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==Overview== | ==Overview== | ||
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]] is caused by [[''Borrelia burgdorferi'']] and is transmitted primarily 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 spirochetes can be transmitted. Very few people affected with lyme disease recall a tick bite. [[''B. Burgdorferi'']] is known to invade a variety of cells in humans. By 'hiding' inside these cells, ''B. burgdorferi'' is able to evade the immune system and is protected to varying degrees against antibiotics. ''B. burgdorferi'' altered [[morphology (biology)|morphological]] forms, i.e. [[spheroplast]]s (cysts, granules). ''B. burgdorferi'' has the ability to vary its surface proteins in response to [[immune system|immune]] attack. *Various survival strategies of ''B. burgdorferi'' includes physical sequestration in tissues and immune system suppression. | ||
==Transmission== | ==Transmission== | ||
[[Image:Ixodes scapularis.png|left|150px|''[[Ixodes scapularis]]'', the primary vector of Lyme disease in eastern North America.]] | [[Image:Ixodes scapularis.png|left|150px|''[[Ixodes scapularis]]'', the primary vector of Lyme disease in eastern North America.]] | ||
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===Primary Vector=== | ===Primary Vector=== | ||
*Hard-bodied [[tick]]s of the genus ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of Lyme disease. | *Hard-bodied [[tick]]s of the genus ''[[Ixodes]]'' are the primary [[vector (biology)|vectors]] of Lyme disease. | ||
*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> | *Majority of Ixodes-vectored human disease are caused by ''I. scapularis'', ''I. pacificus'', ''I. ricinus'', and ''I. persulcatus''. So, they are also known as 'bridge' vectors.<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064 }} </ref> | ||
*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> But the majority of infections are caused by ticks in the nymph stage during late spring and summer.<ref name="pmid10206627">{{cite journal| author=Falco RC, McKenna DF, Daniels TJ, Nadelman RB, Nowakowski J, Fish D et al.| title=Temporal relation between Ixodes scapularis abundance and risk for Lyme disease associated with erythema migrans. | journal=Am J Epidemiol | year= 1999 | volume= 149 | issue= 8 | pages= 771-6 | pmid=10206627 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10206627 }} </ref> | |||
*In Europe, | *In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted.<ref name="pmid2010643">{{cite journal| author=Piesman J, Maupin GO, Campos EG, Happ CM| title=Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method. | journal=J Infect Dis | year= 1991 | volume= 163 | issue= 4 | pages= 895-7 | pmid=2010643 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2010643 }} </ref>. It takes atleast 36 hours for spirohetes to multiply and migrate to salivary glands from mid gut.<ref name="pmid11209063">{{cite journal| author=Ohnishi J, Piesman J, de Silva AM| title=Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks. | journal=Proc Natl Acad Sci U S A | year= 2001 | volume= 98 | issue= 2 | pages= 670-5 | pmid=11209063 | doi=10.1073/pnas.98.2.670 | pmc=14646 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11209063 }} </ref> | ||
*In Europe and Pacific region of North America, the commonly known sheep tick, castor bean tick, or European castor bean tick (''[[Ixodes ricinus]]'') is the transmitter.<ref name="pmid21890064">{{cite journal| author=Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH| title=Updates on Borrelia burgdorferi sensu lato complex with respect to public health. | journal=Ticks Tick Borne Dis | year= 2011 | volume= 2 | issue= 3 | pages= 123-8 | pmid=21890064 | doi=10.1016/j.ttbdis.2011.04.002 | pmc=3167092 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21890064 }} </ref> | |||
*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. | *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. | ||
*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> | *About 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash.<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> | ||
===Other Potential Vectors=== | ===Other Potential Vectors=== | ||
*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 | *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.<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> | ||
*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. | |||
*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> | |||
===Other Modes of Transmission=== | ===Other Modes of Transmission=== | ||
*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> | *While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare.<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><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> | ||
*[[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> | *[[Sexually transmitted infection|Sexual transmission]] have been reported; Lyme spirochetes have been found in semen and breast milk, however transmission of the spirochete by these routes is not known to occur.<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><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><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> | ||
*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> | *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== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
* ''B. burgdorferi'' has been shown to invade a variety of cells, including [[ | * ''B. burgdorferi'' has been shown to invade a variety of cells, including: | ||
* 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> | **[[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> | |||
* The fact that energy is required for the spiral bacterium to convert to the cystic form | **[[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> | ||
**[[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> | |||
* By 'hiding' inside these cells, ''B. burgdorferi'' is able to evade the immune system and is protected to varying degrees against antibiotics, allowing the infection to persist.<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> | |||
*''B. burgdorferi'' altered [[morphology (biology)|morphological]] forms, i.e. [[spheroplast]]s (cysts, granules). The existence of ''B. burgdorferi'' spheroplasts, which lack a [[cell wall]], has been documented in the following models: | |||
**[[In vitro]] model<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]] model<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> | |||
**[[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> | |||
* The fact that energy is required for the spiral bacterium to convert to the cystic form suggests that these altered forms have a survival function, and are not merely end stage degeneration products.<ref name="Alban" /> | |||
* 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> | * 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> | ||
* A number of other factors make ''B. burgdorferi'' [[spheroplast]]s a key factor in the relapsing, | * A number of other factors make ''B. burgdorferi'' [[spheroplast]]s a key factor in the relapsing, persistant nature of Lyme disease. | ||
* Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. | * Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance. | ||
* They also express different surface proteins | * 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. | ||
* In addition, ''B. burgdorferi'' spheroplasts are generally not susceptible to the [[antibiotics]] traditionally used for Lyme disease. | * In addition, ''B. burgdorferi'' spheroplasts are generally not susceptible to the [[antibiotics]] traditionally used for Lyme disease. They have instead shown sensitivity in vitro to [[Human parasitic diseases|antiparasitic]] drugs to which the spiral form of ''B. burgdorferi'' is not sensitive. 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> | |||
**[[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> | |||
===Mechanisms of persistence=== | ===Mechanisms of persistence=== | ||
*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 | *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="pmid15065567">{{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 | volume= 6 | issue= 3 | pages= 312-8 | pmid=15065567 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15065567 }} </ref><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> | ||
* This ability is related to the genomic complexity of ''B. burgdorferi'', and is another way ''B. burgdorferi'' evades the immune system to establish a | * This ability is related to the genomic complexity of ''B. burgdorferi'', and is another way ''B. burgdorferi'' evades the immune system to establish a presistant 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> | ||
*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> | *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 posted to explain this phenomenon, including the following:<ref name="pmid15065567"/> | |||
*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> | **Physical Sequestration | ||
***Physical sequestration of ''B. burgdorferi'' in sites that are inaccessible to the immune system and antibiotics, such as the [[brain]] and [[central nervous system]].<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> | |||
***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> | |||
* [[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=" | **[[Immune system]] suppression | ||
* 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> | ***[[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="pmid15065567"/> | ||
***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> | |||
==References== | ==References== | ||
Revision as of 15:55, 27 July 2017
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Lyme disease is caused by ''Borrelia burgdorferi'' and is transmitted primarily 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 spirochetes can be transmitted. Very few people affected with lyme disease recall a tick bite. ''B. Burgdorferi'' is known to invade a variety of cells in humans. By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics. B. burgdorferi altered morphological forms, i.e. spheroplasts (cysts, granules). B. burgdorferi has the ability to vary its surface proteins in response to immune attack. *Various survival strategies of B. burgdorferi includes physical sequestration in tissues and immune system suppression.
Transmission
Primary Vector
- Hard-bodied ticks of the genus Ixodes are the primary vectors of Lyme disease.
- Majority of Ixodes-vectored human disease are caused by I. scapularis, I. pacificus, I. ricinus, and I. persulcatus. So, they are also known as 'bridge' vectors.[1]
- Adult ticks are more infected then nymph stage by pathogens infectious to humans.[2] But the majority of infections are caused by ticks in the nymph stage during late spring and summer.[3]
- In most cases, the tick must be attached for 36 to 48 hours or more before the spirochetes can be transmitted.[4]. It takes atleast 36 hours for spirohetes to multiply and migrate to salivary glands from mid gut.[5]
- In Europe and Pacific region of North America, the commonly known sheep tick, castor bean tick, or European castor bean tick (Ixodes ricinus) is the transmitter.[1]
- 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.
- About 20% of individuals infected with Lyme disease by the deer tick are aware of having had any tick bite, making early detection difficult in the absence of a rash.[6]
Other Potential Vectors
- 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.[7]
- 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.
- 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.[8]
Other Modes of Transmission
- While Lyme spirochetes have been found in insects other than ticks, reports of actual infectious transmission appear to be rare.[9][10]
- Sexual transmission have been reported; Lyme spirochetes have been found in semen and breast milk, however transmission of the spirochete by these routes is not known to occur.[11][12][13]
- 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.[14]
Pathophysiology
Pathogenesis
- B. burgdorferi has been shown to invade a variety of cells, including:
- By 'hiding' inside these cells, B. burgdorferi is able to evade the immune system and is protected to varying degrees against antibiotics, allowing the infection to persist.[21][22]
- B. burgdorferi altered morphological forms, i.e. spheroplasts (cysts, granules). The existence of B. burgdorferi spheroplasts, which lack a cell wall, has been documented in the following models:
- The fact that energy is required for the spiral bacterium to convert to the cystic form suggests that these altered forms have a survival function, and are not merely end stage degeneration products.[23]
- 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.[29][30]
- A number of other factors make B. burgdorferi spheroplasts a key factor in the relapsing, persistant nature of Lyme disease.
- Compared to the spiral form, spheroplasts have dramatically reduced surface area for immune surveillance.
- They also express different surface proteins; another reason for seronegative disease (i.e. false-negative antibody tests), as current tests only look for antibodies to surface proteins of the spiral form.
- In addition, B. burgdorferi spheroplasts are generally not susceptible to the antibiotics traditionally used for Lyme disease. They have instead shown sensitivity in vitro to antiparasitic drugs to which the spiral form of B. burgdorferi is not sensitive. Drugs such as:
Mechanisms of persistence
- Like the Borrelia that cause relapsing fever, B. burgdorferi has the ability to vary its surface proteins in response to immune attack.[34][35]
- This ability is related to the genomic complexity of B. burgdorferi, and is another way B. burgdorferi evades the immune system to establish a presistant infection.[36]
- 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.[37][38][39]
- Various survival strategies of B. burgdorferi have been posted to explain this phenomenon, including the following:[34]
- Physical Sequestration
- Physical sequestration of B. burgdorferi in sites that are inaccessible to the immune system and antibiotics, such as the brain and central nervous system.[40]
- New evidence suggests that B. burgdorferi may use the host's fibrinolytic system to penetrate the blood-brain barrier.[41]
- Immune system suppression
- Complement inhibition, induction of anti-inflammatory cytokines such as IL-10, and the formation of immune complexes have all been documented in B. burgdorferi infection.[34]
- Furthermore, the existence of immune complexes provides another explanation for seronegative disease (i.e. 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.[42]
- Physical Sequestration
References
- ↑ 1.0 1.1 Rudenko N, Golovchenko M, Grubhoffer L, Oliver JH (2011). "Updates on Borrelia burgdorferi sensu lato complex with respect to public health". Ticks Tick Borne Dis. 2 (3): 123–8. doi:10.1016/j.ttbdis.2011.04.002. PMC 3167092. PMID 21890064.
- ↑ Schwartz, Ira; Fish, Durland; Daniels, Thomas J. (1997). "Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease". New England Journal of Medicine. 337 (1): 49–50. doi:10.1056/NEJM199707033370111. ISSN 0028-4793.
- ↑ Falco RC, McKenna DF, Daniels TJ, Nadelman RB, Nowakowski J, Fish D; et al. (1999). "Temporal relation between Ixodes scapularis abundance and risk for Lyme disease associated with erythema migrans". Am J Epidemiol. 149 (8): 771–6. PMID 10206627.
- ↑ Piesman J, Maupin GO, Campos EG, Happ CM (1991). "Duration of adult female Ixodes dammini attachment and transmission of Borrelia burgdorferi, with description of a needle aspiration isolation method". J Infect Dis. 163 (4): 895–7. PMID 2010643.
- ↑ Ohnishi J, Piesman J, de Silva AM (2001). "Antigenic and genetic heterogeneity of Borrelia burgdorferi populations transmitted by ticks". Proc Natl Acad Sci U S A. 98 (2): 670–5. doi:10.1073/pnas.98.2.670. PMC 14646. PMID 11209063.
- ↑ Wormser G, Masters E, Nowakowski J; et al. (2005). "Prospective clinical evaluation of patients from missouri and New York with erythema migrans-like skin lesions". Clin Infect Dis. 41 (7): 958–65. PMID 16142659.
- ↑ Clark K (2004). "Borrelia species in host-seeking ticks and small mammals in northern Florida" (PDF). J Clin Microbiol. 42 (11): 5076–86. PMID 15528699.
- ↑ Ledin K, Zeidner N, Ribeiro J; et al. (2005). "Borreliacidal activity of saliva of the tick Amblyomma americanum". Med Vet Entomol. 19 (1): 90–95. PMID 15752182.
- ↑ Magnarelli L, Anderson J (1988). "Ticks and biting insects infected with the etiologic agent of Lyme disease, Borrelia burgdorferi" (PDF). J Clin Microbiol. 26 (8): 1482–6. PMID 3170711.
- ↑ Luger S (1990). "Lyme disease transmitted by a biting fly". N Engl J Med. 322 (24): 1752. PMID 2342543.
- ↑ Bach G (2001). "Recovery of Lyme spirochetes by PCR in semen samples of previously diagnosed Lyme disease patients.". 14th International Scientific Conference on Lyme Disease.
- ↑ Schmidt B, Aberer E, Stockenhuber C; et al. (1995). "Detection of Borrelia burgdorferi DNA by polymerase chain reaction in the urine and breast milk of patients with Lyme borreliosis". Diagn Microbiol Infect Dis. 21 (3): 121–8. PMID 7648832.
- ↑ Steere AC (2003-02-01). "Lyme Disease: Questions and Answers" (PDF). Massachusetts General Hospital / Harvard Medical School. Retrieved 2007-03-22.
- ↑ Walsh CA, Mayer EW, Baxi LV (2007). "Lyme disease in pregnancy: case report and review of the literature". Obstetrical & gynecological survey. 62 (1): 41–50. doi:10.1097/01.ogx.0000251024.43400.9a. PMID 17176487.
- ↑ Dorward DW, Fischer ER, Brooks DM (1997). "Invasion and cytopathic killing of human lymphocytes by spirochetes causing Lyme disease". Clin Infect Dis. 25 Suppl 1: S2–8. PMID 9233657.
- ↑ Montgomery RR, Nathanson MH, Malawista SE (1993). "The fate of Borrelia burgdorferi, the agent for Lyme disease, in mouse macrophages. Destruction, survival, recovery". J Immunol. 150 (3): 909–15. PMID 8423346.
- ↑ Aberer E, Kersten A, Klade H, Poitschek C, Jurecka W (1996). "Heterogeneity of Borrelia burgdorferi in the skin". Am J Dermatopathol. 18 (6): 571–9. PMID 8989928.
- ↑ Girschick HJ, Huppertz HI, Russmann H, Krenn V, Karch H (1996). "Intracellular persistence of Borrelia burgdorferi in human synovial cells". Rheumatol Int. 16 (3): 125–32. PMID 8893378.
- ↑ 19.0 19.1 Nanagara R, Duray PH, Schumacher HR Jr (1996). "Ultrastructural demonstration of spirochetal antigens in synovial fluid and synovial membrane in chronic Lyme disease: possible factors contributing to persistence of organisms". Hum Pathol. 27 (10): 1025–34. PMID 8892586.
- ↑ Livengood JA, Gilmore RD (2006). "Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi". Microbes Infect. [Epub ahead of print]. PMID 17045505.
- ↑ Georgilis K, Peacocke M, Klempner MS (1992). "Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro". J Infect Dis. 166 (2): 440–4. PMID 1634816.
- ↑ Brouqui P, Badiaga S, Raoult D (1996). "Eucaryotic cells protect Borrelia burgdorferi from the action of penicillin and ceftriaxone but not from the action of doxycycline and erythromycin" (PDF). Antimicrob Agents Chemother. 40 (6): 1552–4. PMID 8726038.
- ↑ 23.0 23.1 Alban PS, Johnson PW, Nelson DR (2000). "Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi". Microbiology. 146 ( Pt 1): 119–27. PMID 10658658.
- ↑ 24.0 24.1 Mursic VP, Wanner G, Reinhardt S; et al. (1996). "Formation and cultivation of Borrelia burgdorferi spheroplast-L-form variants". Infection. 24 (3): 218–26. PMID 8811359.
- ↑ Kersten A, Poitschek C, Rauch S, Aberer E (1995). "Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi" (PDF). Antimicrob Agents Chemother. 39 (5): 1127–33. PMID 7625800.
- ↑ Schaller M, Neubert U (1994). "Ultrastructure of Borrelia burgdorferi after exposure to benzylpenicillin". Infection. 22 (6): 401–6. PMID 7698837.
- ↑ Phillips SE, Mattman LH, Hulinska D, Moayad H (1998). "A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated". Infection. 26 (6): 364–7. PMID 9861561.
- ↑ Duray PH, Yin SR, Ito Y; et al. (2005). "Invasion of human tissue ex vivo by Borrelia burgdorferi". J Infect Dis. 191 (10): 1747–54. PMID 15838803.
- ↑ Gruntar I, Malovrh T, Murgia R, Cinco M (2001). "Conversion of Borrelia garinii cystic forms to motile spirochetes in vivo". APMIS. 109 (5): 383–8. PMID 11478686.
- ↑ Murgia R, Cinco M (2004). "Induction of cystic forms by different stress conditions in Borrelia burgdorferi". APMIS. 112 (1): 57–62. PMID 14961976.
- ↑ Brorson O, Brorson SH (1999). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to metronidazole". APMIS. 107 (6): 566–76. PMID 10379684.
- ↑ Brorson O, Brorson SH (2004). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to tinidazole" (PDF). Int Microbiol. 7 (2): 139–42. PMID 15248163.
- ↑ Brorson O, Brorson SH (2002). "An in vitro study of the susceptibility of mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine". Int Microbiol. 5 (1): 25–31. PMID 12102233.
- ↑ 34.0 34.1 34.2 Embers ME, Ramamoorthy R, Philipp MT (2004). "Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease". Microbes Infect. 6 (3): 312–8. PMID 15065567.
- ↑ Liang FT, Yan J, Mbow ML; et al. (2004). "Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses". Infect Immun. 72 (10): 5759–67. PMID 15385475.
- ↑ Gilmore RD, Howison RR, Schmit VL; et al. (2007). "Temporal expression analysis of the Borrelia burgdorferi paralogous gene family 54 genes BBA64, BBA65, and BBA66 during persistent infection in mice". Infect. Immun. 75 (6): 2753–64. doi:10.1128/IAI.00037-07. PMID 17371862.
- ↑ Bayer ME, Zhang L, Bayer MH (1996). "Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms. A PCR study of 97 cases". Infection. 24 (5): 347–53. PMID 8923044.
- ↑ Preac-Mursic V, Weber K, Pfister HW; et al. (1989). "Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis". Infection. 17 (6): 355–9. PMID 2613324.
- ↑ Oksi J, Marjamaki M, Nikoskelainen J, Viljanen MK (1999). "Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis". Ann Med. 31 (3): 225–32. PMID 10442678.
- ↑ Miklossy J, Khalili K, Gern L; et al. (2004). "Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease". J Alzheimers Dis. 6 (6): 639–49, discussion 673-81. PMID 15665404.
- ↑ Grab DJ, Perides G, Dumler JS, Kim KJ, Park J, Kim YV, Nikolskaia O, Choi KS, Stins MF, Kim KS (2005). "Borrelia burgdorferi, host-derived proteases, and the blood-brain barrier". Infect Immun. 73 (2): 1014–22. PMID 15664945.
- ↑ Schutzer SE, Coyle PK, Reid P, Holland B (1999). "Borrelia burgdorferi-specific immune complexes in acute Lyme disease". JAMA. 282 (20): 1942–6. PMID 10580460.