Scoping review Lyme disease

CCDR

Volume 44-10, October 4, 2018: Climate change and Lyme disease

Scoping review

A scoping review of Lyme disease research relevant to public health

JD Greig1, I Young2, S Harding1, M Mascarenhas1, LA Waddell1

Affiliations

1 National Microbiology Laboratory at Guelph, Public Health Agency of Canada, Guelph, ON

2 School of Occupational and Public Health, Ryerson University, Toronto, ON

Correspondence

judy.greig@canada.ca

Suggested citation

Greig JD, Young I, Harding S, Mascarenhas M, Waddell LA. A scoping review of Lyme disease research relevant for public health. Can Commun Dis Rep 2018;44(10):243-56. https://doi.org/10.14745/ccdr.v44i10a03

Keywords: scoping review, Lyme disease, public health, Ixodes ticks, research

Abstract

Lyme disease (LD) is an emerging infectious disease in Canada associated with expansion of the geographic range of the tick vector Ixodes scapularis in eastern and central Canada. A scoping review of published research was prioritized to identify and characterize the scientific evidence concerning key aspects of LD to support public health efforts. Prior to initiation of this review, an expert advisory group was surveyed to solicit insight on priority topics and scope. A pre-tested search strategy implemented in eight databases (updated September 2016) captured relevant research. Pre-tested screening and data characterization forms were completed by two independent reviewers and descriptive analysis was conducted to identify topic areas with solid evidence and knowledge gaps. Of 19,353 records screened, 2,258 relevant articles were included in the review under the following six public health focus areas: a) surveillance/monitoring in North America (n=809); b) evaluation of diagnostic tests (n=736); c) risk factors (n=545); d) public health interventions (n=205); e) public knowledge, attitudes and/or perceptions in North America (n=202); and f) the economic burden of LD or cost-benefit of interventions (n=32). The majority of research investigated Borrelia burgdorferi (n=1,664), humans (n=1,154) and Ixodes scapularis (n=459). Sufficient research was identified for potential systematic reviews in four topic areas: a) accuracy of diagnostic tests; b) risk factors for human illness; c) efficacy of LD intervention strategies; and d) prevalence and/or incidence of LD in humans or B. burgdorferi sensu stricto in vertebrate reservoirs or ticks in North America. Future primary research could focus on closing knowledge gaps, such as the role of less studied vertebrate reservoirs in the transmission cycle. Results of this scoping review can be used to quickly identify and summarize relevant research pertaining to specific questions about LD or B. burgdorferi sensu lato in humans, vertebrate hosts or vectors, providing evidence-informed information within timelines that are conducive for public health decision-making.

Introduction

Lyme disease (LD) is the most common tick-borne infection affecting humans in North America and Eurasia Footnote 1. It is a multisystem infectious disease caused by bacteria of the Borrelia burgdorferi sensu lato (s.l.) species complex comprising more than 20 genospecies, including the human pathogens B. burgdorferi sensu stricto (s.s.) in North Americaand B. garinii, B. afzelii, B. burgdorferi s.s., B. spielmanii, B. bissettii and B. bavariensis in Europe Footnote 2Footnote 3. In Canada, LD is an emerging issue, and human cases have increased six-fold (from 144 to 917 cases) between 2009 and 2015 as Ixodes scapularis and Ixodes pacificus ticks’ range has expanded Footnote 4Footnote 5Footnote 6. Predictive models suggest that factors related to climate change and land use are driving changes in the epidemiology of LD Footnote 7Footnote 8Footnote 9.

The tick I. scapularis is the main vector in northeastern and upper midwestern United States (US) and bordering areas of Canada, while I. pacificus is the major vector in western US and western Canada Footnote 10Footnote 11. The main vector in western Europe is Ixodes ricinus Footnote 3 while in eastern Europe and Asia it is I. persulcatus Footnote 12. Immature ticks (larvae and nymphs) require small to medium size vertebrates (rodents, reptiles and birds), while adult ticks feed on medium to large mammals (such as deer) Footnote 3Footnote 13. Other human biting tick species share the same geographic location as known vectors of B. burgdorferi s.l.; however, these ticks are not competent vectors. Competence is established for some tick species that rarely feed upon humans (e.g., I. angustus and I. spinipalpis), but they could be contributing to the maintenance of B. burgdorferi s.l. transmission cycles involving other vertebrate reservoirs Footnote 14Footnote 15.

In general, early symptoms of human infection include a characteristic rash, fever, headache and lethargy. If untreated with antibiotics, infection can progress to early disseminated LD (with neurological or cardiac manifestations) and then to late disseminated LD (comprised of neurological manifestations and Lyme arthritis) Footnote 16.

Lyme disease is a public health issue in Canada. The number of reported LD cases increased more than six-fold, from 144 in 2009 to 917 in 2015, mainly in Central and Eastern Canada Footnote 6. To support evidence-informed decision-making on this emerging public health issue in Canada, synthesis research was prioritized to systematically identify and summarize the global evidence on LD and B. burgdorferi s.l. epidemiology, diagnosis, prevention and control. Synthesis research methodologies include scoping reviews on broadly defined questions and systematic reviews and meta-analysis on narrowly defined questions Footnote 17Footnote 18Footnote 19. Synthesis research methodologies aim to identify and summarize evidence on a topic in a systematic, reproducible and updateable manner Footnote 18Footnote 19. The objective of a scoping review is to identify the quantity and characteristics of research on a defined topic to understand where evidence saturation and knowledge gaps exist Footnote 20Footnote 21Footnote 22Footnote 23. The outputs from this study will identify areas where priority systematic reviews could be conducted and those requiring additional research to address knowledge gaps.

The objective of this review was developed with an expert advisory group and aimed to identify and characterize the available literature addressing the following aspects of LD that are relevant for public health: a) surveillance and monitoring to determine the extent of LD in humans and/or B. burgdorferi s.s. in vertebrate reservoirs or vectors in North America; b) evaluation of diagnostic tests; c) risk factors reported for LD in humans or exposure to B. burgdorferi s.l. and for the occurrence of B. burgdorferi s.l. in vertebrate reservoirs or vectors; d) the efficacy of public health intervention strategies to prevent and/or control LD in humans or B. burgdorferi s.l. in vertebrate reservoirs or vectors; e) North American public attitudes and/or perceptions towards LD and potential prevention and control strategies; and f) the economic burden or cost-benefit of interventions and potential prevention and control strategies.

Methods

Review protocol, team and expertise

A scoping review protocol, which is available upon request, was developed a priori to ensure the synthesis methods are reproducible and applied consistently in a manner that minimized bias. The review team consisted of individuals with multi-disciplinary expertise in epidemiology, microbiology, veterinary public health, zoonoses, knowledge synthesis and information science.

An expert advisory group of six scientists and public health professionals was established to solicit expert insight on the LD issue, the types of research available and the scope of the review. The expert input defined the literature needed for decision-making, planning and response towards preventing and mitigating the public health risks from LD. The experts were specialists in the ecology of zoonotic diseases, laboratory and field-based surveillance, emerging and vectorborne diseases, molecular biology and veterinary medicine. Input was provided through a questionnaire and consensus meeting (materials are available upon request).

Review question and scope

The scoping review question was developed using a modified version of the Cochrane PICOS/ PECOS (population, intervention/exposure, comparison, outcomes and study design) framework Footnote 17. “What is the current state of scientific knowledge on surveillance/monitoring, prevalence and incidence, societal attitudes and/or perceptions in North America and global prevention and control strategies, risk factors and diagnosis of LD in humans and B. burgdorferi s.l. in vector and vertebrate reservoirs?” The “populations” of interest were humans, vectors and vertebrate reservoirs. The “interventions/exposures” were the major topic categories: surveillance/monitoring, prevalence and incidence, societal attitudes and/or perceptions in North America (Canada, US and Mexico) and global evaluation of diagnostic tests, prevention and control strategies and risk factors. The “outcomes” were LD or infection/ exposure to B. burgdorferi s.l. To our knowledge this is the only scoping review with a broad focus on global LD research relevant for public health; a previous scoping review focused only on research from Australia Footnote 24.

Search strategy

A comprehensive search strategy, adapted to the specific requirements of each database, was implemented without limits in the following bibliographic databases on September 13, 2013 and updated on September 27, 2016: Centre for Agriculture and Bioscience (CAB) Abstracts, Scopus, PubMed, BIOSIS, PsycINFO, APA PsycNet, Sociological Abstracts, and EconLit. These databases were chosen to ensure appropriate breadth across multiple disciplines. The original search of BIOSIS (via web of knowledge) could not be updated as the database is no longer available. The search algorithm was optimized in Scopus.

The following search terms were used: (lyme OR borrelia) AND (host OR sentinel OR landscaping OR vector OR vectors OR monitor OR monitoring OR surveillance OR reservoir OR reservoirs OR prevalence OR educate OR education OR barrier OR barriers OR intervene OR intervention OR incidence OR rate OR prevent OR prevention OR control OR risk OR risks OR attitude OR attitudes OR perception OR perceptions OR detection OR diagnostic).

The capacity of the electronic search to identify all relevant primary research was confirmed by hand-searching reference lists from two primary research papers Footnote 25Footnote 26, Practice Guidelines by the Infectious Diseases Society of America Footnote 10, one systematic review Footnote 27, three narrative reviews Footnote 28Footnote 29Footnote 30 and four European conference proceedings Footnote 31Footnote 32Footnote 33Footnote 34.

A search for grey literature on the websites of government and research organizations worldwide was conducted in February 2014, to complement the electronic database search. Only government and research reports and theses/dissertations were considered for inclusion in the review as grey literature.

Relevance screening and inclusion criteria

Citation titles and abstracts were screened using an a priori designed form consisting of two questions: whether the citation described primary research on LD or B. burgdorferi s.l.and whether it was relevant to one or more aspects of the research question. Primary research was considered original research where authors generated and reported their own data. Articles in English, French and Spanish were included while other languages were excluded due to limited translation resources.

Data characterization and extraction

Complete articles of potentially relevant citations were reviewed using a data characterization and utility (DCU) form consisting of 20 questions designed a priori and available upon request. These questions aimed to confirm article relevance, data utility and allow extraction of the main article characteristics to properly classify the study methodology, population(s), laboratory tests, objectives and outcome characteristics. This could result in one study meeting one, two or more categories.

Scoping review management, data charting and analysis

The search results were imported, de-duplicated and managed in reference management software (RefWorks 2.0; ProQuest LLC, Bethesda, Maryland, US). The scoping review was managed in a web-based electronic systematic review management platform (DistillerSR, Evidence Partners, Ottawa, Ontario, Canada). Two reviewers independently completed all steps of the scoping review. Eight reviewers pre-tested the relevance screening tool with 50 abstracts (kappa>0.8) and the DCU form using three articles. Discrepancies between reviewers were examined and following discussion the form was updated to increase clarity and relevance of questions. The protocol and a reviewer guideline were used to standardize reviewer answers and help resolve conflicts. Resolution of conflicts between reviewers was reached by consensus or by consultation with a third reviewer. Data collected in the DCU form were exported into Excel spreadsheets (Microsoft Corporation, Redmond, Washington, US), formatted and analyzed descriptively (frequencies and percentages) to facilitate categorization and charting.

Results

The search identified 19,353 abstracts and titles and 4,910 full papers screened for relevance (Figure 1). The scoping review included 2,258 relevant articles (full list provided in the Supplementary References) Footnote 35. The majority of the included research was published after 1990 (91.4%; n=2,064) and of those (82.8%; n=1,869) were journal articles (Appendix 1). Included articles were in English (n=2,241), French (n=14) and Spanish (n=3); 282 potentially relevant articles were excluded from the review because they were in other languages (e.g., German, n=75 articles; Russian, n=53; and Polish, n=43). The excluded studies represent an unknown language bias for some focus areas: the evaluation of diagnostic tests (n=131); risk factors (n=94); interventions (n=64); and economic evaluations of the burden of LD (n=7). There was a high proportion of North American research (70.8%; n=1,597); this likely results from non-North American exclusions under surveillance and public attitudes and/or perceptions categories in addition to the language exclusions.

Figure 1: Flow diagram of articles through scoping review

Figure 1: Flow diagram of articles through scoping review

Text description: Figure 1

Figure 1: Flow diagram of articles through scoping review

This figure is a flow diagram that represents the screening process for the inclusion of relevant articles to this review. The total number of articles was 39,285. These databases that follow included articles that were retained for the initial screen:

  • BIOSIS (via web of knowledge) = 8,213 articles
  • CAB abstracts = 10,551 articles
  • Scopus = 10,897 articles
  • PubMed  = 9,003 articles
  • PsycINFO = 333 articles
  • APA PsycNet = 151 articles
  • Sociological Abstracts = 21 articles
  • EconLit = 4 articles
  • Grey literature = 102 articles
  • Search validation = 10 articles

In total, 19,932 duplicates were removed. Through the screening process, 19,353 citations were included and 14,443 were excluded. The assessment of data characterization and utility process further screened in 4,910 articles; 2,652 were excluded for the following reasons:

  • Based on full article, is not relevant to the review scope = 1,748
  • SR/MA on a LD related topic other than economics/ perceptions/knowledge/attitudes = 6
  • Review or commentary = 600
  • Duplicate study = 16
  • Language other than English, French and Spanish = 282

Finally, 2,258 articles were retained for the purpose of the review (2,241 in English, 14 in French and 3 in Spanish).


Research activity across the six focus areas has changed over time (Figure 2) starting with the earliest relevant paper by Steere et al., 1977 that described an outbreak of Lyme arthritis, mainly in children Footnote 36.

Figure 2: Bubble plot of research themes by publication year (N=2,258)Figure 2 footnote aFigure 2 footnote b

Figure 2: Bubble plot of research themes by publication year (N=2,258)

Figure 2 footnote c
Text description: Figure 2

Figure 2: Bubble plot of research themes by publication year (N=2,258)Figure 2 footnote aFigure 2 footnote b

Figure 2 has a bubble plot diagram categorising from 1984 to 2016, the publications pertaining to themes related to Lyme disease. As of 1984 up to 2016 there were, 825 publications focused on surveillance; 754 focused on diagnostic testing; 558 publications focused on the identification of risk factors in all sample populations categories; 207 publications focused on public health interventions; 202 publications had focused on attitudes and perceptions; and 63 had focused on Economics.

Note: The studies originated only from North America.


Since then, the majority of LD research has focused on surveillance (n=809), diagnostic tests (n=736) and identification of risk factors (n=545) on all sample population categories (Table 1). The least amount of primary research has been on the economic burden or cost-benefit of interventions for LD (n=32).

Table 1: Heat chart of the number of studies for each of the six focus areas of Lyme disease by population category (N=2,258)
Study focus Total studiesTable 1 footnote a Human Studies Vertebrate reservoirs Vectors
Surveillance and monitoring in North America 809Table 1 footnote c 283Table 1 footnote d 448Table 1 footnote d 432Table 1 footnote d
Accuracy of diagnostic tests 736Table 1 footnote c 546Table 1 footnote d 158Table 1 footnote e 89Table 1 footnote e
Risk factors 545Table 1 footnote d 262Table 1 footnote d 202Table 1 footnote d 297Table 1 footnote d
Public health interventions 205Table 1 footnote d 72Table 1 footnote e 98Table 1 footnote e 106Table 1 footnote e
Attitudes and/or perceptions in North America 202Table 1 footnote d 202Table 1 footnote d 0Table 1 footnote e 0Table 1 footnote e
Economic burden and cost-effective interventions 32Table 1 footnote bTable 1 footnote e 32Table 1 footnote e 0Table 1 footnote e 0Table 1 footnote e

The 2,258 papers were compared not only by publication year (Figure 1) and study focus groups (Table 1), but also by pathogen, host and vectors (Appendix 2). The number and percentage of papers attributed to the different species of the B. burgdorferi s.l. complex are presented as well as the populations studied. The three most investigated human pathogens were B. burgdorferi s. (73.7%; n=1,664), B. afzelii (9.7%; n=220) and B. garinii (9.7%; n=219). Common host species categories included humans (51.2%; n=1,154), rodents (22.5%; n=508) and dogs (10.1%; n=228). Frequently investigated vectors included I. scapularis (20.3%; n=459), I. ricinus (6.6%; n=149) and Dermacentor variabilis (5.0%; n=112). Many non-Ixodes tick species (e.g., D. variabilis) and one Ixodes species (I. cookei) are incompetent or inefficient vectors of B. burgdorferi s.l. Footnote 37, but were sampled and tested in studies of tick range and habitat because their range overlaps with the known vectors.

Surveillance and monitoring in North America

Epidemiological surveys or surveillance and monitoring programs (Table 2) and their results in North America represented 35.9% of articles (n=809) and provided results for one or more population categories; humans with LD 12.6% (n=283) or B. burgdorferi s.s. infection in vertebrate reservoirs (19.8%; n=448) or vectors (19.1%; n=432). Seven articles provided an evaluation of surveillance programs for humans Footnote 38Footnote 39Footnote 40Footnote 41Footnote 42Footnote 43Footnote 44, two for vertebrate reservoirs Footnote 45Footnote 46 and none for vector surveillance programs.

Table 2: Summary of surveillance/monitoring studies in North America (n=809)
Surveillance type/monitoring approach Vectors
(n=432)
Vertebrate reservoirs
(n=448)
Humans
(n=283)
nTable 2 footnote a %Table 2 footnote a nTable 2 footnote a %Table 2 footnote a nTable 2 footnote a %Table 2 footnote a
Active
Targeted samplingTable 2 footnote b 364 84.3 308 68.8 121 42.5
Using sentinel animals 63 14.6 102 22.8 11 3.9
Passive
Physician/veterinarian reporting 50 11.6 41 9.2 135 48.1
Public reporting/submission 31 7.2 21 4.7 16 5.6
Syndromic surveillance 0 0.0 3 0.7 24 8.4
Other 0 0.0 1Table 2 footnote c 0.2 2Table 2 footnote d 0.7
Laboratory-basedTable 2 footnote e 10 2.3 24 5.4 61 21.4
Evaluation of surveillance methods 0 0.0 2 0.4 7 2.5

Studies include both formal surveillance programs with ongoing (routine) active collection and analysis of data, as well as epidemiological surveys that actively collect and analyse data over a specific and/or defined time period. Laboratory-based surveillance differs from population-wide surveillance and passive physician reporting schemes in that only laboratory test submissions are identified by this type of surveillance. Patients who do not seek medical attention or seek medical attention but are not tested will not be captured by this type of surveillance system.

Accuracy of diagnostic tests

A large number of studies, 32.6% (n=736), evaluated the accuracy of diagnostic and/or screening tests for B. burgdorferi s.l. infection or exposure (Appendix 1). Of these, 546 articles evaluated tests for humans, 158 for vertebrate reservoirs and 89 for vectors. More information on this is available in a separate publication Footnote 47.

Risk factors

Risk factors related to human or host exposure to ticks, acquiring LD in humans or B. burgdorferi s.l. infection in hosts or ticks were reported in 24.1% (n=545) of included articles (Table 3). One or more risk factors were significant in most of these articles (n=425 of the 545 articles). The most frequently evaluated potential risk factors were related to geography (region, type of development; 13.0%; n=294), and landscape features (e.g., presence of leaf litter, elevation, woodland type; 9.2%; n=207). Many studies examined human risk factors related to high risk behaviours (e.g., walking in the woods and gardening; n=32) and demographics (e.g., age and gender; n=213).

Table 3: Summary of risk factors studies (n=545)
Risk factor categoryTable 3 footnote a Human
(n=262 studies)Table 3 footnote a
Vertebrate reservoirs
(n=202 studies)Table 3 footnote a
Vector
(n=297 studies)Table 3 footnote a
Host demographic factorsTable 3 footnote a
Age of cases 111 66 Life stage 14
Gender 99 46 7
Other 28Table 3 footnote b 44Table 3 footnote c 0
Human behaviours
Occupational risk 108 - -
Outdoor recreational activities (e.g., picnics, camping) 65 - -
Pet ownership 54 - -
History/number of tick bites 34 - -
Gardening or yard work 18 - -
Walking or jogging in woods 16 - -
Clearing brush in yard during spring and summer 10 - -
OtherTable 3 footnote d 37 - -
Geographic
Region 83 98 102
Urban, suburban or rural setting 33 15 18
Living in a single family home with yards, attached land or woods 14 0 7
Other 11Table 3 footnote e 1Table 3 footnote f 14Table 3 footnote g
Month of year 60 97 99
Climate
Temperature 22 28 64
Rainfall/precipitation 14 26 35
Relative humidity 5 4 26
Other 5Table 3 footnote h 6Table 3 footnote i 9Table 3 footnote j
Landscape features
Woodland type 28 34 94
Drainage 3 4 3
Vegetation type 5 14 0
Birdfeeders 5 0 2
Deer on properties 15 4 10
Rock walls/wood piles 4 1 3
Wooded properties 9 0 4
Elevation/slope of land 11 22 50
Deer on residential property 4 0 8
Presence of moist humus and leaf litter 8 4 17
Animal densities 3 2 3
Other 39Table 3 footnote k 31Table 3 footnote l 75Table 3 footnote m

Public health interventions

Intervention efficacy to prevent tick exposure, LD in humans or B. burgdorferi s.l. infection in vertebrate reservoirs or vectors was reported in 9.1% (n=205) of included articles. Vaccination (3.5%; n=78), was the most evaluated type of intervention for humans (n=26), dogs (n=25), horses (n=1) or animal models using rodents, birds, chickens, embryonated chicken eggs and Rhesus monkeys (n=28) (Table 4). Chemical control measures were reported in 2.5% (n=56) of articles, including treatment of vertebrate hosts, use of persistent acaricides and spraying of acaricides or desiccants on vegetation. A range of personal protective measures for humans were also evaluated in 2.7% of articles (n=62).

Table 4: Summary of intervention categories (n=205)
Intervention nTable 4 footnote a %Table 4 footnote a
Vaccination
Vaccination of humans 26 12.7
Dogs 25 12.2
Horses 1 0.5
Animal models for vaccine developmentTable 4 footnote b 28 13.7
Chemical control measures
Use of persistent acaricides 17 8.3
Rodent-targeted tick-control device use 15 7.3
Spray or broadcast acaricides or desiccants to vegetation 13 6.3
OtherTable 4 footnote c 11 5.4
Personal protective measures for humansTable 4 footnote d 62 30.2
Public education to decrease risk of Lyme disease infection 19 9.3
Landscape features and modificationsTable 4 footnote e 18 8.8
OtherTable 4 footnote f 28 13.7

Attitudes and/or perceptions in North America

Public knowledge, attitudes and/or perceptions towards LD and potential prevention and control strategies in North America were reported in 8.9% (n=202) articles. The general public (n=68) and/or physicians (n=32) were usually the target populations and the research aim was to assess knowledge of LD (n=131), perception of severity and vulnerability to LD (n=73), protective/risky behaviors (n=73) and knowledge and attitudes towards protection measures (n=56) (Table 5). Within this literature, there are examples of how well-designed and relatively inexpensive health education messages, grounded on social learning theory, can result in increased protective behaviors and a reduced rate of LD Footnote 48Footnote 49Footnote 50Footnote 51Footnote 52Footnote 53.

Table 5: Articles reporting on public knowledge, attitudes or perceptions in North America (n=202)
Characteristic n %Table 5 footnote a
(n=202)
Publication date
Before 1990 14 6.9
1990–1994 35 17.3
1995–1999 30 14.9
2000–2004 37 18.3
2005–2009 30 14.9
>2010 56 27.7
Document type
Journal article 137 67.8
Book chapter 16 7.9
OtherTable 5 footnote b 49 24.3
Study type
Primary research, quantitative 76 37.6
Primary research, qualitative 8 4.0
Primary research, mixed methods 3 1.5
Book chapter/review/commentary 115 56.9
Study design
Observational study 74 85.1Table 5 footnote c
Cross-sectional 66 75.9
Cohort 2 2.3
Case-control 2 2.3
Prevalence survey 3 3.4
Surveillance or monitoring program 1 1.1
Experimental study 9 10.3
Controlled trial 7 8.0
Quasi experiment 2 2.3
Qualitative study 6 6.9
Mixed methods 1 1.1
Study location
United States 182 90.1
Canada 27 13.4
Stakeholder populations investigated for contextual information
General public 68 33.7
Physicians 32 15.8
Other medical or public health professionals 16 7.9
Lyme disease experts/researchers 12 5.9
Government personnel 9 4.5
Children/students 7 3.5
Outdoor workers 6 3.0
Veterinarians 3 1.5
OtherTable 5 footnote d 11 5.4
Method of contextual data collection
Quantitative questionnaire or survey 75 37.1
Analysis of documents 25 12.4
Qualitative interview 15 7.4
OtherTable 5 footnote e 18 8.9
Not specified 48 23.8
Article focus
Knowledge 131 64.9
Severity/vulnerability 73 36.1
Behaviours 73 36.1
Efficacy of protection measures 56 27.7
OtherTable 5 footnote f 43 21.3
Theories of human behaviour used to inform data collection
Health belief model 17 8.4
OtherTable 5 footnote g 18 8.9
Formats used to report quantitative study results
Prevalence 33 16.3
Measures of association 27 13.4
Ordinal/Likert scale 22 10.9
Model 19 9.4
2 x 2 data 18 8.9
Continuous outcome 11 5.4
Non extractable 12 5.9
Need for additional studies 59 29.2

Economic burden and cost-effective interventions

Primary studies of the economic burden of LD or cost-benefit of interventions were reported in 1.4% (n=32) of the articles. These included analysis of the cost of diagnostic tests for LD, health care costs for patients and cost of particular interventions.

Discussion

This scoping review provides an assessment of the quantity and characteristics of the global evidence for six focus areas of LD and B. burgdorferi s.l. research on humans, vertebrate reservoirs and vectors, which included surveillance and monitoring in North America, evaluation of diagnostic tests, risk factors, interventions, public attitudes and perceptions in North America and the economic burden or cost benefit of public health interventions.

Knowledge saturation and gaps

Research and surveillance data have been consistently collected throughout North America since 1995. Most of LD in humans are from passive surveillance of LD case information. A smaller group of epidemiological studies examined exposure to B. burgdorferi s.s. by screening apparently healthy populations. Together these data provide some indication of how much exposure is occurring in areas where I. scapularis and other competent vectors have become established and where B. burgdorferi s.s. circulates. Additionally, epidemiological surveys were frequently conducted to evaluate B. burgdorferi s.s. in vertebrate reservoirs and vectors as opposed to data collected through a surveillance program. This information is key to identifying geographic risk status for public health, which aids in the diagnosis of LD in humans and decision-making on appropriate prevention and control strategies Footnote 4Footnote 54. Identification of B. burgdorferi s.s.in vectors and vertebrates also leads to experimental studies to establish competence for transmission and the role different species may play in the maintenance and spread of B. burgdroferi s.s.and how this may change the risk of human exposure to B. burgdorferi s.s. in different areas. There is sufficient evidence to conduct a systematic review on the historical evidence of the burden of LD and B. burgdorferi s.s.in North America, which would allow an examination of how this changes over time. Some knowledge gaps were also noted pertaining to research on the role of migratory birds in the spread of B. burgdorferi s.s. to new areas. The contribution of potential vectors and vertebrate reservoirs to the transmission of B. burgdorferi s.s.has not been established for all species.

The recommended protocol for LD diagnosis is based on clinical symptoms, a history of exposure to infected ticks and/or travel to an endemic area, which may also be supplemented by diagnostic testing Footnote 55. Recommended diagnostic testing in Canada, the US and most European countries includes a two-tiered serologic testing protocol where a positive or equivocal enzyme immunoassay (EIA) screening test is followed by a confirmatory Western blot Footnote 55Footnote 56Footnote 57Footnote 58. Improvements to LD diagnostic tests, particularly improved sensitivity for testing early stages of LD, is an active research area. Thus, periodic updates to the two recently published systematic reviews on the accuracy of diagnostic tests for humans in North America, prioritized from this scoping review, and Europe is warranted Footnote 47Footnote 59.

There are many parallels between the significant risk factors studied and the intervention strategies evaluated, particularly for human personal protective measures and outcomes of tick presence or risk of tick exposure and landscape modification. Overall, the quantity of research on each risk factor or intervention was quite small; most authors highlighted additional needed research. Even though there may not be a lot of research, systematic reviews summarizing evidence on significant risk factors and intervention efficacy would be useful for the development of new prevention and education strategies for public health. Vaccination was the only intervention category for which there were many studies evaluating potential or commercial vaccines for humans, dogs or horses. No further work on this topic is warranted as a systematic review was recently published Footnote 60. Lyme vaccines are currently approved and used in dogs, and there has not been a commercial vaccine available for humans since the withdrawal of LYMErix in 2002 Footnote 61Footnote 62Footnote 63Footnote 64.

Research estimating the economic impact of LD or public attitudes and perceptions compliment many of the other research focuses. Where economic information is useful in placing an issue on the public health agenda and for the justification of allocated resources Footnote 1Footnote 65, understanding the drivers and barriers to behavior change can determine the success of a public education intervention. This review captured several different types of economic models and data that could be used as a framework to estimate the cost of LD or other outcomes using local cost estimates. Similarly, research investigating public attitudes and/or perceptions towards LD and potential prevention and control strategies provides an in depth understanding of the context and would be a complimentary addition to results from systematic reviews of public health interventions. These include evaluations of knowledge, attitudes, willingness to pay and the impact of public programs on behaviour (e.g., the use of personal protective measures) Footnote 26. Several limitations to this research exist: few studies were based on a model of human behavior change, studies were small thus less generalizable and surrogate and subjective outcome measures for behavior change were often used due to difficulties in obtaining objective measurements Footnote 66Footnote 67Footnote 68.

Limitations of study

Limitations to this scoping review include the language bias noted above and the potential for publication bias if all relevant research is not identified; the impact of these biases on the review results is largely unknown. There may also be limitations in the utility of the review due to the scope, but this depends on the needs of the end user.

This review focuses on the utility of evidence from each focus area and highlights where there is knowledge saturation and gaps in the literature.

Conclusion

This scoping review is an evidence-informed overview of the quantity and characteristics of the research underpinning each focus area; surveillance and monitoring, diagnostic tests, risk factors, interventions, attitudes and perceptions and economic research on LD and B. burgdorferi s.l. in humans, vertebrate reservoirs and vectors. The review provides a very broad understanding of what is known and unknown on this topic at this time and the identified knowledge gaps can be used to prioritize funding for future research. The searchable database created during this scoping review will facilitate addressing both anticipated and unanticipated questions using a systematic review methodology along timelines that are more conducive to decision-making, which is only possible because the relevant research has already been identified and characterized. Thus, several systematic reviews (e.g., on risk factors and interventions for each study population) could be undertaken to provide evidence-informed summaries of information on LD and B. burgdorferi s.l. where estimates of specific outcomes are needed for decision-making.

Authors’ statement

JG – Conceptualization, methodology, formal analysis, investigation, data collection and curation, writing-original draft, review and editing, visualization, supervision, project administration
IY – Conceptualization, methodology, investigation, writing-review and editing, visualization
SH – Formal analysis, investigation, data collection and curation, writing-review and editing, visualization
MM – Investigation, data collection and curation, writing-review and editing
LW – Conceptualization, methodology, formal analysis, investigation, data collection and curation, writing-original draft, review and editing, visualization

Conflict of interest

None.

Acknowledgements

We thank Janet Harris and the Public Health Agency of Canada library staff for procurement of articles and Drs. Carl Uhland, Lea Nogueira-Borden and Malcolm Weir for assistance conducting relevance screening and data characterization. Thank you to our expert LD Advisory Group who helped determine and validate the scope of the project. Thank you to Drs. Nicholas Ogden, Robbin Lindsay and Pascal Michel for their expertise which they contributed to this project.

Funding

This work was supported by the Public Health Agency of Canada.

Appendices

Appendix 1: General characteristics of 2,258 included articles
Characteristic No. % of total
Publication date
before 1990 194 8.6
1990–1994 406 18.0
1995–1999 398 17.6
2000–2004 334 14.8
2005–2009 342 15.2
>2010 584 25.8
Document type
Journal article 1,869 82.8
Conference proceeding/abstract 183 8.1
Government or research report 79 3.5
Thesis 21 0.9
Book chapter 16 0.7
OtherAppendix 1 footnote a 90 4.0
Study locationAppendix 1 footnote b
North America (Canada, USA, Mexico) 1,597Appendix 1 footnote c 70.8
Europe 615 27.2
Asia 57 2.5
Central/South America 7 0.3
Australasia 6 0.3
Africa 3 0.1
Study designAppendix 1 footnote b
Evaluation of diagnostic testAppendix 1 footnote d 736 32.6
Observational study
Cross-sectional 664 29.4
Prevalence surveys 371 16.4
Case study or case-series 49 2.2
Cohort 47 2.1
Case-control 34 1.5
Experimental study
Controlled trial 93 4.1
Challenge trial 68 3.0
Quasi experiment 13 0.6
Surveillance program 181 8.1
Risk assessment 11 0.5
Qualitative study 13 0.6
Economic model 8 0.4
Disease transmission model 3 0.1
OtherAppendix 1 footnote e 26 1.2
Format used to report study results
Prevalence 1,278 56.6
Dichotomous outcome 556 24.6
Continuous outcome 358 15.8
Measure of association (e.g., odds ratio, relative risk) 202 8.9
Spatial analysis (includes satellite/remote sensing) 43 1.9
Ordinal/Likert scale scores 33 1.5
Model outcomes
P-values 265 11.7
Sensitivity and specificity 121 5.4
Coefficients/beta parameters 97 4.3
Confidence limits 96 4.2
R2 83 3.7
Standard error/standard deviation 77 3.4
Sensitivity only 13 0.6
Specificity only 7 0.3
OtherAppendix 1 footnote f 11 0.5
Non-extractable format 798 35.3
Author identified need for more studies (yes vs no) 806 35.7
Appendix 2: Summary of primary research articles on B. burgdorferi s.l., host species and vectors (N=2,258)
Pathogen, host and vector Number of studiesAppendix 2 footnote a %Appendix 2 footnote a
Borrelia burgdorferi s.l.species (n=1,808)
burgdorferi s.s. 1,664 73.7
garinii 219 9.7
afzelii 220 9.7
burgdorferi s.l.Appendix 2 footnote b 118 5.3
valaisiana 57 2.5
miyamotoi 53 2.3
lonestari 44 1.9
bissetti 31 1.4
spielmanii 25 1.1
lusitaniae 22 1.0
Borrelia spp. 18 0.8
andsersonii 12 0.5
anserina 10 0.4
OtherAppendix 2 footnote c 128 5.7
Host species (n=1,841)
Humans 1,154 51.2
Rodents
Mouse 261 11.5
Voles 78 3.5
Rat 59 2.6
Chipmunk 51 2.3
Squirrel 50 2.2
OtherAppendix 2 footnote d 9 0.4
Dogs (companion) 228 10.1
Deer 138 6.1
Birds 76 3.4
Horses 60 2.7
Shrew 44 1.9
Farm animalsAppendix 2 footnote e 35 1.5
Raccoons 32 1.4
Rabbits 28 1.2
Cats (companion) 26 1.2
Lizards 22 1.0
Opossums 17 0.8
OtherAppendix 2 footnote f 75 3.3
Vectors (n=789)
Ixodes scapularis 459 20.3
Ixodes ricinus 149 6.6
Dermacentor variabilis 112 5.0
Ixodes ipacificus 104 4.6
Amblyomma americanum 92 4.1
Haemaphysalis leporispalustris 46 2.0
Ixodes dentatus 32 1.4
Amblyomma maculatum 27 1.2
Dermacentor occidentalis 26 1.2
Dermacentor albipictus 27 1.2
Ixodes spinipalpis 24 1.1
Ixodes cookei 24 1.1
Rhipicephalus sanguineus 18 0.8
Ixodes muris 20 0.9
Ixodes angustus 18 0.8
Ixodes persulcatus 16 0.7
Ixodes texanus 12 0.5
Ixodes affinis 13 0.6
OtherAppendix 2 footnote g 207 9.2
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