Lyme borreliosis

doi:10.1016/S0140-6736(11)60103-7

The Lancet

Volume 379, Issue 9814, 4–10 February 2012, Pages 461-473

https://doi.org/10.1016/S0140-6736(11)60103-7 Get rights and content

Summary

Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2–4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings.

Introduction

Lyme borreliosis, or Lyme disease, is caused by a group of related spirochaetes—Borrelia burgdorferi sensu lato or Lyme borrelia—that are transmitted by specific Ixodes spp ticks. Lyme borreliosis is the most common tick-borne infectious disease in North America and in countries with moderate climates in Eurasia. The disease is of public health importance in both regions.

Section snippets

The pathogens

In North America, the only species of Lyme borrelia known to cause human disease is Borrelia burgdorferi sensu stricto (hereafter referred to as B burgdorferi). In Europe, at least five species of Lyme borrelia (Borrelia afzelii, Borrelia garinii, B burgdorferi, Borrelia spielmanii, and Borrelia bavariensis) can cause the disease, leading to a wider variety of possible clinical manifestations in Europe than in North America. A further three species (Borrelia bissettii, Borrelia lusitaniae, and

Ecology of the pathogens and their vectors

The main vector of Lyme borrelia in Europe is Ixodes ricinus, whereas Ixodes persulcatus is the main vector in Asia. Ixodes scapularis is the main vector in northeastern and upper midwestern USA and Ixodes pacificus is the vector in western USA (figure 1).¹³ These ticks have a four-stage life cycle—egg, larva, nymph, and adult (figure 2)—feeding only once during every active stage. Male ticks rarely feed and never engorge. Unfed (flat) ticks attach to the skin of a host animal using specialised

Pathogenesis

Lyme borrelia are carried in the midgut of unfed Ixodes ticks. When an infected tick takes a blood meal, the ingested spirochaetes increase in number and undergo phenotypic changes, including the expression of outer surface protein C (OspC), which allows them to invade the host tick's salivary glands. This process takes several days and explains why transmission occurs only after a delay. Expression of OspC plays an essential part in the establishment of infection in a mammalian host, although

Clinical manifestations and epidemiological aspects

Localised infection is typically manifested by a erythema migrans skin lesion. Early disseminated disease is usually characterised by two or more erythema migrans skin lesions or as an objective manifestation of Lyme neuroborreliosis or Lyme carditis. Late Lyme borreliosis usually manifests as arthritis or the skin disorder known as acrodermatitis chronica atrophicans, but can also include specific rare neurological manifestations. The often used division of the disease into stages is somewhat

Treatment

In-vitro studies have shown that Lyme borrelia are susceptible to tetracyclines, most penicillins, many second-generation and third-generation cephalosporins, and macrolides.33, 77, 78 Lyme borrelia are resistant to specific fluoroquinolones, rifampicin, and first-generation cephalosporins.33, 77, 78

Although erythema migrans will eventually resolve without antibiotic treatment, oral antibiotic treatment is recommended to prevent dissemination and development of later sequelae (table 3).

Post-treatment symptoms and post-Lyme borreliosis syndrome

The objective manifestations of Lyme borreliosis, such as erythema migrans, meningitis, or arthritis, typically resolve during or after completion of a course of antibiotic treatment. Any accompanying subjective symptoms also usually resolve, but some patients (median of 11·5% in eight treatment trials of patients with erythema migrans in the USA and 15·4% in five treatment trials in Europe) report long-term (≥6 months) persistence of fatigue, musculoskeletal pain, or difficulties with

Prevention

Lyme borreliosis can be prevented by avoidance of tick-infested environments, and, when in such environments, covering bare skin and use of tick repellents on skin or clothing. The density of tick populations around residences can be reduced by the removal of leaf litter, the placing of wood chips where lawns are adjacent to forests, application of acaricides, and the construction of fences to keep out deer.¹²² Bathing within 2 h of tick exposure decreases the risk of Lyme borreliosis.¹²³ Daily

Prognosis

Most patients with Lyme borreliosis have an excellent prognosis. Although most manifestations of Lyme borreliosis will resolve spontaneously without treatment, antibiotic treatment might speed the resolution of symptoms and signs, and will prevent the development of objective late complications. Precautions to prevent future tick bites should be taken to prevent re-infections.

Contributors

GS, GPW, JG, and FS searched the published work and contributed to the scientific and technical content of

Search strategy and selection criteria

We searched Medline and Scopus from Jan 1, 2003, onwards, with the search terms “Lyme”, “borreliosis”, “borrelia”, “erythema migrans”, “borrelia lymphocytoma”, “neuroborreliosis”, “Lyme carditis”, “acrodermatitis atrophicans”, “Lyme arthritis”, and “Lyme encephalopathy”. In relation to clinical studies, we placed particular value on randomised controlled trials. Additionally, key reviews were consulted, particularly 9, 13, 25, 26, 33, 44, 45, 63, 107.

References (129)

V Fingerle et al.
Epidemiological aspects and molecular characterization of Borrelia burgdorferi sl from southern Germany with special respect to the new species Borrelia spielmanii sp
Int J Med Microbiol
(2008)
RB Nadelman et al.
Lyme borreliosis
Lancet
(1998)
V Preac-Mursic et al.
European Borrelia burgdorferi isolated from humans and ticks culture conditions and antibiotic susceptibility
Zentralbl Bakteriol Mikrobiol Hyg A
(1986)
O Kahl et al.
Risk of infection with Borrelia burgdorferi sensu lato for a host in relation to the duration of nymphal Ixodes ricinus feeding and the method of tick removal
Zentralbl Bakteriol
(1998)
T Bykowski et al.
Borrelia burgdorferi complement regulator-acquiring surface proteins (BbCRASPs): Expression patterns during the mammal-tick infection cycle
Int J Med Microbiol
(2008)
FC Cabello et al.
Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix
Trends Microbiol
(2007)
F Strle
Lyme borreliosis in Slovenia
Zentralbl Bakteriol
(1999)
G Stanek et al.
Lyme borreliosis
Lancet
(2003)
G Stanek et al.
Lyme borreliosis: Clinical case definitions for diagnosis and management in Europe
Clin Microbiol Infect
(2011)
B Kütting et al.
Borrelia burgdorferi-associated primary cutaneous B cell lymphoma: complete clearing of skin lesions after antibiotic pulse therapy or intralesional injection of interferon alfa-2a
J Am Acad Dermatol
(1997)

C Schöllkopf et al.

Borrelia infection and risk of non-Hodgkin lymphoma

Blood

(2008)

P Brouqui et al.

ESCMID Study Group on Coxiella, Anaplasma, Rickettsia and Bartonella; European network for surveillance of tick-borne diseases—guidelines for the diagnosis of tick-borne bacterial diseases in Europe

Clin Microbiol Infect

(2004)

E Hilton et al.

Seroprevalence and seroconversion for tick-borne diseases in a high-risk population in the northeast United States

Am J Med

(1999)

D Cerar et al.

Subjective symptoms after treatment of early Lyme disease

Am J Med

(2010)

U Ljøstad et al.

Oral doxycycline versus intravenous ceftriaxone for European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blind, randomised trial

Lancet Neurol

(2008)

A Marques

Chronic Lyme disease: a review

Infect Dis Clin North Am

(2008)

E Ružić-Sabljić et al.

Characterization of Borrelia burgdorferi sensu lato strains isolated from human material in Slovenia

Wien Klin Wochenschr

(2002)

G Foldvari et al.

Borrelia spielmanii erythema migrans, Hungary

Emerg Infect Dis

(2005)

V Maraspin et al.

Lyme borreliosis and Borrelia spielmanii

Emerg Infect Dis

(2006)

F Strle et al.

Clinical findings for patients with Lyme borreliosis caused by Borrelia burgdorferi sensu lato with genotypic and phenotypic similarities to strain 25015

Clin Infect Dis

(1997)

G Margos et al.

A new Borrelia species defined by multilocus sequence analysis of housekeeping genes

Appl Environ Microbiol

(2009)

M Collares-Pereira et al.

First isolation of Borrelia lusitaniae from human patient

J Clin Microbiol

(2004)

F Strle et al.

Clinical manifestations and diagnosis of Lyme borreliosis

Curr Probl Dermatol

(2009)

CM Fraser et al.

Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi

Nature

(1997)

AG Barbour

Isolation and cultivation of Lyme disease spirochetes

Yale J Biol Med

(1984)

JS Gray

The ecology of ticks transmitting Lyme borreliosis

Exp Appl Acarol

(1998)

J Piesman et al.

Lyme borreliosis in Europe and North America

Parasitology

(2004)

F des Vignes et al.

Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis nymphs

J Infect Dis

(2001)

CA Peavey et al.

Transmission of Borrelia burgdorferi by Ixodes pacificus nymphs and reservoir competence of deer mice (Peromyscus maniculatus) infected by tick-bite

J Parasitol

(1995)

L Eisen et al.

Vectors of Borrelia burgdorferi sensu lato

GA Scoles et al.

A relapsing fever group spirochete transmitted by Ixodes scapularis ticks

Vector Borne Zoonotic Dis

(2001)

DT Dennis et al.

Epidemiology of Lyme borreliosis

NH Ogden et al.

Natural Lyme disease cycles maintained via sheep by co-feeding ticks

Parasitology

(1997)

JS Gray et al.

The spatial distribution of Borrelia burgdorferi-infected Ixodes ricinus in the Connemara region of Co. Galway, Ireland

Experimental Appl Acarol

(1995)

FR Matuschka et al.

Diversionary role of hoofed game in the transmission of Lyme disease spirochetes

Am J Trop Med Hyg

(1993)

AC Steere et al.

The emergence of Lyme disease

J Clin Invest

(2004)

P Rosa

Lyme disease agent borrows a practical coat

Nat Med

(2005)

GP Wormser et al.

Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease

J Infect Dis

(2008)

G Baranton et al.

Borrelia burgdorferi sensu lato diversity and its influence on pathogenicity in humans

Curr Probl Dermatol

(2009)

AC Steere et al.

Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide

J Exp Med

(2006)

K Strle et al.

Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii

J Infect Dis

(2009)

GP Wormser et al.

The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America

Clin Infect Dis

(2006)

J Berglund et al.

An epidemiologic study of Lyme disease in southern Sweden

N Engl J Med

(1995)

HI Huppertz et al.

Incidence of Lyme borreliosis in the Würzburg region of Germany

Eur J Clin Microbiol Infect Dis

(1999)

AC Steere et al.

Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group

N Engl J Med

(1998)

LH Sigal et al.

A vaccine consisting of recombinant Borrelia burgdorferi outer-surface protein A to prevent Lyme disease. Recombinant Outer-Surface Protein A Lyme Disease Vaccine Study Consortium

N Engl J Med

(1998)

J Aucott et al.

Diagnostic challenges of early Lyme disease: lessons from a community case series

BMC Infect Dis

(2009)

Anonymous. Institute of Public Health of the Republic of Slovenia. 2008 Health Statistics Yearbook. Surveillance of...

Anonymous. Institute of Public Health of the Republic of Slovenia. Registered communicable diseases in Slovenia in...

Cited by (1013)

Does bird life-history influence the prevalence of ticks? A citizen science study in North East Spain
2024, One Health
After mosquitoes, ticks are among the most important vector of pathogens of concern for animal and public health, but unless mosquitoes ticks remain attached to their hosts for long time periods providing an opportunity to analyse their role in the dispersal and dynamics of different zoonotic pathogens. Given their interest in public health it is important to understand which factors affect their incidence in different hosts and to stablish effective surveillance programs to determine the risk of transmission and spill-over of zoonotic pathogens. Taking benefit of a large network of volunteer ornithologists, we analysed the life-history traits associated to the presence of ticks using information of 620,609 individuals of 231 avian species. Bird phylogeny, locality and year explained a large amount of variance in tick prevalence. Non-colonial species non breeding in grasslands and non-spending the non-breeding season as gregarious groups or isolated individuals (e.g. thrushes, quails and finches) had the higher prevalence of ticks and appear as good candidates for zoonosis surveillance programs based on the analyses of ticks collected from wild birds. Ringers underestimated tick prevalence but can be considered as an important source of information of ticks for public and animal health surveillance programs if properly trained for the detection and collection of the different tick development phases.
Paretic complications of tick-borne encephalitis and Lyme neuroborreliosis in the Czech Republic: Characteristics and clinical outcome
2024, Ticks and Tick-borne Diseases
Tick-borne encephalitis (TBE) and Lyme neuroborreliosis (LNB), the most common tick-borne diseases of the central nervous system in Central Europe, are frequently associated with pareses. The aim of this study was to characterise paretic complications in patients with TBE and LNB, including their severity, persistence and impact on the patients' quality of life. Our retrospective observational study included patients with aseptic CNS infection due to TBE virus or Borrelia burgdorferi sensu lato. Paretic complications were evaluated in the acute phase and the patients were followed up until complete regression or long-term stabilisation of any neurological deficit. The severity of the neurological deficit was graded according to the modified Rankin Scale (mRS).
A total of 823 patients (582 with TBE, 241 with LNB) was included. Paretic complications were diagnosed in 63 TBE patients (10.8 %) and in 147 LNB patients (61.0 %). In TBE, the most common neurological deficit was brachial plexus paresis in 21 patients (33 %) and bulbar symptoms in 18 patients (29 %). In LNB patients, facial nerve palsy was the most frequent neurological deficit (117patients; 79.6 %), followed by lower limb paresis in 23 patients (15.6 %). Forty-nine TBE patients and 134 LNB paretic patients completed follow-up. Paresis resolved within 3 weeks in 16 TBE patients (33 %) and 53 LNB patients (39.5 %), but the proportion of patients with paresis persisting for more than 12 months was significantly higher in TBE (34.7 vs. 3.7 %, p < 0.001). The mean mRS was significantly higher in TBE paretic patients compared to LNB (p < 0.001).
Paretic complications are significantly more common in LNB than in TBE but pareses associated with TBE last longer than in LNB and considerably reduce the quality of life of patients. Prevention remains the only way to influence the long-term motor deficits of TBE.
Background incidence rates of health outcomes in populations at risk for Lyme disease using US administrative claims data
2024, Vaccine
Background incidence rates (IRs) of health outcomes in Lyme disease endemic regions are useful to contextualize events reported during Lyme disease vaccine clinical trials or post-marketing. The objective of this study was to estimate and compare IRs of health outcomes in Lyme disease endemic versus non-endemic regions in the US during pre-COVID and COVID era timeframes.
IQVIA PharMetrics® Plus commercial claims database was used to estimate IRs of 64 outcomes relevant to vaccine safety monitoring in the US during January 1, 2017-December 31, 2019 and January 1, 2020-December 31, 2021. Analyses included all individuals aged ≥ 2 years with ≥ 1 year of continuous enrollment. Outcomes were defined by International Classification of Diseases Clinical Modification, 10th Revision (ICD-10-CM) diagnosis codes. IRs and 95 % confidence intervals (CIs) were calculated for each outcome and compared between endemic vs. non-endemic regions, and pre-COVID vs. COVID era using IR ratios (IRR).
The study population included 8.7 million (M) in endemic and 27.8 M in non-endemic regions. Mean age and sex were similar in endemic and non-endemic regions. In both study periods, the IRs were statistically higher in endemic regions for anaphylaxis, meningoencephalitis, myocarditis/pericarditis, and rash (including erythema migrans) as compared with non-endemic regions. Conversely, significantly lower IRs were observed in endemic regions for acute kidney injury, disseminated intravascular coagulation, heart failure, myelitis, myopathies, and systemic lupus erythematosus in both study periods. Most outcomes were statistically less frequent during the COVID-era.
This study identified potential differences between Lyme endemic and non-endemic regions of the US in background IRs of health conditions during pre-COVID and COVID era timeframes to inform Lyme disease vaccine safety monitoring. These regional and temporal differences in background IRs should be considered when contextualizing possible safety signals in clinical trials and post-marketing of a vaccine targeted at Lyme disease prevention.
Risk of haematologic cancers among individuals tested for Borrelia burgdorferi antibodies, and Borrelia burgdorferi seropositive individuals: a nationwide population-based matched cohort study
2024, Clinical Microbiology and Infection
In a nationwide, matched cohort study, we aimed to investigate risks of haematologic cancers among individuals tested for Borrelia burgdorferi (Bb) antibodies, and among serum Bb seropositive individuals.
We identified all Bb seropositive individuals in Denmark (1993–2020) (n = 52 200) and constructed two age- and sex-matched comparison cohorts: (a) Bb seronegative controls (n = 104 400) and (b) background population controls (n = 261 000). We calculated short-term OR (aOR) (<1 month of study inclusion), and long-term hazard ratios (aHR) (>1 month after study inclusion) adjusted for age and sex. We stratified seropositive individuals on only Bb-IgM seropositive (n = 26 103), only Bb-IgG seropositive (n = 18 698), and Bb-IgM-and-IgG seropositive (n = 7399).
Compared with the background population, individuals tested for Bb antibodies had increased short-term (aOR: 12.6, 95% CI: 10.1–15.6) and long-term (aHR: 1.3, 95% CI: 1.2–1.4) risk of haematologic cancers. The Bb seropositive individuals had no increased risk of haematologic cancers compared with those who tested negative for Bb, except that Bb-IgM-and-IgG seropositive individuals had increased long-term risk of chronic lymphatic leukaemia (aHR: 2.0, 95% CI: 1.2–3.4).
Our results suggest that Bb antibody testing is included in the work-up of unspecific symptoms preceding diagnosis of haematologic cancers. Bb-IgM-and-IgG seropositivity was associated with a two-fold increased long-term risk of chronic lymphatic leukaemia, which warrants further investigation.
Tick-Borne Illnesses in Emergency and Wilderness Medicine
2024, Emergency Medicine Clinics of North America
The cardiac conduction system: History, development, and disease
2024, Current Topics in Developmental Biology
The heart is the first organ to form during embryonic development, establishing the circulatory infrastructure necessary to sustain life and enable downstream organogenesis. Critical to the heart’s function is its ability to initiate and propagate electrical impulses that allow for the coordinated contraction and relaxation of its chambers, and thus, the movement of blood and nutrients. Several specialized structures within the heart, collectively known as the cardiac conduction system (CCS), are responsible for this phenomenon. In this review, we discuss the discovery and scientific history of the mammalian cardiac conduction system as well as the key genes and transcription factors implicated in the formation of its major structures. We also describe known human diseases related to CCS development and explore existing challenges in the clinical context.

View all citing articles on Scopus

View full text

SeminarLyme borreliosis

Summary

Introduction

Section snippets

The pathogens

Ecology of the pathogens and their vectors

Pathogenesis

Clinical manifestations and epidemiological aspects

Treatment

Post-treatment symptoms and post-Lyme borreliosis syndrome

Prevention

Prognosis

Search strategy and selection criteria

Int J Med Microbiol

Lancet

Zentralbl Bakteriol Mikrobiol Hyg A

Zentralbl Bakteriol

Int J Med Microbiol

Trends Microbiol

Zentralbl Bakteriol

Lancet

Clin Microbiol Infect

J Am Acad Dermatol

Blood

Clin Microbiol Infect

Am J Med

Am J Med

Lancet Neurol

Infect Dis Clin North Am

Characterization of Borrelia burgdorferi sensu lato strains isolated from human material in Slovenia

Wien Klin Wochenschr

Borrelia spielmanii erythema migrans, Hungary

Emerg Infect Dis

Lyme borreliosis and Borrelia spielmanii

Emerg Infect Dis

Clinical findings for patients with Lyme borreliosis caused by Borrelia burgdorferi sensu lato with genotypic and phenotypic similarities to strain 25015

Clin Infect Dis

A new Borrelia species defined by multilocus sequence analysis of housekeeping genes

Appl Environ Microbiol

First isolation of Borrelia lusitaniae from human patient

J Clin Microbiol

Clinical manifestations and diagnosis of Lyme borreliosis

Curr Probl Dermatol

Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi

Nature

Isolation and cultivation of Lyme disease spirochetes

Yale J Biol Med

The ecology of ticks transmitting Lyme borreliosis

Exp Appl Acarol

Lyme borreliosis in Europe and North America

Parasitology

Effect of tick removal on transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis nymphs

J Infect Dis

Transmission of Borrelia burgdorferi by Ixodes pacificus nymphs and reservoir competence of deer mice (Peromyscus maniculatus) infected by tick-bite

J Parasitol

Vectors of Borrelia burgdorferi sensu lato

A relapsing fever group spirochete transmitted by Ixodes scapularis ticks

Vector Borne Zoonotic Dis

Epidemiology of Lyme borreliosis

Natural Lyme disease cycles maintained via sheep by co-feeding ticks

Parasitology

The spatial distribution of Borrelia burgdorferi-infected Ixodes ricinus in the Connemara region of Co. Galway, Ireland

Experimental Appl Acarol

Diversionary role of hoofed game in the transmission of Lyme disease spirochetes

Am J Trop Med Hyg

The emergence of Lyme disease

J Clin Invest

Lyme disease agent borrows a practical coat

Nat Med

Borrelia burgdorferi genotype predicts the capacity for hematogenous dissemination during early Lyme disease

J Infect Dis

Borrelia burgdorferi sensu lato diversity and its influence on pathogenicity in humans

Curr Probl Dermatol

Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide

J Exp Med

Borrelia burgdorferi stimulates macrophages to secrete higher levels of cytokines and chemokines than Borrelia afzelii or Borrelia garinii

J Infect Dis

The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America

Clin Infect Dis

An epidemiologic study of Lyme disease in southern Sweden

Seminar
Lyme borreliosis