Special Issue "Lyme Disease: The Role of Big Data, Companion Diagnostics and Precision Medicine"

A special issue of Healthcare (ISSN 2227-9032).

Deadline for manuscript submissions: closed (30 June 2018)

Special Issue Editor

Guest Editor
Dr. Raphael B. Stricker

Union Square Medical Associates, San Francisco, CA, United States
Website | E-Mail
Interests: tickborne diseases; immunodeficiency diseases; immunological infertility

Special Issue Information

Dear Colleagues,

Lyme disease, caused by the spirochete Borrelia burgdorferi, has become a major worldwide epidemic. Studies based on Big Data registries show that >300,000 people are diagnosed with Lyme disease each year in the USA alone, and up to two-thirds of individuals infected with B. burgdorferi will fail conventional 30-year-old antibiotic therapy. Recent studies have highlighted metabolic and molecular persistence mechanisms that allow the Lyme spirochete to survive in the face of immunological and antibiotic challenges. Consequently, improved companion diagnostic tests and novel treatment approaches for Lyme disease are urgently needed to combat the epidemic. In particular, therapies based on the principles of precision medicine could be modeled on successful “designer drug” treatment for other diseases. This Special Issue of Healthcare examines the use of Big Data registries, companion diagnostics and precision medicine that will revolutionize the diagnosis and treatment of Lyme disease in the coming years.

Dr. Raphael B. Stricker
Guest Editor

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Keywords

  • Lyme disease
  • Borrelia burgdorferi
  • tickborne diseases
  • persistent infection

Published Papers (11 papers)

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Research

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Open AccessArticle Under-Detection of Lyme Disease in Canada
Healthcare 2018, 6(4), 125; https://doi.org/10.3390/healthcare6040125
Received: 31 July 2018 / Revised: 30 September 2018 / Accepted: 2 October 2018 / Published: 15 October 2018
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Abstract
Lyme disease arises from infection with pathogenic Borrelia species. In Canada, current case definition for confirmed Lyme disease requires serological confirmation by both a positive first tier ELISA and confirmatory second tier immunoblot (western blot). For surveillance and research initiatives, this requirement is
[...] Read more.
Lyme disease arises from infection with pathogenic Borrelia species. In Canada, current case definition for confirmed Lyme disease requires serological confirmation by both a positive first tier ELISA and confirmatory second tier immunoblot (western blot). For surveillance and research initiatives, this requirement is intentionally conservative to exclude false positive results. Consequently, this approach is prone to false negative results that lead to underestimation of the number of people with Lyme disease. The province of New Brunswick (NB), Canada, can be used to quantify under-detection of the disease as three independent data sets are available to generate an estimate of the true human disease prevalence and incidence. First, detailed human disease incidence is available for the US states and counties bordering Canada, which can be compared with Canadian disease incidence. Second, published national serology results and well-described sensitivity and specificity values for these tests are available and deductive reasoning can be used to query for discrepancies. Third, high-density tick and canine surveillance data are available for the province, which can be used to predict expected human Lyme prevalence. Comparison of cross-border disease incidence suggests a minimum of 10.2 to 28-fold under-detection of Lyme disease (3.6% to 9.8% cases detected). Analysis of serological testing predicts the surveillance criteria generate 10.4-fold under-diagnosis (9.6% cases detected) in New Brunswick for 2014 due to serology alone. Calculation of expected human Lyme disease cases based on tick and canine infections in New Brunswick indicates a minimum of 12.1 to 58.2-fold underestimation (1.7% to 8.3% cases detected). All of these considerations apply generally across the country and strongly suggest that public health information is significantly under-detecting and under-reporting human Lyme cases across Canada. Causes of the discrepancies between reported cases and predicted actual cases may include undetected genetic diversity of Borrelia in Canada leading to failed serological detection of infection, failure to consider and initiate serological testing of patients, and failure to report clinically diagnosed acute cases. As these surveillance criteria are used to inform clinical and public health decisions, this under-detection will impact diagnosis and treatment of Canadian Lyme disease patients. Full article
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Open AccessArticle Removing the Mask of Average Treatment Effects in Chronic Lyme Disease Research Using Big Data and Subgroup Analysis
Healthcare 2018, 6(4), 124; https://doi.org/10.3390/healthcare6040124
Received: 4 September 2018 / Revised: 9 October 2018 / Accepted: 9 October 2018 / Published: 12 October 2018
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Abstract
Lyme disease is caused by the bacteria borrelia burgdorferi and is spread primarily through the bite of a tick. There is considerable uncertainty in the medical community regarding the best approach to treating patients with Lyme disease who do not respond fully to
[...] Read more.
Lyme disease is caused by the bacteria borrelia burgdorferi and is spread primarily through the bite of a tick. There is considerable uncertainty in the medical community regarding the best approach to treating patients with Lyme disease who do not respond fully to short-term antibiotic therapy. These patients have persistent Lyme disease symptoms resulting from lack of treatment, under-treatment, or lack of response to their antibiotic treatment protocol. In the past, treatment trials have used small restrictive samples and relied on average treatment effects as their measure of success and produced conflicting results. To provide individualized care, clinicians need information that reflects their patient population. Today, we have the ability to analyze large data bases, including patient registries, that reflect the broader range of patients more typically seen in clinical practice. This allows us to examine treatment variation within the sample and identify groups of patients that are most responsive to treatment. Using patient-reported outcome data from the MyLymeData online patient registry, we show that sub-group analysis techniques can unmask valuable information that is hidden if averages alone are used. In our analysis, this approach revealed treatment effectiveness for up to a third of patients with Lyme disease. This study is important because it can help open the door to more individualized patient care using patient-centered outcomes and real-world evidence. Full article
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Open AccessCommunication Systematic Approach to the Diagnosis and Treatment of Lyme Carditis and High-Degree Atrioventricular Block
Healthcare 2018, 6(4), 119; https://doi.org/10.3390/healthcare6040119
Received: 27 July 2018 / Revised: 21 August 2018 / Accepted: 21 September 2018 / Published: 22 September 2018
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Abstract
Lyme carditis (LC) is a manifestation of the early disseminated stage of Lyme disease and often presents as high-degree atrioventricular (AV) block. High-degree AV block in LC can be treated with antibiotics, usually resolving with a highly favorable prognosis, thus preventing the unnecessary
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Lyme carditis (LC) is a manifestation of the early disseminated stage of Lyme disease and often presents as high-degree atrioventricular (AV) block. High-degree AV block in LC can be treated with antibiotics, usually resolving with a highly favorable prognosis, thus preventing the unnecessary implantation of permanent pacemakers. We present a systematic approach to the diagnosis and management of LC that implements the Suspicious Index in Lyme Carditis (SILC) risk stratification score. Full article
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Open AccessArticle Pilot Study of Immunoblots with Recombinant Borrelia burgdorferi Antigens for Laboratory Diagnosis of Lyme Disease
Received: 17 May 2018 / Revised: 7 August 2018 / Accepted: 10 August 2018 / Published: 14 August 2018
Cited by 1 | PDF Full-text (872 KB) | HTML Full-text | XML Full-text
Abstract
Accurate laboratory diagnosis of Lyme disease (Lyme borreliosis), caused by the spirochete Borrelia burgdorferi (BB), is difficult and yet important to prevent serious disease. The US Centers for Disease Control and Prevention (CDC) presently recommends a screening test for serum antibodies followed by
[...] Read more.
Accurate laboratory diagnosis of Lyme disease (Lyme borreliosis), caused by the spirochete Borrelia burgdorferi (BB), is difficult and yet important to prevent serious disease. The US Centers for Disease Control and Prevention (CDC) presently recommends a screening test for serum antibodies followed by confirmation with a more specific Western blot (WB) test to detect IgG and IgM antibodies against antigens in whole cell lysates of BB. Borrelia species related to BB cause tick-borne relapsing fever (TBRF). TBRF is increasingly recognized as a health problem in the US and occurs in areas where Lyme disease is prevalent. The two groups of Borrelia share related antigens. We have developed a modified WB procedure termed the Lyme immunoblots (IBs) using recombinant antigens from common strains and species of the BB sensu lato complex for serological diagnosis of Lyme disease. A reference collection of 178 sera from 26 patients with and 152 patients without Lyme disease were assessed by WB and IB in a blinded manner using either criteria for positive antibody reactions recommended by the CDC or criteria developed in-house. The sensitivity, specificity, positive and negative predictive values obtained with the reference sera suggest that the Lyme IB is superior to the Lyme WB for detection of specific antibodies in Lyme disease. The Lyme IB showed no significant reaction with rabbit antisera produced against two Borrelia species causing TBRF in the US, suggesting that the Lyme IB may be also useful for excluding TBRF. Full article
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Open AccessArticle Far-Reaching Dispersal of Borrelia burgdorferi Sensu Lato-Infected Blacklegged Ticks by Migratory Songbirds in Canada
Received: 8 June 2018 / Revised: 9 July 2018 / Accepted: 18 July 2018 / Published: 25 July 2018
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Abstract
Lyme disease has been documented in northern areas of Canada, but the source of the etiological bacterium, Borrelia burgdorferi sensu lato (Bbsl) has been in doubt. We collected 87 ticks from 44 songbirds during 2017, and 24 (39%) of 62 nymphs of the
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Lyme disease has been documented in northern areas of Canada, but the source of the etiological bacterium, Borrelia burgdorferi sensu lato (Bbsl) has been in doubt. We collected 87 ticks from 44 songbirds during 2017, and 24 (39%) of 62 nymphs of the blacklegged tick, Ixodes scapularis, were positive for Bbsl. We provide the first report of Bbsl-infected, songbird-transported I. scapularis in Cape Breton, Nova Scotia; Newfoundland and Labrador; north-central Manitoba, and Alberta. Notably, we report the northernmost account of Bbsl-infected ticks parasitizing a bird in Canada. DNA extraction, PCR amplification, and DNA sequencing reveal that these Bbsl amplicons belong to Borrelia burgdorferi sensu stricto (Bbss), which is pathogenic to humans. Based on our findings, health-care providers should be aware that migratory songbirds widely disperse B. burgdorferi-infected I. scapularis in Canada’s North, and local residents do not have to visit an endemic area to contract Lyme disease. Full article
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Open AccessArticle Lyme Disease Transmission Risk: Seasonal Variation in the Built Environment
Received: 18 June 2018 / Revised: 10 July 2018 / Accepted: 17 July 2018 / Published: 19 July 2018
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Abstract
Seasonal variation in spatial distribution and pathogen prevalence of Borrelia burgdorferi in blacklegged ticks (Ixodes scapularis) influences human population risk of Lyme disease in peri-urban built environments. Parks, gardens, playgrounds, school campuses and neighborhoods represent a significant risk for Lyme disease
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Seasonal variation in spatial distribution and pathogen prevalence of Borrelia burgdorferi in blacklegged ticks (Ixodes scapularis) influences human population risk of Lyme disease in peri-urban built environments. Parks, gardens, playgrounds, school campuses and neighborhoods represent a significant risk for Lyme disease transmission. From June 2012 through May 2014, ticks were collected using 1 m2 corduroy cloths dragged over low-lying vegetation parallel to walkways with high human foot traffic. DNA was extracted from ticks, purified and presence of B. burgdorferi assessed by polymerase chain reaction amplification. Summer is reported as the time of highest risk for Lyme disease transmission in the United States and our results indicate a higher tick density of 26.0/1000 m2 in summer vs. 0.2/1000 m2 to 10.5/1000 m2 in spring and fall. However, our findings suggest that tick infection rate is proportionally higher during the fall and spring than summer (30.0–54.7% in fall and 36.8–65.6% in spring vs. 20.0–28.2% in summer). Seasonal variation in infected tick density has significant implications for Lyme disease transmission as people are less likely to be aware of ticks in built environments, and unaware of increased infection in ticks in spring and fall. These factors may lead to more tick bites resulting in Lyme infection. Full article
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Open AccessArticle A Community Study of Borrelia burgdorferi Antibodies among Individuals with Prior Lyme Disease in Endemic Areas
Received: 3 May 2018 / Revised: 12 June 2018 / Accepted: 13 June 2018 / Published: 19 June 2018
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Abstract
The objective was to examine the prevalence of Borrelia antibodies among symptomatic individuals with recent and past Lyme disease in endemic communities using standard assays and novel assays employing next-generation antigenic substrates. Single- and two-tiered algorithms included different anti-Borrelia ELISAs and immunoblots.
[...] Read more.
The objective was to examine the prevalence of Borrelia antibodies among symptomatic individuals with recent and past Lyme disease in endemic communities using standard assays and novel assays employing next-generation antigenic substrates. Single- and two-tiered algorithms included different anti-Borrelia ELISAs and immunoblots. Antibody prevalence was examined in sera from 32 individuals with recent erythema migrans (EM), 335 individuals with persistent symptoms following treatment for Lyme disease (PTLS), and 41 community controls without a history of Lyme disease. Among convalescent EM cases, sensitivity was highest using the C6 ELISA (93.8%) compared to other single assays; specificity was 92.7% for the C6 ELISA vs. 85.4–97.6% for other assays. The two-tiered ELISA-EUROLINE IgG immunoblot combinations enhanced case detection substantially compared to the respective ELISA-IgG Western blot combinations (75.0% vs. 34.4%) despite similar specificity (95.1% vs. 97.6%, respectively). For PTLS cohorts, two-tier ELISA-IgG-blot positivity ranged from 10.1% to 47.4%, depending upon assay combination, time from initial infection, and clinical history. For controls, the two-tier positivity rate was 0–14.6% across assays. A two-tier algorithm of two-ELISA assays yielded a high positivity rate of 87.5% among convalescent EM cases with specificity of 92.7%. For convalescent EM, combinations of the C6 ELISA with a second-tier ELISA or line blot may provide useful alternatives to WB-based testing algorithms. Full article
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Open AccessArticle Human Babesiosis Caused by Babesia duncani Has Widespread Distribution across Canada
Received: 6 February 2018 / Revised: 14 May 2018 / Accepted: 15 May 2018 / Published: 17 May 2018
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Abstract
Human babesiosis caused by Babesia duncani is an emerging infectious disease in Canada. This malaria-like illness is brought about by a protozoan parasite infecting red blood cells. Currently, controversy surrounds which tick species are vectors of B. duncani. Since the availability of a
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Human babesiosis caused by Babesia duncani is an emerging infectious disease in Canada. This malaria-like illness is brought about by a protozoan parasite infecting red blood cells. Currently, controversy surrounds which tick species are vectors of B. duncani. Since the availability of a serological or molecular test in Canada for B. duncani has been limited, we conducted a seven-year surveillance study (2011–2017) to ascertain the occurrence and geographic distribution of B. duncani infection country-wide. Surveillance case data for human B. duncani infections were collected by contacting physicians and naturopathic physicians in the United States and Canada who specialize in tick-borne diseases. During the seven-year period, 1119 cases were identified. The presence of B. duncani infections was widespread across Canada, with the highest occurrence in the Pacific coast region. Patients with human babesiosis may be asymptomatic, but as this parasitemia progresses, symptoms range from mild to fatal. Donors of blood, plasma, living tissues, and organs may unknowingly be infected with this piroplasm and are contributing to the spread of this zoonosis. Our data show that greater awareness of human babesiosis is needed in Canada, and the imminent threat to the security of the Canadian blood supply warrants further investigation. Based on our epidemiological findings, human babesiosis should be a nationally notifiable disease in Canada. Whenever a patient has a tick bite, health practitioners must watch for B. duncani infections, and include human babesiosis in their differential diagnosis. Full article
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Open AccessArticle Persistent Borrelia Infection in Patients with Ongoing Symptoms of Lyme Disease
Received: 7 March 2018 / Revised: 27 March 2018 / Accepted: 11 April 2018 / Published: 14 April 2018
Cited by 3 | PDF Full-text (8431 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Introduction: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, in patients who have been treated with recommended
[...] Read more.
Introduction: Lyme disease is a tickborne illness that generates controversy among medical providers and researchers. One of the key topics of debate is the existence of persistent infection with the Lyme spirochete, Borrelia burgdorferi, in patients who have been treated with recommended doses of antibiotics yet remain symptomatic. Persistent spirochetal infection despite antibiotic therapy has recently been demonstrated in non-human primates. We present evidence of persistent Borrelia infection despite antibiotic therapy in patients with ongoing Lyme disease symptoms. Methods: In this pilot study, culture of body fluids and tissues was performed in a randomly selected group of 12 patients with persistent Lyme disease symptoms who had been treated or who were being treated with antibiotics. Cultures were also performed on a group of ten control subjects without Lyme disease. The cultures were subjected to corroborative microscopic, histopathological and molecular testing for Borrelia organisms in four independent laboratories in a blinded manner. Results: Motile spirochetes identified histopathologically as Borrelia were detected in culture specimens, and these spirochetes were genetically identified as Borrelia burgdorferi by three distinct polymerase chain reaction (PCR)-based approaches. Spirochetes identified as Borrelia burgdorferi were cultured from the blood of seven subjects, from the genital secretions of ten subjects, and from a skin lesion of one subject. Cultures from control subjects without Lyme disease were negative for Borrelia using these methods. Conclusions: Using multiple corroborative detection methods, we showed that patients with persistent Lyme disease symptoms may have ongoing spirochetal infection despite antibiotic treatment, similar to findings in non-human primates. The optimal treatment for persistent Borrelia infection remains to be determined. Full article
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Open AccessArticle Citizen Science and Community Engagement in Tick Surveillance—A Canadian Case Study
Received: 14 January 2018 / Revised: 22 February 2018 / Accepted: 27 February 2018 / Published: 2 March 2018
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Abstract
Lyme disease is the most common tick-borne disease in North America and Europe, and on-going surveillance is required to monitor the spread of the tick vectors as their populations expand under the influence of climate change. Active surveillance involves teams of researchers collecting
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Lyme disease is the most common tick-borne disease in North America and Europe, and on-going surveillance is required to monitor the spread of the tick vectors as their populations expand under the influence of climate change. Active surveillance involves teams of researchers collecting ticks from field locations with the potential to be sites of establishing tick populations. This process is labor- and time-intensive, limiting the number of sites monitored and the frequency of monitoring. Citizen science initiatives are ideally suited to address this logistical problem and generate high-density and complex data from sites of community importance. In 2014, the same region was monitored by academic researchers, public health workers, and citizen scientists, allowing a comparison of the strengths and weaknesses of each type of surveillance effort. Four community members persisted with tick collections over several years, collectively recovering several hundred ticks. Although deviations from standard surveillance protocols and the choice of tick surveillance sites makes the incorporation of community-generated data into conventional surveillance analyses more complex, this citizen science data remains useful in providing high-density longitudinal tick surveillance of a small area in which detailed ecological observations can be made. Most importantly, partnership between community members and researchers has proven a powerful tool in educating communities about of the risk of tick-vectored diseases and in encouraging tick bite prevention. Full article
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Review

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Open AccessReview Neuropsychiatric Lyme Borreliosis: An Overview with a Focus on a Specialty Psychiatrist’s Clinical Practice
Healthcare 2018, 6(3), 104; https://doi.org/10.3390/healthcare6030104
Received: 10 July 2018 / Revised: 22 August 2018 / Accepted: 23 August 2018 / Published: 25 August 2018
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Abstract
There is increasing evidence and recognition that Lyme borreliosis (LB) causes mental symptoms. This article draws from databases, search engines and clinical experience to review current information on LB. LB causes immune and metabolic effects that result in a gradually developing spectrum of
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There is increasing evidence and recognition that Lyme borreliosis (LB) causes mental symptoms. This article draws from databases, search engines and clinical experience to review current information on LB. LB causes immune and metabolic effects that result in a gradually developing spectrum of neuropsychiatric symptoms, usually presenting with significant comorbidity which may include developmental disorders, autism spectrum disorders, schizoaffective disorders, bipolar disorder, depression, anxiety disorders (panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder, intrusive symptoms), eating disorders, decreased libido, sleep disorders, addiction, opioid addiction, cognitive impairments, dementia, seizure disorders, suicide, violence, anhedonia, depersonalization, dissociative episodes, derealization and other impairments. Screening assessment followed by a thorough history, comprehensive psychiatric clinical exam, review of systems, mental status exam, neurological exam and physical exam relevant to the patient’s complaints and findings with clinical judgment, pattern recognition and knowledgeable interpretation of laboratory findings facilitates diagnosis. Psychotropics and antibiotics may help improve functioning and prevent further disease progression. Awareness of the association between LB and neuropsychiatric impairments and studies of their prevalence in neuropsychiatric conditions can improve understanding of the causes of mental illness and violence and result in more effective prevention, diagnosis and treatment. Full article
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