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| | {{CMG}}; {{AE}} {{Anmol}} |
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| | ==Tables== |
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| {{Lyme disease}}
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| {{CMG}}
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| ==Overview==
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| Lyme disease is caused by Borrelia burgdorferi and is transmitted by tick named [[Ixodes scapularis]]. Ticks can attach to any part of the human body but are often found in hard-to-see areas such as the groin, armpits, and scalp. In most cases, the tick must be attached for 36 to 48 hours or more before the Lyme disease bacterium can be transmitted.
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| ==Transmission==
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| [[Image:Ixodes scapularis.png|left|150px|''[[Ixodes scapularis]]'', the primary vector of Lyme disease in eastern North America.]]
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| <br clear="left" />
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| ===Primary Vector===
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| *Hard-bodied [[tick]]s of the genus ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of Lyme disease.
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| *Adult ticks are more infected then nymph stage by pathogens infectious to humans.<ref name="SchwartzFish1997">{{cite journal|last1=Schwartz|first1=Ira|last2=Fish|first2=Durland|last3=Daniels|first3=Thomas J.|title=Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease|journal=New England Journal of Medicine|volume=337|issue=1|year=1997|pages=49–50|issn=0028-4793|doi=10.1056/NEJM199707033370111}}</ref> ButThe majority of infections are caused by ticks in the nymph stage, as adult ticks do not become infected through feeding.
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| *
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| *In Europe, the commonly known sheep tick, castor bean tick, or European castor bean tick (''[[Ixodes ricinus]]'') is the transmitter.
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| *In North America, the black-legged tick or deer tick (''Ixodes scapularis'') has been identified as the key to the disease's spread on the east coast.
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| *About 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite,<ref name="Wormser">{{cite journal | author=Wormser G, Masters E, Nowakowski J, ''et al'' | title=Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions. | journal=Clin Infect Dis | volume=41 | issue=7 | pages=958-65 | year=2005 | pmid= 16142659}}</ref> making early detection difficult in the absence of a rash.
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| ===Other Potential Vectors===
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| *The lone star tick (''Amblyomma americanum''), which is found throughout the southeastern U.S. as far west as Texas, and increasingly in northeastern states as well.
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| *These tick bites usually go unnoticed due to the small size of the tick in its nymphal stage, as well as tick secretions that prevent the host from feeling any itch or pain from the bite.
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| *On the west coast, the primary vector is the western black-legged tick (''Ixodes pacificus'').<ref name="Clark">{{cite journal | author=Clark K | title=''Borrelia'' species in host-seeking ticks and small mammals in northern Florida. | journal=J Clin Microbiol | volume=42 | issue=11 | pages=5076-86 | year=2004 | pmid= 15528699 | url=http://jcm.asm.org/cgi/reprint/42/11/5076.pdf | format=PDF}}</ref> It was once thought to be a vector, although recent studies demonstrate that this tick species is not a competent vector of ''Borrelia burgdorferi'' sensu lato.<ref name="Ledin-k">{{cite journal | author = Ledin K, Zeidner N, Ribeiro J, "et al" | title = Borreliacidal activity of saliva of the tick Amblyomma americanum. | journal = Med Vet Entomol | volume = 19 | issue = 1 | pages = 90-95 | year = 2005 | pmid = 15752182}}</ref>
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| ===Other Modes of Transmission===
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| *While Lyme spirochetes have been found in insects other than ticks,<ref name="Magnarelli">{{cite journal | author=Magnarelli L, Anderson J | title=Ticks and biting insects infected with the etiologic agent of Lyme disease, ''Borrelia burgdorferi''. | journal=J Clin Microbiol | volume=26 | issue=8 | pages=1482-6 | year=1988 | pmid= 3170711 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=266646&blobtype=pdf | format=PDF}}</ref> reports of actual infectious transmission appear to be rare.<ref name="Luger">{{cite journal | author=Luger S | title=Lyme disease transmitted by a biting fly. | journal=N Engl J Med | volume=322 | issue=24 | pages=1752 | year=1990 | pmid = 2342543 | url=http://cassia.org/library/N_Engl_J_Med_1990_Jun_14,322(24),1752.htm}}</ref>
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| *[[Sexually transmitted infection|Sexual transmission]] have been reported; Lyme spirochetes have been found in semen<ref name="Bach">{{cite conference | author=Bach G | title=Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients. | booktitle=14th International Scientific Conference on Lyme Disease | year=2001 | url=http://www.anapsid.org/lyme/bach.html}}</ref> and breast milk,<ref name="Schmidt">{{cite journal | author=Schmidt B, Aberer E, Stockenhuber C, ''et al'' | title=Detection of ''Borrelia burgdorferi'' DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis. | journal=Diagn Microbiol Infect Dis | volume=21 | issue=3 | pages=121-8 | year=1995 | pmid = 7648832}}</ref> however transmission of the spirochete by these routes is not known to occur.<ref name="Steere_2003">{{cite web | author = Steere AC | title = Lyme Disease: Questions and Answers |publisher = Massachusetts General Hospital / Harvard Medical School | url = http://www.mgh.harvard.edu/medicine/rheu/Q&ALYME.pdf | format = PDF | date = 2003-02-01 | accessdate = 2007-03-22}}</ref>
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| *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.<ref>{{cite journal |author=Walsh CA, Mayer EW, Baxi LV |title=Lyme disease in pregnancy: case report and review of the literature |journal=Obstetrical & gynecological survey |volume=62 |issue=1 |pages=41-50 |year=2007 |pmid=17176487 |doi=10.1097/01.ogx.0000251024.43400.9a}}</ref>
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| ==Pathophysiology==
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| ===Pathogenesis===
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| * ''B. burgdorferi'' has been shown to invade a variety of cells, including [[endothelium]],<ref name="Ma-b">{{cite journal | author=Ma Y, Sturrock A, Weis JJ | title=Intracellular localization of Borrelia burgdorferi within human endothelial cells | journal=Infect Immun | year=1991 | pages=671-8 | volume=59 | issue=2 | pmid= 1987083 | url=http://www.pubmedcentral.gov/picrender.fcgi?artid=257809&blobtype=pdf | format=PDF}}</ref> [[fibroblasts]],<ref name="Klempner-b">{{cite journal | author=Klempner MS, Noring R, Rogers RA | title=Invasion of human skin fibroblasts by the Lyme disease spirochete, Borrelia burgdorferi | journal=J Infect Dis | year=1993 | pages=1074-81 | volume=167 | issue=5 | pmid= 8486939}}</ref> [[lymphocytes]],<ref name="Dorward">{{cite journal | author=Dorward DW, Fischer ER, Brooks DM | title=Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease | journal=Clin Infect Dis | year=1997 | pages=S2-8 | volume=25 Suppl 1 | pmid= 9233657}}</ref> [[macrophages]],<ref name="Montgomery">{{cite journal | author=Montgomery RR, Nathanson MH, Malawista SE | title=The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery | journal=J Immunol | year=1993 | pages=909-15 | volume=150 | issue=3 | pmid= 8423346}}</ref> [[keratinocytes]],<ref name="Aberer">{{cite journal | author=Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W | title=Heterogeneity of Borrelia burgdorferi in the skin | journal=Am J Dermatopathol | year=1996 | pages=571-9 | volume=18 | issue=6 | pmid= 8989928}}</ref> [[synovium]],<ref name="Girschick">{{cite journal | author=Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H | title=Intracellular persistence of Borrelia burgdorferi in human synovial cells | journal=Rheumatol Int | year=1996 | pages=125-32 | volume=16 | issue=3 | pmid= 8893378}}</ref><ref name="Nanagara">{{cite journal | author=Nanagara R, Duray PH, Schumacher HR Jr | title=Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms | journal=Hum Pathol | year=1996 | pages=1025-34 | volume=27 | issue=10 | pmid= 8892586}}</ref> and most recently [[neuronal]] and [[glial cells]]. <ref name="Livengood">{{cite journal | author=Livengood JA, Gilmore RD | title = Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. | journal = Microbes Infect | volume = [Epub ahead of print] | year=2006 | id = PMID 17045505}}</ref>
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| * By 'hiding' inside these cells, ''B. burgdorferi'' is able to evade the immune system and is protected to varying degrees against antibiotics,<ref name="Georgilis">{{cite journal | author=Georgilis K, Peacocke M, Klempner MS | title=Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone ''in vitro'' | journal=J Infect Dis | year=1992 | pages=440-4 | volume=166 | issue=2 | pmid= 1634816}}</ref><ref name="Brouqui">{{cite journal | author=Brouqui P, Badiaga S, Raoult D | title=Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin | journal=Antimicrob Agents Chemother | year=1996 | pages=1552-4 | volume=40 | issue=6 | pmid= 8726038 | url=http://aac.asm.org/cgi/reprint/40/6/1552.pdf | format=PDF}}</ref> allowing the infection to persist in a chronic state.
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| *Altered [[morphology (biology)|morphological]] forms, i.e. [[spheroplast]]s (cysts, granules).
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| * The existence of ''B. burgdorferi'' spheroplasts, which lack a [[cell wall]], has been documented [[in vitro]],<ref name="Alban">{{cite journal | author=Alban PS, Johnson PW, Nelson DR | title=Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi | journal=Microbiology | year=2000 | pages=119-27 | volume=146 ( Pt 1) | pmid= 10658658 | url =http://mic.sgmjournals.org/cgi/content/full/146/1/119}}</ref><ref name="Mursic">{{cite journal | author=Mursic VP, Wanner G, Reinhardt S, ''et al'' | title=Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants | journal=Infection | year=1996 | pages=218-26 | volume=24 | issue=3 | pmid= 8811359}}</ref><ref name="Kersten">{{cite journal | author=Kersten A, Poitschek C, Rauch S, Aberer E | title=Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi | journal=Antimicrob Agents Chemother | year=1995 | pages=1127-33 | volume=39 | issue=5 | pmid= 7625800 | url=http://aac.asm.org/cgi/reprint/39/5/1127.pdf | format=PDF}}</ref><ref name="Schaller">{{cite journal | author=Schaller M, Neubert U | title=Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin | journal=Infection | year=1994 | pages=401-6 | volume=22 | issue=6 | pmid= 7698837}}</ref> [[in vivo]],<ref name="Nanagara" /><ref name="Mursic" /><ref name="Phillips-c">{{cite journal | author=Phillips SE, Mattman LH, Hulinska D, Moayad H | title=A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated | journal=Infection | year=1998 | pages=364-7 | volume=26 | issue=6 | pmid= 9861561 | url=http://www.cbc.ca/ideas/features/Aids/phillips.html}}</ref> and in an [[ex vivo]] model.<ref name="Duray">{{cite journal | author=Duray PH, Yin SR, Ito Y, ''et al'' | title=Invasion of human tissue ex vivo by Borrelia burgdorferi | journal=J Infect Dis | year=2005 | pages=1747-54 | volume=191 | issue=10 | pmid= 15838803}}</ref>
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| * The fact that energy is required for the spiral bacterium to convert to the cystic form<ref name="Alban" /> suggests that these altered forms have a survival function, and are not merely end stage degeneration products.
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| * The spheroplasts are indeed [[virulent]] and [[infectious]], able to survive under adverse environmental conditions, and have been shown to revert back to the spiral form in vitro, once conditions are more favorable.<ref name="Gruntar">{{cite journal | author=Gruntar I, Malovrh T, Murgia R, Cinco M | title=Conversion of Borrelia garinii cystic forms to motile spirochetes ''in vivo'' | journal=APMIS | year=2001 | pages=383-8 | volume=109 | issue=5 | pmid= 11478686}}</ref><ref name="Murgia">{{cite journal | author=Murgia R, Cinco M | title=Induction of cystic forms by different stress conditions in Borrelia burgdorferi | journal=APMIS | year=2004 | pages=57-62 | volume=112 | issue=1 | pmid= 14961976}}</ref>
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| * A number of other factors make ''B. burgdorferi'' [[spheroplast]]s a key factor in the relapsing, chronic nature of Lyme disease.
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| * Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance.
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| * They also express different surface proteins - another reason for [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] antibody tests), as current tests only look for antibodies to surface proteins of the ''spiral'' form.
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| * In addition, ''B. burgdorferi'' spheroplasts are generally not susceptible to the [[antibiotics]] traditionally used for Lyme disease.
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| * They have instead shown sensitivity in vitro to [[Human parasitic diseases|antiparasitic]] drugs such as [[metronidazole]], <ref name="Brorson-c">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole | journal=APMIS | year=1999 | pages=566-76 | volume=107 | issue=6 | pmid= 10379684}}</ref> [[tinidazole]], <ref name="Brorson-d">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole | journal=Int Microbiol | year=2004 | pages=139-42 | volume=7 | issue=2 | pmid= 15248163 | url=http://www.im.microbios.org/26June04/09%20Brorson.pdf | format=PDF}}</ref> and [[hydroxychloroquine]], <ref name="Brorson-e">{{cite journal | author=Brorson O, Brorson SH | title=An ''in vitro'' study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine | journal=Int Microbiol | year=2002 | pages=25-31 | volume=5 | issue=1 | pmid= 12102233}}</ref> to which the spiral form of ''B. burgdorferi'' is not sensitive.
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| ===Mechanisms of persistence===
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| *Like the Borrelia that cause [[relapsing fever]], ''B. burgdorferi'' has the ability to vary its surface proteins in response to [[immune system|immune]] attack.<ref name="Embers" /><ref name="Liang">{{cite journal | author=Liang FT, Yan J, Mbow ML, ''et al'' | title=Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses | journal=Infect Immun | year=2004 | pages=5759-67 | volume=72 | issue=10 | pmid= 15385475 | url=http://iai.asm.org/cgi/content/full/72/10/5759 }}</ref>
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| * This ability is related to the genomic complexity of ''B. burgdorferi'', and is another way ''B. burgdorferi'' evades the immune system to establish a chronic infection.<ref>{{cite journal |author=Gilmore RD, Howison RR, Schmit VL, ''et al'' |title=Temporal expression analysis of the Borrelia burgdorferi paralogous gene family 54 genes BBA64, BBA65, and BBA66 during persistent infection in mice |journal=Infect. Immun. |volume=75 |issue=6 |pages=2753-64 |year=2007 |pmid=17371862 |doi=10.1128/IAI.00037-07}}</ref>
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| *While ''B. burgdorferi'' is susceptible to a number of [[antibiotics]] [[in vitro]], there are contradictory reports as to the efficacy of antibiotics [[in vivo]]. ''B. burgdorferi'' may persist in humans and animals for months or years despite a robust immune response and standard antibiotic treatment, particularly when treatment is delayed and dissemination widespread. Numerous studies have demonstrated persistence of infection despite antibiotic therapy.<ref name="Bayer">{{cite journal | author=Bayer ME, Zhang L, Bayer MH | title=Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases | journal=Infection | year=1996 | pages=347-53 | volume=24 | issue=5 | pmid= 8923044}}</ref><ref name="Preac-Mursic">{{cite journal | author=Preac-Mursic V, Weber K, Pfister HW, ''et al'' | title=Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis | journal=Infection | year=1989 | pages=355-9 | volume=17 | issue=6 | pmid= 2613324}}</ref><ref name="Oksi-c">{{cite journal | author=Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK | title=Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis | journal=Ann Med | year=1999 | pages=225-32 | volume=31 | issue=3 | pmid= 10442678}}</ref> Various survival strategies of ''B. burgdorferi'' have been posited to explain this phenomenon,<!--
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| --><ref name="Embers">{{cite journal | author=Embers ME, Ramamoorthy R, Philipp MT | title=Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease | journal=Microbes Infect | year=2004 | pages=312-8 | volume=6 | issue=3 | pmid=15065567}}</ref> including the following:
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| *Physical sequestration of ''B. burgdorferi'' in sites that are inaccessible to the immune system and antibiotics, such as the [[brain]]<ref name="Miklossy">{{cite journal | author=Miklossy J, Khalili K, Gern L, ''et al'' | title=Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease | journal=J Alzheimers Dis | year=2004 | pages=639-49; discussion 673-81 | volume=6 | issue=6 | pmid= 15665404}}</ref> and [[central nervous system]]. New evidence suggests that ''B. burgdorferi'' may use the host's [[fibrinolytic]] system to penetrate the [[blood-brain barrier]].<ref name="Grab">{{cite journal | author=Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS | title=Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier | journal=Infect Immun | year=2005 | pages=1014-22 | volume=73 | issue=2 | pmid= 15664945 | url=http://iai.asm.org/cgi/content/full/73/2/1014}}</ref>
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| ===[[Immune system]] suppression===
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| * [[Complement system|Complement]] inhibition, induction of anti-inflammatory [[cytokines]] such as [[Interleukin 10|IL-10]], and the formation of [[immune complex]]es have all been documented in ''B. burgdorferi'' infection.<ref name="Embers" />
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| * Furthermore, the existence of immune complexes provides another explanation for [[seronegative]] disease (i.e. [[Type I and type II errors|false-negative]] antibody tests of [[blood]] and [[cerebrospinal fluid]]), as studies have shown that substantial numbers of seronegative Lyme patients have antibodies bound up in these complexes.<ref name="Schutzer">{{cite journal | author=Schutzer SE, Coyle PK, Reid P, Holland B | title=Borrelia burgdorferi-specific immune complexes in acute Lyme disease | journal=JAMA | year=1999 | pages=1942-6 | volume=282 | issue=20 | pmid= 10580460}}</ref>
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| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
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| [[Category:Bacterial diseases]]
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| [[Category:Insect-borne diseases]]
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| [[Category:Lyme disease]]
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| [[Category:Zoonoses]]
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| [[Category:Spirochaetes]]
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| [[Category:Disease]]
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| [[Category:Infectious disease]]
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| [[Category:Dermatology]]
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| [[Category:Emergency medicine]]
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| [[Category:Intensive care medicine]]
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