick vectors would favor the establishment of Lyme infection in Africa.[84] In East Africa, two cases of Lyme disease have been reported in Kenya.[85]
In Australia there is no definitive evidence for the existence of ''B. burgdorferi'' or for any other tick-borne spirochete that may be responsible for a local syndrome being reported as Lyme disease.[86] Cases of neuroborreliosis have been documented in Australia but are often ascribed to travel to other continents. The existence of Lyme disease in Australia is controversial.
To date, data shows that Northern hemisphere temperate regions are most endemic for Lyme disease.[87][88]
Controversy
Main articles: Lyme disease controversy
Most clinicians agree on the treatment of early Lyme disease infections.[89] There is, however, considerable disagreement regarding prevalence of the disease, diagnostic criteria, treatment of late-stage Lyme disease, and the likelihood of a chronic, antibiotic-resistant infections. Some authorities contend that Lyme disease is relatively rare, easily diagnosed with available blood tests, and most often easily treated with two to four weeks of antibiotics,[90] while others propose that the disease is under-diagnosed, available blood tests are unreliable, and that extended antibiotic treatment is often necessary.[91][92][93]
The majority of public health agencies such as the U.S. Centers for Disease Control maintain the former position. While this narrower position is sometimes described as the "mainstream" view of Lyme disease, published studies involving non-randomized surveys of physicians in endemic areas found physicians evenly split in their views, with the majority recognizing seronegative Lyme disease, and roughly half prescribing extended courses of antibiotics for chronic Lyme disease.[94][95]
In recent years a few prominent American Lyme researchers have received funding for the study of organisms known as bioweapons that could be used in bioterrorism attacks. The funding has been granted by various U.S. Government agencies including the National Institute of Health (NIH), and the National Institute of Allergy and Infectious Diseases (NIAID).
These grants have become a source of controversy. Some argue that these researchers have a conflict of interest in receiving these U.S. Government funds due to the politicization of Lyme disease and their roles in the history of the controversy, others cite that the grants are warranted as the infectious agents that the researchers are studying for bioterror defense are similar to the genetic makeup and pathogenesis of ''Borrelia'', such as tularemia, brucellosis and Q fever.
In October 2006, further controversy erupted with the release of updated diagnosis and treatment guidelines from the Infectious Diseases Society of America (IDSA). New Lyme Disease Guidelines Spark Showdown The new IDSA recommendations are more restrictive than prior IDSA treatment guidelines for Lyme,[96] and now require either an EM rash or positive laboratory tests for diagnosis; seronegative Lyme disease is no longer acknowledged (except incidentally in early Lyme disease). The authors of the guidelines maintain that chronic Lyme disease does not result from persistent infection, and therefore treatment beyond 2-4 weeks is not recommended, even in late stage cases. An opposing viewpoint has been expressed by the International Lyme and Associated Disease Society (ILADS), which proposes extended antibiotic treatment beyond four weeks for both early and late Lyme disease.[97]
Advancing immunology research
The role of T cells concomitant to ''Borrelia'' infection was first made in 1984,[98] and long term persistance of T cell lymphocyte responses to ''B. burgdorferi'' as an "immunological scar syndrome" was hypothesized in 1990.[99] The role of Th1 and interferon-gamma (IFN-gamma) in borrelia was first described in 1995.[100] The cytokine pattern of Lyme disease, and the role of Th1 with down regulation of interleukin-10 (IL-10) was first proposed in 1997.[101]
Inflammation
Recent studies in both acute and antibiotic refractory, or chronic, Lyme disease have shown a distinct pro-inflammatory immune process. This pro-inflammatory process is a cell-mediated immunity and results in Th1 upregulation. These studies have shown a significant decrease in cytokine output of (IL-10), an upregulation of Interleukin-6 (IL-6), Interleukin-12 (IL-12) and IFN-gamma and disregulation in TNF-alpha predominantly.[102]
These studies suggest that the host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. IFN-gamma alters gene expression by endothelia exposed to ''B. burgdorferi'' in a manner that promotes recruitment of T cells and suppresses that of neutrophils.
Studies also suggest suppressors of cytokine signaling (SOCS) proteins are induced by cytokines, and T cell receptor can down-regulate cytokine and T cell signaling in macrophages. It is hypothesized that SOCS are induced by IL-10 and ''B. burgdorferi'' and its lipoproteins in macrophages, and that SOCS may mediate the inhibition of IL-10 by concomitantly elicited cytokines. IL-10 is generally regarded as an anti-inflammatory cytokine, since it acts on a variety of cell types to suppress production of proinflammatory mediators.
Researchers are also beginning to identify microglia as a previously unappreciated source of inflammatory mediator production following infection with ''B. burgdorferi''. Such production may play an important role during the development of cognitive disorders in Lyme neuroborreliosis. This effect is associated with induction of nuclear factor-kappa B (NF-KB) by ''Borrelia''.[103][104]
Disregulated production of pro-inflammatory cytokines such as IL-6 and TNF-alpha can lead to neuronal damage in ''Borrelia'' infected patients.[105] IL-6 and TNF-Alpha cytokines produce fatigue and malaise, two of the more prominent symptoms experienced by patients with chronic Lyme disease.[106][107]IL-6 is also significantly indicated in cognitive impairment.[108]
Neuroendocrine
A developing hypothesis is that the chronic secretion of stress hormones as a result of ''Borrelia'' infection may reduce the effect of neurotransmitters, or other receptors in the brain by cell-mediated pro-inflammatory pathways, thereby leading to the dysregulation of neurohormones, specifically glucocorticoids and catecholamines, the major stress hormones. [109][110]This process is mediated via the Hypothalamic-pituitary-adrenal axis. Additionally Tryptophan, a precursor to serotonin appears to be reduced within the CNS in a number of infectious diseases that affect the brain, including Lyme.[111] Researchers are investigating if this neurohormone secretion is the cause of neuro-psychiatric disorders developing in some patients with borreliosis.[112]
Antidepressants acting on serotonin, norepinephrine and dopamine receptors have been shown to be immunomodulatory and anti-inflammatory against pro-inflammatory cytokine processes, specifically on the regulation of IFN-gamma and IL-10, as well as TNF-alpha and IL-6 through a psycho-neuroimmunological process.[113] Antidepressants have also been shown to suppress Th1 upregulation.[114]These studies warrant investigation for antidepressants for use in a psycho-neuroimmunological approach for optimal pharmacotherapy of antibiotic refractory Lyme patients.
New developments
New research has also found that chronic Lyme patients have higher amounts of ''Borrelia''-specific forkhead box P3 (FoxP3) than healthy controls, indicating that regulatory T cells might also play a role, by immunosuppression, in the development of chronic Lyme disease. FoxP3 are a specific marker of regulatory T cells.[115] The signaling pathway P38 mitogen-activated protein kinases (p38 MAP kinase) has also been identified as promoting expression of pro-inflammatory cytokines from ''Borrelia''.[105]
The culmination of these new and ongoing immunological studies suggest this cell-mediated immune disruption in the Lyme patient amplifies the inflammatory process, often rendering it chronic and self-perpetuating, regardless of whether the ''Borrelia'' bacterium is still present in the host, or in the absence of the inciting pathogen in an autoimmune pattern.[117]
Researchers hope that this new developing understanding of the biomolecular basis and pathology of cell-mediated signaling events caused by ''B. burgdorferi'' infection will lead to a greater understanding of immune response and inflammation caused by Lyme disease and, hopefully, new treatment strategies for chronic antibiotic-resistant disease.
Lyme funding and treatment controversy
Many of the scientists involved in formulating what have become controversial Lyme diagnostic tests and treatment guidelines have been heavily involved in both bioweapons research and commercial vaccine and diagnostic test development, which the Lyme patient community views as a conflict of interest. [118]
In response to these and other concerns expressed by the expanding national community of patients, Richard Blumenthal, the Attorney General of Connecticut has launched an investigation exploring possible corruption.
To date, federal research aimed at developing treatments for chronic Lyme disease is roughly $30 million, as contrasted to a $22 billion budget for military bioweapons. Scientists setting Lyme treatment and diagnostic testing policy in the United States have a well publicised history in the bioweapons field, and many have recently received lucrative bioweapons grants for Bsl-3 and Bsl-4 Labs where, critics contend, Lyme treatment research lacks transparency, accountability and focus on treatment research.[119][120]
In 2003, Lyme researcher Dr. Mark Klempner was appointed head of the new $1.6 billion biowarfare top-security facility at Boston University.[121] In 2004, Lyme researcher Dr. Jorge Benach,[122] was reportedly chosen as a recipient for a $3 million biowarfare research grant, and in 2005, Lyme researcher Dr. Alan Barbour was reportedly placed in charge of a $40 million dollar new biowarfare complex based at UC Irvine. [123]
Former NIH Lyme disease program officer, Edward McSweegan has published numerous articles and letters to editorial pages relating to biowarfare topics ranging from anthrax to plague. Curiously, Mr. McSweegan's novel, Deliberate Release, is biowarfare thriller that describes the deliberate release of a germ weapon. [124]
History
The first record of a condition associated with Lyme disease dates to 1883 in Breslau (formerly in Germany) where physician Alfred Buchwald described a degenerative skin disorder now known as acrodermatitis chronica atrophicans. In 1909, Arvid Afzelius presented research about an expanding, ring-like lesion he had observed. Afzelius published his work 12 years later and speculated that the rash came from the bite of an ''Ixodes'' tick, and that meningitic symptoms and signs in a number of case; this rash is now known as erythema migrans (EM), the skin rash found in early stage Lyme disease.[125] In 1911, parasitologist Andrew Balfour of the Wellcome Research Laboratory in Khartoum identified "infective granules" or spore-type "cysts" as the cause of persistence of spirochetal infection in the Sudanese Fowl.[126]
In the 1920s, French physicians Garin and Bujadoux described a patient with meningoencephalitis, painful sensory radiculitis, and erythema migrans following a tick bite, and they postulated the symptoms were due to a spirochetal infection. In the 1940s, German neurologist Alfred Bannwarth described several cases of chronic lymphocytic meningitis and polyradiculoneuritis, some of which were accompanied by erythematous skin lesions.
In 1948 spirochete-like structures were observed in skin specimens by Swedish dermatologist Carl Lennhoff.[127] In the 1950s, relations between tick bite, lymphocytoma, EM and Bannwarth's syndrome are seen throughout Europe leading to the use of penicillin for treatment.[128][129][130]
Interest in tick-borne infections in the U.S. began with the first report of tick-borne relapsing fever (''Borrelia hermsii'') in 1915, following the recognition of five human patients in Colorado.[131]
In 1970 a physician in Wisconsin named Rudolph Scrimenti reports the first case of EM in U.S. and treats it with penicillin based on European literature.[132]
The full syndrome now known as Lyme disease was not recognized until a cluster of cases originally thought to be juvenile rheumatoid arthritis was identified in three towns in southeastern Connecticut in 1975, including the towns Lyme and Old Lyme, which gave the disease its popular name.[133] This was investigated by Dr. David Snydman and Dr.Allen Steere of the Epidemic Intelligence Service, and by others from Yale University. The recognition that the patients in the United States had EM led to the recognition that "Lyme arthritis" was one manifestation of the same tick-borne condition known in Europe. Willy Burgdorfer: Lyme disease., Sternbach G, Dibble C, , , J Emerg Med, 1996
Before 1976, elements of ''B. burgdorferi'' sensu lato infection were called or known as ''tickborne meningopolyneuritis'', ''Garin-Bujadoux syndrome'', ''Bannworth syndrome'', ''Afzelius syndrome'', ''Montauk Knee'' or ''sheep tick fever''. Since 1976 the disease is most often referred to as Lyme disease,[134][135] Lyme borreliosis or simply borreliosis.
In 1976, Jay Sanford, a former physician at the Walter Reed Army Institute of Research, published a chapter in the book ''The Biology of Parasitic Spirochetes.'' In it, Dr. Sanford stated: "the ability of borrelia, especially tick-borne strains, to persist in the brain and in the eye during remission after treatment with arsenic or with penicillin or even after apparent cure, is well known.” [136] Although the notion of persistent neurological infection was identified early on by military researchers such as Dr. Sanford, later Lyme researchers curiously denied the possibility of persistent ''Borrelia'' infection in the brain, with many researchers ignoring evidence of persistent infection.
In 1980 Steere, et al, began to test antibiotic regimens in adult patients with Lyme disease[137] In 1982 a novel spirochete was cultured from the mid-gut of ''Ixodes'' ticks in Shelter Island, New York, and subsequently from patients with Lyme disease. The infecting agent was then identified by Jorge Benach at the State University of New York at Stony Brook, and soon after isolated by Willy Burgdorfer, a researcher at the National Institutes of Health, who specialized in the study of spirochete microorganisms such as ''Borrelia'' and ''Rickettsia''. The spirochete was named ''Borrelia burgdorferi'' in his honor. Burgdorfer was the partner in the successful effort to culture the spirochete, along with Alan Barbour.
After identification ''B. burgdorferi'' as the causative agent of Lyme disease, antibiotics were selected for testing, guided by in vitro antibiotic sensitivities, including tetracycline antibiotics, amoxicillin, cefuroxime axetil, intravenous and intramuscular penicillin and intravenous ceftriaxone.[138][139] The mechanism of tick transmission was also the subject of much discussion. ''B. burgdorferi'' spirochetes were identified in tick saliva in 1987, confirming the hypothesis that transmission occured via tick salivary glands.[140]
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External links
'General'
★
★ CDC Lyme disease page
★ Columbia University - Overview of Neuropsychiatric Lyme Disease
★ Eurosurveillance: Lyme disease in Europe
★ Lyme Disease ''The Merck Manual''
'Images'
★ Lyme disease images (Hardin MD/Univ of Iowa)
'Professional societies, foundations, advocacy'
★
★ National Research Fund of Tick-Borne Diseases
'Other'
★ Lyme Disease Medical Literature Summaries
★ Lyme Disease Research Database
★ Prehistoric Lyme - (The History of Lyme Disease) Lymenet Newsletter Volume: 1 Issue: 24 25-Oct-93
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