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2019 Topic Development Briefs








  
  
    

  
      





At the June 4, 2019, meeting, the Working Group identified three questions for literature reviews. *Ad hoc* subcomittees were formed to refine the questions and help develop literature search criteria. The process and findings for the three briefs are documented below.

Increases in Tick-Borne Diseases

Diagnostic Tests for Tick-Borne Diseases

Persistent Symptoms of Lyme Disease

Topic Development Brief on Increases in Tick-Borne Diseases

Results of Topic Selection Process and Next Steps

The Tick-Borne Disease Working Group is interested in using an assessment of available literature to research the causes of the increase in tick-borne diseases in the United States. Given the large volume of original research on this topic, a new systematic literature review would be feasible.

Topic Brief

*Topic Name:*  Increases in Tick-Borne Diseases*Topic Brief Date:*  September 6, 2019*Date of Nomination:* July 18, 2019*Working Group Leads:*  Adalberto Pérez de León, DVM, PhD, MS, and Robert Sabatino*Authors:* Selena Gonzales, MPH, and Christina Li, MPH*Conflict of Interest:*The nominator and authors have no affiliations or financial involvement that conflict with the material presented in this report.

Background

The increasing incidence of tick-borne diseases poses a serious threat to public health (Gray & Herwaldt, 2019; Petersen, Foster, McWilliams, & Irwin, 2015; Raghavan, Goodin, Neises, Anderson, & Ganta, 2016; Raghavan, Peterson, Cobos, Ganta, & Foley, 2019). Currently, the

U.S. Centers for Disease Control and Prevention recognize 18 tick-borne pathogens in the United States. However, researchers and clinicians continue to discover emerging pathogens and new medical conditions associated with tick bites. Proposed causes for the increasing incidence of tick-borne diseases include:

the climate’s effects on tick biology and ecology,
	the interaction of climatic and environmental factors,
	changes in host availability,
	changes in tick abundance,
	changes in the geographic distribution of ticks, and
	changes in the prevalence of pathogens in tick populations.An enhanced understanding of the reasons for the rising incidence of tick-borne diseases will help scientists and health care professionals develop strategies to lower the risk for disease transmission.

Topic Nomination Development

Nominator and Stakeholder Engagement

During a conference call with the nominator, the authors reviewed and clarified the key question, guiding questions, and PICOTS (population, interventions/indicators, comparators, outcomes, timing of interest, and setting). The nominator provided final approval of those items via email.

Key Question

The key question for this topic nomination is: Considering tick biology, ecology, and control, what are the causes for the increased number of tick-borne disease cases in the United States?

Proposed Guiding Questions

Based on the variable level of evidence development, we proposed the following guiding questions.

Is the problem with ticks and tick-borne diseases particular to the United States or is it a global issue?
	If it is a global problem, what are the particular drivers (e.g., climate variability, environmental change, host and vector population increases, range expansion) for the problem with ticks and tick-borne diseases in the United States during the past 50 years?
	What are the challenges for implementation research on integrated tick management focused on controlling host and vector populations to decrease the risk of tick-borne disease transmission?Proposed PICOTS

To define inclusion criteria for the key question, we specified the PICOTS.

Key Question and PICOTS
			Topic InformationKey Question
			Considering tick biology, ecology, and control, what are the causes for the increased number of tick-borne disease cases in the United States?Population
			People diagnosed with tick-borne diseases in the United States and globallyInterventions/Indicators
			Understanding how climate variability, environmental change, host and vector population increases, and range expansion increase the risk of tick-borne disease transmission so we can adapt interventionsComparators
			Compare findings from interventions/indicators to each otherOutcomes
			Identifiable causes for an increase in tick-borne diseases to adapt integrated tick-management interventions targeting the vector- host-pathogen interface by disrupting vulnerabilities in the biology and ecology of ticksTiming
			Past 50 years (1968–2018)Setting
			Geographic areas with increased risk of tick-borne disease transmission in the United StatesMethods

We assessed the nomination of Increased Tick-borne Diseases as a topic brief priority using the following established selection criteria. Assessment of each criterion determined the need to evaluate the next one.

Determine the appropriateness of the topic.
	Establish the overall importance of the topic as representing a health or health care issue in the United States.
	Determine the desirability of a new evidence review by examining whether a systematic literature review would be duplicative.
	Assess the potential impact of a new systematic literature review.
	Assess whether the current state of the evidence allows for a systematic literature review (feasibility).
	Determine the potential value of a new systematic literature review.Results

Appropriateness and Importance

This topic is appropriate and important. Lyme disease is one of the most commonly reported and widely known tick-borne diseases. However, cases of alpha-gal syndrome, anaplasmosis, babesiosis, ehrlichiosis, and rickettsiosis are now increasing, too (Gray & Herwaldt, 2019; Petersen et al., 2015; Raghavan et al., 2016; Raghavan et al., 2019).

Desirability of New Review/Duplication

A new evidence review would not be duplicative. The causes of the increase in tick-borne diseases and tick populations have not been systematically reviewed. Further research is needed to understand the increase in tick-borne diseases.

Impact of a New Evidence Review

A new systematic review may prove useful in the development of public health strategies to mitigate the impact of the growing threat of tick-borne diseases.

Feasibility of a New Evidence Review

We conducted a literature search in EBSCOhost in August 2019 using the key question, guiding questions, and PICOTS to develop keyword searches. See Appendix A for the EBSCOhost search strategy.

A new systematic literature review is likely feasible with some modifications to the selection criteria. There is adequate information to perform a systematic literature review on the causes of the increase in tick populations and tick-borne diseases.

There is little research on the targeted management of host and vector populations. The evidence base is broad and includes many articles on the management of tick-borne diseases in regards to the impact on livestock. A focused review on strategies to manage populations of tick species that cause disease in livestock might provide information that is applicable to human health.

Discussion

In the United States, ticks cause more illness in humans than any other arthropod. Lyme disease is one of the most commonly reported and widely known tick-borne diseases. However, cases of alpha-gal syndrome, anaplasmosis, babesiosis, ehrlichiosis, and rickettsiosis are now increasing, too (Gray & Herwaldt, 2019; Petersen et al., 2015; Raghavan et al., 2016; Raghavan et al., 2019).

A global problem, tick-borne diseases pose a threat to the health of non-U.S. populations as well as U.S. military personnel and civilian employees living and working abroad. Some of those diseases are not currently occurring in the United States. One notable example is tick-borne encephalitis (TBE). Endemic to various areas of Europe and Asia, TBE is becoming more common in Sweden (Jaenson et al., 2018). The virus that causes TBE is transmitted by the *Ixodes ricinus*tick, which also carries the spirochetes that cause Lyme disease in Europe (Hauser et al., 2018).

Themes From the Literature

In an effort to answer this topic brief’s key question, we conducted a preliminary assessment of the literature and identified the following key themes:

the climate’s effects on tick biology and ecology,
	the interaction of climatic and environmental factors,
	changes in host availability,
	changes in tick abundance,
	changes in the geographic distribution of ticks, and
	changes in the prevalence of pathogens in tick populations.The following section elaborates on each key theme and features highlights from the literature, as appropriate.

The Climate’s Effects on Tick Biology and Ecology

The climate has been shown to affect tick biology and ecology, which has practical implications for tick prevalence, tick distribution, and the incidence of tick-borne diseases.

A 2017 study (Ginsberg et al.) suggests that the greater number of cases of Lyme disease in the northeastern and upper midwestern regions of the United States, compared with the southern states, may be related to the effects of temperature and humidity on tick behavior. Ginsberg et al. replicated environmentally realistic conditions in their laboratory. The authors found that *I. scapularis*stays below the leaf litter surface in warmer, dryer areas of the southern United States and on the leaf litter surface in cooler, more humid regions of the northern United States. The study suggests people walking through the woods in warmer, dryer areas are less likely to be bitten by *I. scapularis*ticks and may therefore be at lower risk for infection with the pathogens that cause Lyme disease.

Estrada-Peña and Estrada-Sánchez (2014) conducted a study of development and mortality rates of *I. ricinus*ticks in western Europe. The authors found that the season for tick development was three times longer in southern regions of the tick’s geographic range than in northern regions. Notably, conditions were warmer and dryer in the southern regions.

However, a longer season for development was not necessarily advantageous, as it was correlated with lower tick survival rates. Although this study’s implications for the incidence of tick-borne diseases in western Europe remain unclear, the lack of clarity does suggest a need for additional research on tick development that considers tick ecology, vegetation composition, and host availability.

The Interaction of Climatic and Environmental Factors

Between 1978 and 2008, the geographic range of *I. ricinus*within southern Norway expanded due to a complex combination of the following climatic and environmental factors (Jore et al., 2014):

large diurnal changes in ground surface temperature,
	duration of snow cover,
	spring precipitation,
	an abundance of red deer and farm animals, and
	changes in land use resulting in bush encroachment of open fields.*I. ricinus*transmits TBE, which poses a significant health threat to people living in southern Norway (Andreassen et al., 2012). However, Jore et al. (2014) stop short of directly linking the tick’s range expansion to the increased incidence of TBE or other tick-borne diseases in humans.

Changes in Host Availability

Some research suggests that changes in host availability might be driving the incidence of tick- borne diseases upward. The above-mentioned study by Jore et al. (2014) of *I. ricinus*populations in southern Norway found that an abundance of red deer and farm animals, in combination with other factors, helped facilitate the expansion of the ticks’ geographic range over a 30-year period (1978–2008). And a recent study by Jaenson et al. (2018) suggests the increased availability of deer in Sweden may have contributed to increases in the density of *I. ricinus*populations and the incidence of TBE.

However, results of research on *I. ricinus*in eastern Russia between 1977 and 2011 seem to downplay the role of host availability in the increase of tick-borne diseases. In that study, Korotkov, Kozlova, and Kozlovskaya (2015) observed long-term growth in tick populations but little change in the number of vertebrates that ticks feed on. And a more recent study conducted by Gleim et al. (2014) in the southern United States found no relation between host abundance and tick abundance.

Changes in Tick Abundance

Several studies suggest ticks will become more abundant with continued climate change. For instance, Ogden et al. (2014) found that rising temperatures from 1971–2010 boosted the reproduction capacity of *I. scapularis*, which may have contributed to the emergence of Lyme disease in the northeastern United States.

Estrada-Peña, de la Fuente, Latapia, and Ortega (2015) assessed the effects of climate trends between 1901 and 2009 on the life cycle of *Hyalomma marginatum*, a tick species that is the main vector of Crimean-Congo hemorrhagic fever virus in the Mediterranean basin and the Middle East. According to the authors’ analysis, recent climate trends have helped *H. marginatum*become more abundant in areas of Europe with successfully established populations of that tick species.

However, Hauser et al. (2018) collected *I. ricinus*in a forest in Switzerland from 2000–2014, a time period that saw global increases in daily mean temperatures and daily mean values of relative humidity. The authors observed a decrease in the tick population and recommended further studies to assess the impact of host abundance and the role of microhabitats on tick population density.

Changes in the Geographic Distribution of Ticks

Research suggests that ticks’ widening geographic distribution has led to an increase in the incidence of Lyme disease in North America (Ogden et al., 2010; Ogden et al., 2014; Cheng et al., 2017). For example, Cheng et al. determined that, between 1979 and 2013, the range of sustainable tick habitat within Ontario expanded as a result of climate change, and populations of *I. scapularis*colonized new regions of the province.

Scientists predict that climate change will continue to cause shifts in the geographic distribution of ticks and the areas where tick-borne diseases are endemic (Ogden et al., 2014; Cheng et al., 2017). In some cases, the distribution will widen to include areas beyond different latitudes.

However, elevation is also an important factor to consider. For instance, in the case of *Ornithodoros hermsi*, a tick species that transmits tick-borne relapsing fever in North America, we are more likely to see shifts to higher elevations where temperatures and precipitation amounts are more conducive to the tick’s survival (Sage, Johnson, Teglas, Nieto, & Schwan, 2017).

That being said, a recently published paper by MacDonald (2018) suggests climate change will lead to overall reductions in the habitat and activity of *I. pacificus*, a vector of Lyme disease in California. Notably, established populations of *I. pacificus*are found in dense forest habitats with cool and moist microclimates, and adult ticks of that species tend to be more abundant in areas with lower average winter temperatures.

Changes in the Prevalence of Pathogens in Tick Populations

Several studies indicate that the prevalence of disease-causing pathogens varies among established tick populations.

Estrada-Peña et al. (2018) analyzed data spanning 2000–2017 for a study of *I. ricinus*in Europe. They found a higher prevalence of *Borrelia*spirochetes in the tick populations of central European regions characterized by warmer temperatures, a steady rise in springtime temperatures, and less abrupt changes in vegetation from one year to the next.

Gasmi et al. (2018) analyzed tick surveillance data collected in Quebec from 2007–2015, with a focus on tick species other than *I. scapularis*. The analysis revealed a trend of increased abundance for the following four tick species:

*I. cookei*, the primary vector for Powassan virus;
	*Dermacentor variabilis*, a vector of Rocky Mountain spotted fever (RMSF) and tularemia;
	*Rhipicephalus sanguineus,*a vector of RMSF; and
	*Amblyomma americanum,*a vector of tularemia and two types of ehrlichiosis.Notably, studies to assess the prevalence of pathogens in tick species other than *I. scapularis*in Quebec had not been conducted. Furthermore, although *I. cookei*had been endemic to Quebec for many years, only six cases of Powassan encephalitis were reported between 2004 and 2014.

The low incidence of Powassan encephalitis, despite the abundance of *I. cookei,*seems to reinforce the findings of Ogden et al. (2010). According to their study, the establishment of *B. burgdorferi*in Quebec and the emergence of Lyme disease occurred several years after migratory birds brought *I. scapularis*into the province from the northeastern United States.

Such findings suggest a need for heightened surveillance to identify the factors that increase or decrease the prevalence of tick-borne pathogens and to determine how changes in pathogen prevalence relate to changes in tick abundance and tick distribution.

Mitigating the Public Health Threat Posed by Tick-Borne Diseases

Strategies to prevent tick-borne diseases in the general public are currently limited. Many scientists and clinicians recommend the use of personal protective measures to prevent tick bites. Landscape and environmental measures, such as prescribed burning, have also been proposed as strategies for reducing tick populations (Petersen et al., 2015; Gleim et al., 2014).

Gleim et al. (2014) evaluated the effects of long-term prescribed burning on tick population dynamics in southwestern Georgia and northwestern Florida. Results of their study, which considered differences in vegetation and microclimate, suggest that prescribed burning reduces tick counts. However, the ticks sampled by the researchers after prescribed burning were not tested for disease-causing pathogens.

To be successful, efforts to prevent Lyme disease and other tick-borne diseases require adequate support for surveillance activities. Surveillance is most likely to be effective when it determines the density of tick populations in a given area and identifies the species comprising those populations. Given the continued emergence of tick-borne diseases and pathogens, surveillance efforts should encompass all tick species that are considered vectors. Testing ticks for established and newly emerging pathogens is also warranted (Petersen et al., 2015).

Although the incidence of Lyme disease is higher in the northeastern and upper midwestern regions of the United States, broader surveillance is needed to determine the risk of acquiring the disease in other areas of North America. As reported by Feria-Arroyo et al. (2014), the southern United States is typically portrayed as low risk for Lyme disease. Yet southern states experience a steady number of Lyme disease cases each year. Moreover, contrary to the findings of previous research, results of the study by Feria-Arroyo et al. indicate that much of eastern Texas and northeastern Mexico is either already home to, or capable of sustaining, populations of *I. scapularis*. And *B. burgdorferi*was present in 45% of the *I. scapularis*sampled in the study.

The question of how host availability affects tick abundance and tick distribution merits further investigation. Migratory birds, deer, and cattle are commonly assumed to be the primary hosts of ticks (Ogden et al., 2010; Feria-Arroyo et al., 2014; Petersen et al., 2015). However, other vertebrates may play a role in expanding the geographic range of ticks and tick-borne pathogens. For example, the *Ornithodoros turicata*—a vector of the relapsing fever spirochete *B. turicatae*—reportedly feeds on a wide range of mammals (including humans), reptiles, and birds, but is almost never found attached to a vertebrate host (Donaldson et al., 2016). Additionally, tick distribution models should consider the role of humans’ domestic and international travel in the spread of tick-borne diseases (Feria-Arroyo et al., 2014).

Summary of Findings

Appropriateness and Importance

The topic is both appropriate and important.

Duplication

A new review would not be duplicative of an existing product. We found no systematic reviews related to the scope of the nomination.

Impact

A new systematic review may prove useful in the development of public health strategies to mitigate the impact of the growing threat of tick-borne diseases.

Feasibility

A new systematic literature review is likely feasible with some modifications to the selection criteria.

References

Andreassen, A., Jore, S., Cuber, P., Dudman, S., Tengs, T., Isaksen, K., ... Vainio, K. (2012). Prevalence of tick borne encephalitis virus in tick nymphs in relation to climatic factors on the southern coast of Norway. *Parasites & Vectors, 5*(177). doi:10.1186/1756-3305-5-177

Cheng, A., Chen, D., Woodstock, K., Ogden, N. H., Wu, X., Wu, J. (2017). Analyzing the potential risk of climate change on Lyme disease in Eastern Ontario, Canada using time series remotely sensed temperature data and tick population modelling. *Remote Sensing, 9*(6), 609-622. doi:10.3390/rs9060609

Donaldson, T. G., Pèrez de León, A. A., Li, A. Y., Castro-Arellano, I, Wozniak, E., Boyle, W. K., ... Lopez, J. E. (2016). Assessment of the geographic distribution of *Ornithodoros turicata*(Argasidae): Climate variation and host diversity. *PLOS Neglected Tropical Diseases, 10*(3), e0004383. doi:10.1371/journal.pntd.0004383

Estrada-Peña, A., Cutler, S., Potkonjak, A., Vassier-Tussaut, M., Van Bortel, W., Zeller, H., ... Mihalca, A. D. (2018). An updated meta-analysis of the distribution and prevalence of *Borrelia burgdorferi*s.l. in ticks in Europe. *International Journal of Health Geographics, 17*(41). doi:10.1186/s12942-018-0163-7

Estrada-Peña, A., de la Fuente, J., Latapia, T., Ortega, C. (2015). The impact of climate trends on a tick affecting public health: A retrospective modeling approach for *Hyalomma marginatum*(Ixodidae). *PLOS ONE, 10*(5), e0125760. doi:10.1371/journal.pone.0125760

Estrada-Peña, A., Estrada-Sánchez, D. (2014). Deconstructing *Ixodes ricinus*: A partial matrix model allowing mapping of tick development, mortality and activity rates. *Medical and Veterinary Entomology, 28*(1), 35-49. doi:10.1111/mve.12009

Feria-Arroyo, T. P., Castro-Arellano, I., Gordillo-Perez, G., Cavazos, A. L., Vargas-Sandoval, M., Grover, A., ... Esteve-Gassent, M. D. (2014). Implications of climate change on the distribution of the tick vector *Ixodes scapularis*and risk for Lyme disease in the Texas- Mexico transboundary region. *Parasites & Vectors, 7*(199). doi:10.1186/1756-3305-7-199

Gasmi, S., Bouchard, C., Ogden, N. H., Adam-Poupart, A., Pelcat, Y., Rees, E. E., ... Thivierge, K. (2018). Evidence for increasing densities and geographic ranges of tick species of public health significance other than *Ixodes scapularis*in Québec, Canada. *PLOS ONE, 13*(8), e0201924. doi:10.1371/journal.pone.0201924

Ginsberg, H. S., Albert, M., Acevedo, L., Dyer, M. C., Arsnoe, I. M., Tsao, J. I., ... LeBrun, R. A. (2017). Environmental factors affecting survival of immature *Ixodes scapularis*and implications for geographical distribution of Lyme disease: The climate/behavior hypothesis. *PLOS ONE, 12*(1), e0168723. doi:10.1371/journal.pone.0168723

Gleim, E. R., Conner, L. M., Berghaus, R. D., Levin, M. L., Zemtsova, G. E., Yabsley, M. J. (2014). The phenology of ticks and the effects of long-term prescribed burning on tick population dynamics in southwestern Georgia and northwestern Florida. *PLOS ONE, 9*(11), e112174. doi:10.1371/journal.pone.0112174

Gray, E. B., & Herwaldt, B. L. (2019). Babesiosis surveillance--United States, 2011–2015. *MMWR Surveillance Summaries, 68*(6), 1-11. Retrieved from https://www.cdc.gov/mmwr/volumes/68/ss/ss6806a1.htm

Hauser, G., Rais, O., Morán Cadenas, F., Gonseth, Y., Bouzelboudjen, M., Gern, L. (2018). Influence of climatic factors on *Ixodes ricinus*nymph abundance and phenology over a long-term monthly observation in Switzerland (2000–2014). *Parasites & Vectors, 11*(289). doi:10.1186/s13071-018-2876-7

Jaenson, T. G. T., Petersson, E. H., Jaenson, D. G. E., Kindberg, J., Pettersson, J. H.-O., Hjertqvist, M., ... Bengtsson, H. (2018). The importance of wildlife in the ecology and epidemiology of the TBE virus in Sweden: Incidence of human TBE correlates with abundance of deer and hares. *Parasites & Vectors,*11(477). doi:10.1186/s13071-018-3057-4

Jore, S., Vanwambeke, S. O., Viljugrein, H., Isaksen, K., Kristoffersen, A. B., Woldehiwet, Z., ... Hofshagen, M. (2014). Climate and environmental change drives *Ixodes ricinus*geographical expansion at the northern range margin. *Parasites & Vectors, 7*(11). doi:10.1186/1756- 3305-7-11

Korotkov, Y. U., Kozlova, T., Kozlovskaya, L. (2015). Observations on changes in abundance of questing *Ixodes ricinus*, castor bean tick, over a 35-year period in the eastern part of its range (Russia, Tula region). *Medical and Veterinary Entomology, 29*(2), 129-136. doi:10.1111/mve.12101

MacDonald, A. J. (2018). Abiotic and habitat drivers of tick vector abundance, diversity, phenology and human encounter risk in southern California. *PLOS ONE, 13*(7), e0201665. doi:10.1371/journal.pone.0201665

Ogden, N. H., Bouchard, C., Kurtenbach, K., Margos, G., Lindsay, L. R., Trudel, L., ... Milord, F. (2010). Active and passive surveillance and phylogenetic analysis of *Borrelia burgdorferi*elucidate the process of Lyme disease risk emergence in Canada. *Environmental Health Perspectives, 118*(7). doi:10.1289/ehp.0901766

Ogden, N. H., Radojević, M., Wu, X., Duvvuri, V. R.; Leighton, P. A.; Wu, J. (2014). Estimated effects of projected climate change on the basic reproductive number of the Lyme disease vector *Ixodes scapularis*. *Environmental Health Perspectives, 122*(6). doi:10.1289/ehp.1307799

Petersen, W. H., Foster, E., McWilliams, B., Irwin, W. (2015, January-March). Tick-borne disease surveillance. *U.S. Army Medical Department Journal,*49-55. Retrieved from https://ufdc.ufl.edu/AA00062689/00037/pdf

Raghavan, R. K., Goodin, D. G., Neises, D., Anderson, G. A., Ganta, R. R. (2016). Hierarchical Bayesian spatio-temporal analysis of climatic and socio-economic determinants of Rocky Mountain spotted fever. *PLOS ONE, 11*(3), e0150180. doi:10.1371/journal.pone.0150180

Raghavan, R. K., Peterson, A. T., Cobos, M. E.; Ganta, R., Foley, D. (2019). Current and future distribution of the lone star tick, *Amblyomma americanum*(L.) (Acari: Ixodidae) in North America. *PLOS ONE, 14*(1), e0209082. doi:10.1371/journal.pone.0209082

Sage, K. M., Johnson, T. L., Teglas, M. B., Nieto, N. C., Schwan, T. G. (2017). Ecological niche modeling and distribution of *Ornithodoros hermsi*associated with tick-borne relapsing fever in western North America. *PLOS Neglected Tropical Diseases, 11*(10), e0006047. doi:10.1371/journal.pntd.0006047

Appendix A: Selection Criteria Assessment, Search Strategy

A literature search was conducted using EBSCOhost in August 2019. Keywords and exclusion criteria were derived from the criteria set forth in the PICOTS. Additional articles were excluded when:

the full article was missing or there was not enough information in the abstract,
	the article was not from a peer-reviewed scholarly journal, or
	the article was not relevant to the topic area.EBSCOhost search terms
			Initial Search Results“tick population” AND “increase"
			21“tick” AND “climate variability”
			110“tick” AND “climate change”
			209“tick population” AND “management”
			16“tick” AND “integrated management”
			18"tick host" AND "management"
			9“Ixodes” AND “management”
			87"Ixodes host" AND "management"
			0"Ixodes” AND “host" AND "management"
			54Topic Development Brief on Diagnostic Tests for Tick-Borne Diseases

Results of Topic Selection Process & Next Steps

The Tick-Borne Disease Working Group is interested in using an assessment of available literature to research the current diagnostic tests available for the following tick-borne diseases:

anaplasmosis,
	babesiosis,
	*Borrelia miyamotoi*disease,
	Bourbon virus disease,
	Colorado tick fever (CTF),
	ehrlichiosis,
	Heartland virus disease,
	Lyme disease,
	Powassan virus disease,
	Southern Tick-Associated Rash Illness (STARI),
	Tick-borne Relapsing Fever (TBRF),
	tularemia, and
	alpha-gal allergy.The authors of this topic brief identified one systematic literature review and a reference manual that address diagnostics for most, but not all, of the above-mentioned tick-borne diseases. There is a limited amount of original research on the topic areas that are not addressed in the systematic review or reference manual. Therefore, a new systematic literature review is not feasible at this time.

Topic Brief

*Topic Name*:  Diagnostic Tests for Tick-Borne Diseases*Topic Brief Date*:  September 6, 2019*Date of Nomination*:  July 18, 2019*Working Group Leads*:  Leigh Ann Soltysiak, MS, and Charles Benjamin Beard, PhD*Authors*:  Selena Gonzales, MPH, and Christina Li, MPH*Conflict of Interest*:  The nominators and authors have no affiliations or financial involvement that conflict with the material presented in this report.

Background

Tick-borne diseases are an increasingly common cause of illness and disability. Notably, 18 tick-borne pathogens are currently recognized by the U.S. Centers for Disease Control and Prevention (CDC). That number is expected to rise, given ongoing surveillance efforts. One such finding is the identification of the alpha-gal allergy. It is suspected that tick bites may cause this allergy, but more research is needed to confirm this (CDC, 2019).

Accurate and rapid diagnosis of tick-borne infections, followed by prompt treatment, can decrease the severity and duration of illness and, in some cases, prevent death. Various tests for tick-borne infections are available (see Appendix A). However, each test has performance issues that limit their usability and affect their interpretation.

Work is underway to improve currently available diagnostics and develop new tests in an effort to enhance long-term health outcomes among patients with tick-borne diseases.

Topic Nomination Development

Key Question

The key question for this topic nomination is: What are the current diagnostic tests available for tick-borne diseases, and what is the state of the tests?

Proposed Guiding Questions

Based on the variable level of evidence development, we proposed the following guiding questions.

What are the current and future diagnostic tests/assays for tick-borne diseases?
	What is the state of the science for diagnostic tests, including direct diagnostic tests (antigen, DNA, RNA), for tick-borne diseases?
	What are the technological challenges to the utilization and development of diagnostic tests?
	Utilization: Identify key challenges/gaps with the current diagnostic tests/assays utilized for tick-borne diseases (accuracy, conflicting tests, other).
		Technical: What are the biggest challenges when developing new diagnostic tests?
	What is the current range of clinical and economic diagnostic test practices for tick- borne disease diagnosis and treatment?Proposed PICOTS

To define inclusion criteria for the key question, we specified the PICOTS.

Key Question and PICOTS
			Topic InformationKey Question
			What are the current diagnostic tests available for tick-borne diseases, and what is the state of the tests?Population
			People at risk for, or diagnosed with tick-borne diseasesInterventions/Indicators
			All diagnostic tests available for tick-borne diseases; most utilized diagnostic tests available for tick-borne diseasesComparators
			Compare findings from interventions/indicatorsOutcomes
			A catalog of the current state of all diagnostic tests available for tick-borne diseasesTiming
			Past 20 years (1998–2018)Setting
			Not applicableMethods

We assessed the nomination of Diagnostic Tests for Tick-Borne Diseases as a topic brief priority using the following established selection criteria. Assessment of each criterion determined the need to evaluate the next one.

Determine the appropriateness of the topic.
	Establish the overall importance of the topic as representing a health or health care issue in the United States.
	Determine the desirability of a new evidence review by examining whether a new systematic literature review would be duplicative.
	Assess the potential impact of a new systematic literature review.
	Assess whether the current state of the evidence allows for a systematic literature review (feasibility).
	Determine the potential value of a new systematic literature review.Results

Appropriateness and Importance

This topic is appropriate and important. The increasing incidence of tick-borne diseases poses a serious threat to public health (Gray & Herwaldt, 2019; Petersen, Foster, McWilliams, & Irwin, 2015; Raghavan, Goodin, Neises, Anderson, & Ganta, 2016; Raghavan, Peterson, Cobos, Ganta, & Foley, 2019). Early diagnosis and treatment have been shown to improve health outcomes for people diagnosed with Lyme disease and other tick-borne diseases (Aucott, Seifter, & Rebman, 2012; Prince, Shah, Martinez, & Moran, 2007). Improving currently available diagnostics and developing new tests for tick-borne diseases may result in better long-term health outcomes.

Desirability of a New Review/Duplication

A new systematic review would be partially duplicative of a systematic literature review (Waddell et al., 2016) and a reference manual (CDC, 2018b) identified by the authors of this topic brief. The systematic review addresses the accuracy of diagnostic tests for Lyme disease in humans. The reference manual, which is intended for health care professionals, lists the diagnostics available for most, but not all, of the tick-borne diseases listed on page 1 of this topic brief. (Notably, the manual does not cover STARI or alpha-gal allergy.)

Impact of a New Evidence Review

Given the limited amount of original research that addresses the topic’s scope, the impact of a new systematic literature review is likely to be low at this time.

Feasibility of a New Evidence Review

We conducted a literature search in EBSCOhost in August 2019 using the key question, guiding questions, and PICOTS to develop keyword searches. See Appendix B for the EBSCOhost search strategy. We also conducted a scan of public health-related Federal websites. See Appendix C for a list of those websites.

Currently, there are six registered clinical trials for diagnostic tests, but most of those trials are in the early recruiting phases. Therefore, data are unavailable. We also reviewed the literature for data on clinical diagnostic practices, payment for diagnostics, and the management of patient management issues as they relate to these practices. There were no literature and no data on these topics found in our review.

Discussion

Tick-borne diseases are an increasingly common cause of illness and disability. Ticks are found in various regions of the United States, and some tick species, such as *Ixodes scapularis*, can transmit two or more pathogens via a single bite (Nathavitharana & Mitty, 2015). Notably, CDC currently recognizes 18 tick-borne pathogens. That number is expected to rise, given ongoing surveillance efforts.

Accurate and rapid diagnosis of tick-borne infections, followed by prompt treatment, can decrease the severity and duration of illness and, in some cases, prevent death. Various tests for tick-borne infections are available (see Appendix A). However, each test has performance issues that limit their usability and affect their interpretation. The following sections provide an overview of diagnostic challenges and feature highlights from the literature, as appropriate.

Limitations of Diagnostic Tests Available for Lyme Disease

Lyme disease is caused by an infection with *Borrelia burgdorferi*. Tests intended to detect the pathogen’s presence—i.e., polymerase chain reaction (PCR) and bacterial isolation by culture— are commercially available. However, because of biologic limitations, PCR and bacterial isolation are not routinely used to diagnose Lyme disease and are not licensed by the U.S. Food and Drug Administration (FDA) for that purpose (Waddell et al., 2016). Therefore, serologic testing for the presence of antibodies to the pathogen is the primary means of diagnosing Lyme disease in the laboratory.

Until recently, CDC recommended a particular two-step process of serologic testing. The first step involved either an enzyme immunoassay (EIA) or immunofluorescence assay (IFA). If the EIA or IFA test result was positive or equivocal, then a western immunoblot assay (better known as a western blot) would follow (Mead, Petersen, & Hinckley, 2019). In July 2019, FDA cleared new indications for four tests that can be used to diagnose Lyme disease (FDA, 2019). Accordingly, CDC’s Lyme disease testing algorithm now allows for the use of an EIA instead of a western blot in the second step of the two-step process (Mead, Petersen, & Hinckley, 2019).

Unfortunately, serologic tests for Lyme disease have several limitations. For instance, the tests are not likely to detect antibodies to *B. burgdorferi*during the first few weeks of infection. Also, because serologic tests are unable to distinguish between active and past infection with *B. burgdorferi*, they should not be relied upon to measure a patient’s response to treatment for Lyme disease. Finally, EIA and IFA have low specificity, meaning that patients without infection are likely to have a false positive result when undergoing either serologic test (CDC, 2018b).

Waddell et al. (2016) conducted a systematic review of evidence on the accuracy of tests and testing regimens used to diagnose Lyme disease in North America. Given the expected sensitivities and specificities of the tests available, the authors concluded that clinicians should base their diagnoses on the presence of signs and symptoms that are typical for each stage of illness, rather than relying entirely on imperfect serologic test protocols. The authors also reported a high prevalence of antibodies that cross-react in serologic tests for *B. burgdorferi*.

Challenges Hindering Diagnosis of Other Tick-Borne Diseases

Many challenges hinder the accurate and timely diagnosis of tick-borne infections other than Lyme disease. For instance, clinicians may not always know when to test for a specific tick- borne disease, because (Nathavitharana & Mitty, 2015; Wilder et al., 2015; Sosa-Gutierrez et al., 2016; Morshed et al., 2017; CDC, 2018b):

the patient’s symptoms may resemble those seen with other infections,the clinician may be unaware that tick-borne diseases are present in the area where a patient lives or has traveled, and/or
	the patient may not recall being bitten by a tick.Moreover, clinical manifestations may not become apparent until several weeks or months after infection with a tick-borne pathogen (CDC, 2018b). And in the case of alpha-gal allergy, symptoms may not occur after every exposure to products containing the allergen that causes illness (CDC, 2019).

Additionally, tests for tick-borne infections have limitations. For example, as mentioned previously, the potential for cross-reactivity can affect the diagnostic accuracy of EIA and IFA (Waddell et al., 2016; CDC, 2018b). Also, serologic tests may be unable to detect antibodies against a disease-causing pathogen during the early stages of infection (CDC, 2018b). And culture and PCR may only be useful during the first week or two of illness (CDC, 2018b).

Furthermore, accurate diagnosis of infections such as babesiosis and *B. miyamotoi*disease may require the expertise of a reference laboratory (CDC, 2018b). In the case of illness caused by Bourbon virus disease, Heartland virus disease, Powassan virus disease, or STARI, the availability of routine testing may be limited or non-existent (CDC, 2018a; CDC, 2018b).

Ongoing and Future Efforts to Overcome Diagnostic Challenges

To improve long-term health outcomes, many researchers are working to develop new tests for tick-borne infections or improve currently available diagnostics.

The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, partners with CDC to support various research projects aimed at improving Lyme disease diagnostics. Some promising approaches include (NIAID, 2018):

the development of a new cytokine-based immunoassay that would allow for earlier and faster diagnosis of Lyme disease;
	a new diagnostic that uses lateral flow technologies;
	the identification and characterization of metabolic biomarkers and biosignatures for diagnosis of Lyme disease during its early stages or assessment of a patient’s response to treatment; and
	the use of newly available genetic information combined with advances in microarray technology, imaging, and proteomics.Work is also underway to develop tests that would distinguish between people with active *B. burgdorferi*infection and those with antibodies against *B. burgdorferi*as the result of receipt of Lyme disease vaccine, which was used in the United States, between 1998 and 2002 (NIAID, 2018). Additionally, scientists are investigating approaches to improve Lyme disease diagnosis in patients who are co-infected with *B. burgdorferi*and other tick-borne pathogens (NIAID, 2018).

A number of researchers have focused on the potential applications of PCR to help detect tick- borne infections. Recently published work by Hansmann et al. (2019) indicates that a combination of PCR and serology should be used to diagnose anaplasmosis. A case review by Morshed et al. (2017) demonstrates that PCR and Giemsa stain testing are the most sensitive methods for detecting infection with the spirochetes that cause TBRF. Additionally, several other studies (Chan, Marras, & Parveen, 2013; Akoolo et al., 2017; Primus et al., 2018) suggest multiplex quantitative PCR might be useful for detection of the pathogens that cause anaplasmosis, babesiosis, and Lyme disease.

However, an investigation conducted in Russia by Karan et al. (2018) showed poor sensitivity of quantitative PCR for the detection of *B. burgdorferi sensu lato*RNA. The study also demonstrated that PCR detects *B. miyamotoi*disease only during the first few days of infection. Clearly, more work is needed to better define the applications of PCR in the area of tick-borne diseases.

Another area of interest to researchers is advances in serologic testing. A study by Wilder et al. (2015) found that serologic responses to two antigens—recombinant glycerophosphodiester phosphodiesterase (rGlpQ) and recombinant *Borrelia*immunogenic protein A (rBipA)—can be useful for diagnosing TBRF, a disease for which serologic tests remain commercially unavailable. More recently, a retrospective serologic analysis by Vázquez-Guerrero et al. (2019) confirms rGlpQ and rBipA can be used to discriminate between *Borrelia*infections that cause TBRF and those that cause Lyme disease. Further, a study by Lindsey et al. (2019) suggests that a plaque reduction neutralization test, which can differentiate between related phleboviruses, might enhance our ability to detect antibodies to Heartland virus.

Summary of Findings

Appropriateness and Importance

The topic is appropriate and important.

Desirability of a New Review/Duplication

A new systematic literature review would be partially duplicative.

Impact of a New Evidence Review

The impact of a new systematic literature review is likely to be low.

Feasibility of a New Evidence Review

We identified a systematic literature review and one reference manual that partially address the topic’s scope. There is limited original research for the portion of this nomination that is not addressed in the systematic review and reference manual. A new systematic literature review is not feasible at this time.

References

Akoolo, L., Schlachter, S., Khan, R., Alter, L., Rojtman, A. D., Gedroic, K., ... Parveen, N. (2017). A novel quantitative PCR detects Babesia infection in patients not identified by currently available non-nucleic acid amplification tests. *BMC Microbiology, 17,*1-9. doi:10.1186/s12866-017-0929-2

Aucott, J. N., Seifter, A., & Rebman, A. W. (2012). Probable late Lyme disease: A variant manifestation of untreated *Borrelia burgdorferi*infection. *BMC Infectious Diseases, 12*(1), 173-182. doi:10.1186/1471-2334-12-173

Centers for Disease Control and Prevention (CDC). (2018a). *Southern Tick-Associated Rash Illness: Symptoms, Diagnosis and Treatment.*Retrieved from https://www.cdc.gov/stari/symptoms/index.html

CDC. (2018b). *Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers*(5th ed.). Retrieved from https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf

CDC, National Center for Emerging and Zoonotic Infectious Diseases, Division of Vector-Borne Diseases. (2019). *Alpha-gal Allergy.*Retrieved from https://www.cdc.gov/ticks/alpha- gal/index.html

Chan, K., Marras, S. A. E., & Parveen, N. (2013). Sensitive multiplex PCR assay to differentiate Lyme spirochetes and emerging pathogens *Anaplasma phagocytophilum*and *Babesia microti*. *BMC Microbiology, 13*(1), 295. doi:10.1186/1471-2180-13-295

Food and Drug Administration. (2019, July 29). *FDA Clears New Indications for Existing Lyme Disease Tests that May Help Streamline Diagnosis.*Retrieved from https://www.fda.gov/news-events/press-announcements/fda-clears-new-indications- existing-lyme-disease-tests-may-help-streamline-diagnoses

Gray, E. B., & Herwaldt, B. L. (2019). Babesiosis surveillance--United States, 2011–2015. *Morbidity and Mortality Weekly Report (MMWR) Surveillance Summaries, 68*(6),1-11. Retrieved from https://www.cdc.gov/mmwr/volumes/68/ss/ss6806a1.htm

Hansmann, Y., Jaulhac, B., Kieffer, P., Martinot, M., Wurtz, E., Dukic, R., ... De Martino, S. (2019). Value of PCR, serology, and blood smears for human granulocytic anaplasmosis diagnosis, France. *Emerging Infectious Diseases, 25*(5), 996-998. doi:10.3201/eid2505.171751

Karan, L., Makenov, M., Kolyasnikova, N., Stukolova, O., Toporkova, M., & Olenkova, O. (2018). Dynamics of spirochetemia and early PCR detection of *Borrelia miyamotoi*. *Emerging Infectious Diseases, 24*(5), 860-867. doi:10.3201/eid2405.170829

Lindsey, N. P., Menitove, J. E., Biggerstaff, B. J., Turabelidze, G., Parton, P., Peck, K., ... Staples, J. E. (2019). Seroprevalence of Heartland virus antibodies in blood donors, northwestern Missouri, USA. *Emerging Infectious Diseases, 25*(2), 358-360. doi:10.3201/eid2502.181288

Mead, P., Petersen, J., & Hinckley A. (2019). Updated CDC recommendation for serologic diagnosis of Lyme disease. *MMWR, 68*(32), 703. Retrieved from https://www.cdc.gov/mmwr/volumes/68/wr/pdfs/mm6832a4-H.pdf

Morshed, M. G., Drews, S. J., Lee, M.-K., Fernando, K., Man, S., Mak, S., ... Patrick, D. (2017). Tick-borne relapsing fever in British Columbia: A 10-year review (2006-2015). *British Columbia Medical Journal, 59*(8), 412-417. Retrieved from https://www.researchgate.net/publication/320539623_Tick- borne_relapsing_fever_in_British_Columbia_A_10-year_review_2006-2015

Nathavitharana, R. R., & Mtty, J. A. (2015). Diseases from North America: Focus on tick-borne infections. *Clinical Medicine, 15*(1), 74-77. doi:10.7861/clinmedicine.14-6-74

National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. (2018). *Lyme Disease Diagnostics Research.*Retrieved from https://www.niaid.nih.gov/diseases-conditions/lyme-disease-diagnostics-research

Petersen, W. H., Foster, E., McWilliams, B., Irwin, W. (2015, January-March). Tick-borne disease surveillance. *U.S. Army Medical Department Journal,*49-55. Retrieved from https://ufdc.ufl.edu/AA00062689/00037/pdf

Primus, S., Akoolo, L., Schlachter, S., Gedroic, K., Rojtman, A. D., Parveen, N. (2018). Efficient detection of symptomatic and asymptomatic patient samples for *Babesia microti*and *Borrelia burgdorferi*infection by multiplex qPCR. *PLOS ONE, 13*(5), e0196748. doi:10.1371/journal.pone.0196748

Prince, L. K., Shah, A. A., Martinez, L. J., Moran, K. A. (2007). Ehrlichiosis: Making the diagnosis in the acute setting. *Southern Medical Journal, 100*(8), 825-828. doi:10.1097/SMJ.0b013e31804aa1ad

Raghavan, R. K., Goodin, D. G., Neises, D., Anderson, G. A., Ganta, R. R. (2016). Hierarchical Bayesian spatio-temporal analysis of climatic and socio-economic determinants of Rocky Mountain spotted fever. *PLOS ONE, 11*(3), e0150180. doi:10.1371/journal.pone.0150180

Raghavan, R. K., Peterson, A. T., Cobos, M. E., Ganta, R., Foley, D. (2019). Current and future distribution of the lone star tick, *Amblyomma americanum*(L.) (Acari: Ixodidae) in North America. *PLOS ONE, 14*(1), e0209082. doi:10.1371/journal.pone.0209082

Sosa-Gutierrez, C. G., Solorzano-Santos, F., Walker, D. H., Torres, J., Serrano, C. A., Gordillo- Perez, G. (2016). Fatal monocytic ehrlichiosis in woman, Mexico, 2013. *Emerging Infectious Diseases, 22*(5), 871-874. doi:10.3201/eid2205.151217

Vázquez-Guerrero, E., Adan-Bante, N. P., Mercado-Uribe, M. C., Hernández-Rodríguez, C., Villa- Tanaca, L., Lopez, J. E., & Ibarra, J. A. (2019). Case report: A retrospective serological analysis indicating human exposure to tick-borne relapsing fever spirochetes in Sonora, Mexico. *PLOS Neglected Tropical Diseases, 13*(4), e0007215. doi:10.1371/journal.pntd.0007215

Waddell, L. A., Greig, J., Mascarenhas, M., Harding, S., Lindsay, R., Ogden, N. (2016). The accuracy of diagnostic tests for Lyme disease in humans, a systematic review and meta- analysis of North American research. *PLOS ONE, 11*(12), e0168613. doi:10.1371/journal.pone.0168613

Wilder, H. K., Wozniak, E., Huddleston, E., Tata, S. R., Fitzkee, N. C., Lopez, J. E. (2015). Case report: A retrospective serological analysis indicating human exposure to tick-borne relapsing fever spirochetes in Texas. *PLOS Neglected Tropical Diseases, 9*(4), e0003617. doi:10.1371/journal.pntd.0003617

Appendix A. Tick-Borne Diseases: Laboratory Diagnosis and Diagnostic Limitations

Serologic assays (IgM- capture EIA, indirect fluorescent antibody, and plaque-reduction neutralization) on convalescent samples

Tick-Borne Disease
			Laboratory Diagnosis
			LimitationsAnaplasmosis
			Detection of DNA by polymerase chain reaction (PCR) of whole blood
				IgG-specific antibody titer by indirect immunofluorescence antibody (IFA) assay in paired serum samples
				Immunohistochemical (IHC) staining of organism from biopsies
			Sensitivity decreases after the first week of illness and may decrease after tetracycline-class antibiotics
				First sample should be taken within the first week of illness, and the second sample should be taken 2–4 weeks later
				Antibody titers are frequently negative in the first 7–10 days of illness
				Blood smear examination is insensitive and should never be relied upon as the sole means of diagnosing or ruling out anaplasmosisBabesiosis
			Light-microscopic examination of a peripheral blood smear
				PCR analysis
				Isolation of parasites from whole blood specimen by animal inoculation
				IgG-specific antibody titer by indirect IFA assay can be used to support diagnosis
			Manual (nonautomated) review of blood smears should be explicitly requested
				Multiple smears may need to be examined
				A reference laboratory may need to confirm the diagnosis and species, as it can be difficult to distinguish between *Babesia*and malaria parasites
				Antibody detection by serologic testing does not reliably distinguish between active and prior infection*Borrelia miyamotoi* disease
			Diagnosis relies on signs and symptoms coupled with:
			PCR tests that detect DNA from the organism
				Antibody-based tests
				C6 peptide ELISA test (under review)
			Tests are available from a limited number of CLIA-approved reference laboratoriesBourbon virus disease
			No routine testing available
				CDC provides reference diagnostic testing for this agent at the request of state health departments
				Lab findings include leukopenia and thrombocytopenia
			No routine testing availableColorado tick fever
			Culture and RT-PCR
				Serologic assays (IgM- capture EIA, indirect fluorescent antibody, and plaque-reduction neutralization) on convalescent samples
			Culture and RT-PCR only during first 2 weeks of illness
				IgM antibodies do not usually appear until 14–21 days after onset of illnessEhrlichiosis
			Detection of DNA by PCR of whole blood
				IgG-specific antibody titer by indirect immunofluorescence antibody (IFA) assay in paired serum samples
				IHC staining of organism from biopsies of the skin, tissue, or bone marrow
			PCR of whole blood is most sensitive during the first week of illness and sensitivity can decrease after use of tetracycline-class antibiotics
				The first sample for antibody titer should be taken within the first week of illness, and the second should be taken 2–4 weeks laterHeartland virus disease
			No routine testing available
				CDC provides reference diagnostic testing for this agent at the request of state health departments
				People can be tested for evidence of Heartland virus RNS and IgM and IgG antibodies
			No routine testing availableLyme disease
			Diagnostic IgM or IgG antibodies in serum (EIA or IFA should be performed first, followed by a Western blot or second EIA)
				Isolation of organism from a clinical specimen
				Testing for intrathecal IgM or IgG antibodies may be helpful in suspected cases of Lyme meningitis
			Serologic tests are insensitive during the first few weeks of infection. Patients with an erythema migrans rash can be diagnosed clinically during this time.
				IgG testing should be performed (not IgM) in persons with illness >1 month.
				Single positive serologic test results cannot distinguish between active and past infection
				Enzyme immunoassay and immunofluorescence assay tests have low specificity and may yield false- positive resultsPowassan virus disease
			Testing available through CDC and selected state health departments
				Measurement of virus- specific IgM antibodies in serum or CSF
				RT-PCR may detect viral RNA in acute CSF specimens or tissues
			Limited commercial testing
				Cross-reaction with other flaviviruses can occur when measuring virus- specific IgM antibodies
				Sensitivity of RT-PCR is unknown and should not be used to rule out diagnosisSouthern tick- associated rash illness
			No routine blood testing available
			Not applicableTick-borne relapsing fever
			Microscopy or culture to detect organism in blood
				Peripheral blood smear with observations of *Borrelia*spirochetes
				Serologic testing for convalescent samples
			Blood must be obtained while person is febrile to detect organism via microscopy or culture
				Samples for serologic tests must be drawn 10–14 days post-illness onsetTularemia
			Isolation of *Francisella tularensis*from a clinical specimen
				Serum antibody titer to *F. tularensis*antigen between acute and convalescent specimens
				Direct immunofluorescence assay or PCR assay
			Not applicableAlpha-gal allergy
			Blood test for specific IgE antibodies to alpha-gal
			Not applicableSources

Centers for Disease Control and Prevention (CDC). (2018a). *Southern Tick-Associated Rash Illness: Symptoms, Diagnosis and Treatment.*Retrieved from https://www.cdc.gov/stari/symptoms/index.html

CDC. (2018b). *Tickborne Diseases of the United States: A Reference Manual for Healthcare Providers*(5th ed.). Retrieved from https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf

CDC, National Center for Emerging and Zoonotic Infectious Diseases, Division of Vector-Borne Diseases. (2019). *Alpha-gal allergy.*Retrieved from https://www.cdc.gov/ticks/alpha- gal/index.html

Mead, P., Petersen, J., & Hinckley A. (2019). Updated CDC recommendation for serologic diagnosis of Lyme disease. *Morbidity and Mortality Weekly Report, 68*(32), 703. Retrieved from https://www.cdc.gov/mmwr/volumes/68/wr/pdfs/mm6832a4-H.pdf

Appendix B. Selection Criteria Assessment and Search Strategy

A literature search was conducted using EBSCOhost in August 2019. Keywords and exclusion criteria were derived from the criteria set forth in the PICOTS. Additional articles were excluded when:

the full article was missing or there was not enough information in the abstract,
	the article was not from a peer-reviewed scholarly journal, or
	the article was not relevant to the topic area.To define inclusion criteria for the key question, we specified the PICOTS.

EBSCOhost search terms
			Initial Search Results“tick” AND “diagnostic” AND “United States”
			130“diagnostic test” AND “tick” AND “United States”
			2“Babesiosis” AND “diagnosis”
			297“Anaplasmosis” AND “diagnosis”
			154“Borrelia miyamotoi” AND “diagnosis”
			28“Ehrlichiosis” AND “diagnosis”
			209“Heartland” AND “virus”
			61“Powassan” AND “virus”
			97“Southern tick associated rash illness”
			36“Tick-borne relapsing fever”
			106“Cost” AND “tick-borne disease” AND “diagnostics”
			0“Cost” AND “tick” AND “diagnostics”
			3“Cost of Lyme diagnostics”
			1Appendix C. Federal Documents Reviewed

Centers for Disease Control and Prevention (CDC). (2018). *Tickborne Diseases of the Unites States: A Reference Manual for Healthcare Providers*(5th ed.). Retrieved from https://www.cdc.gov/ticks/tickbornediseases/TickborneDiseases-P.pdf

CDC, National Center for Emerging and Zoonotic Infectious Diseases, Division of Vector-Borne Diseases. (2019). *Alpha-gal Allergy.*Retrieved from https://www.cdc.gov/ticks/alpha- gal/index.html

Food and Drug Administration. (2019, July 29). *FDA Clears New Indications for Existing Lyme Disease Tests That May Help Streamline Diagnoses*. Retrieved from https://www.fda.gov/news-events/press-announcements/fda-clears-new-indications- existing-lyme-disease-tests-may-help-streamline-diagnoses

Mead, P., Petersen, J., Hinckley, A. (2019). Updated CDC recommendation for serologic diagnosis of Lyme disease. *Morbidity and Mortality Weekly Report, 68*(32), 703. Retrieved from https://www.cdc.gov/mmwr/volumes/68/wr/mm6832a4.htm?s_cid=mm6832a4_w

National Institutes of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). (2018). *Lyme Disease Diagnostics Research.*Retrieved from https://www.niaid.nih.gov/diseases-conditions/lyme-disease-diagnostics-research

NIH U.S. National Library of Medicine. (n.d.). ClinicalTrials.gov. https://clinicaltrials.gov/

Topic Development Brief on Persistent Symptoms of Lyme Disease

Results of Topic Selection Process & Next Steps

The Tick-Borne Disease Working Group is interested in using an assessment of available literature to research the causes of persistent symptoms of Lyme disease.

There is a large volume of original research on this topic; however, the research is inconclusive. Although the impact of a new systematic literature review would be low, such a review is feasible at this time and may provide some direction for future research.

Topic Brief

*Topic Name:*  Persistent Symptoms of Lyme Disease*Topic Brief Date*:  September 6, 2019*Date of Nomination*:  July 19, 2019*Working Group Leads:*  Commander Rebecca Bunnell, MPAS, PA-C, and Sam T. Donta, MD*Authors:*  Selena Gonzales, MPH, and Christina Li, MPH*Conflict of Interest:*  The nominators and authors have no affiliations or financial involvement that conflict with the material presented in this report.

Background

Patients who have been diagnosed with Lyme disease are prescribed antibiotics to eliminate the causative pathogens and restore health. However, in many cases, symptoms of Lyme disease persist despite treatment. Examples of persistent symptoms, which can be severe, include arthralgia, musculoskeletal or radicular pain, paresthesia, dysesthesia with persistent fatigue, and neurocognitive impairment (Tjernberg, Carlsson, Ernerudh, Eliasson, & Forsberg, 2010).

The reasons for treatment-refractory symptoms of Lyme disease remain up for debate. Proposed causes of symptom persistence include (Bolz and Weis, 2004; Chandra et al, 2010; Singh & Girschick, 2004; Ekerfelt, Andersson, Olausson, Bergström, & Hultman, 2007; Bhanot & Parveen, 2019):

inadequate treatment,
	genomic differences among subspecies of *B. burgdorferi*,
	long-term persistence of the *B. burgdorferi*spirochete,
	the presence of one or more co-infections,
	the immune response to infection with *B. burgdorferi*, and
	autoimmunity involvement.An enhanced understanding of the reasons for symptom persistence following treatment for Lyme disease will bolster clinicians’ efforts to improve patient care and decrease the burdens associated with ongoing illness.

Topic Nomination Development

Nominator and Stakeholder Engagement

During a conference call with the nominators, we reviewed and clarified the key question, guiding questions, and PICOTS (population, interventions/indicators, comparators, outcomes, timing of interest, and setting). The nominators provided final approval of those items via email.

Key Question

The key question for this topic nomination is: What are the causes of persistent symptoms of Lyme disease in the United States and globally?

Proposed Guiding Questions

Based on the variable level of evidence development, we proposed the following guiding questions.

What is the evidence for persisting symptoms of Lyme disease in treated and untreated patients?
	What is/are the cause(s) of persistent symptoms? (Persisting infection, inadequate treatment, autoimmunity, other potential reasons, or a combination of causes?)
	What is the epidemiology of persisting symptoms of Lyme disease?Proposed PICOTS

To define inclusion criteria for the key question, we specified the PICOTS.

Key Question and PICOTS
			Topic InformationKey Question
			What are the causes of persistent symptoms of Lyme disease in the United States and globally?Population
			People diagnosed with Lyme disease exhibiting persistent symptomsInterventions/Indicators
			Adequate and timely treatment, autoimmune responses, other causesComparators
			Compare findings from interventions/indicatorsOutcomes
			Identifiable causes of persistent Lyme diseaseTiming
			Last 20 years (1998)Setting
			Not applicableMethods

We assessed the nomination of Persistent Symptoms of Lyme Disease as a topic brief priority using the following established selection criteria. Assessment of each criterion determined the need to evaluate the next one.

Determine the appropriateness of the topic.
	Establish the overall importance of the topic as representing a health or health care issue in the United States.
	Determine the desirability of a new evidence review by examining whether a new systematic literature review would be duplicative.
	Assess the potential impact of a new systematic literature review.
	Assess whether the current state of the evidence allows for a systematic literature review (feasibility).
	Determine the potential value of a new systematic literature review.Results

Appropriateness and Importance

This topic is appropriate and important. Persistent symptoms of Lyme disease cause significant short- and long-term disability. There are no nationally mandated surveillance data to illustrate the extent of this public health issue, but cohort studies have shown anywhere between 10% and 40% of patients with Lyme disease continue to have persistent symptoms post-treatment.

Desirability of a New Review/Duplication

A new review would not be duplicative of an existing product. We found no systematic reviews related to the scope of the nomination.

Impact of a New Evidence Review

A 2019 invited review paper by Bhanot and Parveen references the mixed results of studies of antibiotic-refractory Lyme arthritis in mice. The authors also allude to our poor understanding of factors contributing to chronic/treatment-refractory inflammatory Lyme disease. These statements suggest the need for more research on the topic of persistent symptoms of Lyme disease. Therefore, the impact of a new evidence review is likely to be low.

Feasibility of a New Evidence Review

We conducted a search of surveillance systems managed by the U.S. Centers for Disease Control and Prevention (https://www.cdc.gov/ticks/surveillance/index.html) and the European Centre for Disease Prevention and Control (https://ecdc.europa.eu/en/surveillance-and-disease-data). Notably, neither surveillance system is used to collect information regarding the epidemiology of persistent symptoms of Lyme disease.

We also conducted a literature search in EBSCOhost in August 2019, using the key question, guiding questions, and PICOTS to develop keyword searches. See Appendix A for the EBSCOhost search strategy.

There is a large volume of original research on the topic of persistent symptoms of Lyme disease; however, the research is inconclusive. Although the impact of a new systematic literature review would be low, such a review is feasible at this time and may provide some direction for future research.

Discussion

In an effort to answer this topic brief’s key question and guiding questions, we conducted a preliminary assessment of the literature and identified several proposed causes of persistent symptoms of Lyme disease (Bolz and Weis, 2004; Chandra et al, 2010); Singh & Girschick, 2004; Ekerfelt et al., 2007; Bhanot & Parveen, 2019):

inadequate treatment,
	genomic differences among subspecies of *B. burgdorferi*,
	long-term persistence of the *B. burgdorferi*spirochete,
	the presence of one or more co-infections,
	the immune response to infection with *B. burgdorferi*, and
	autoimmunity involvement.Most of the studies identified in our literature assessment focus on either the immune response to infection or autoimmunity involvement. The following sections elaborate on our findings and feature highlights from the literature as appropriate. Readers should bear in mind that epidemiologic data on persistent symptoms of Lyme disease (also known as chronic Lyme disease) do not appear to be available at this time.

Immune Response to Infection

Many clinical trials have suggested that persistent symptoms of Lyme disease are the result of a patient’s immune response to infection with *B. burgdorferi*. A 2004 study by Fleming et al. found that levels of antibodies to C6—a peptide that reproduces a region of VlsE, the antigenic variation protein of *B. burgdorferi*—remain elevated in patients with persistent symptoms of Lyme disease. Notably, the authors concluded that the presence of C6 antibodies should not be viewed as evidence of active *B. burgdorferi*infection.

Somewhat more recently, another study (Stricker, Savely, Motanya, & Giclas, 2009) demonstrated that a lack of response to antibiotic therapy for Lyme disease is associated with a significant increase in levels of an immunologic marker known as complement split product C4a. More importantly, C4a levels were elevated in patients with persistent musculoskeletal symptoms of Lyme disease, but not in patients with persistent neurologic symptoms. Such findings suggest that the etiology of persistent symptoms of Lyme disease may depend on whether a patient’s symptoms are predominantly musculoskeletal or neurologic.

Ekerfelt et al., 2007, investigated cytokine responses in mice infected with *B. burgdorferi*. The researchers concluded that Type 1 T helper cell (Th1)-like responses during the early stages of infection are necessary for the eradication of *B. burgdorferi*. Their conclusion suggests an aberrant immune response fails to eradicate the initial infection and leads to persistent symptoms of Lyme disease.

Jarefors, Janefjord, Forsberg, Jenmalm, and Ekerfelt (2007) arrived at a similar conclusion. They assessed blood samples from patients with chronic Lyme borreliosis, patients with subacute Lyme borreliosis, asymptomatic individuals who tested positive for *Borrelia*, and healthy controls. *Chronic*was defined as having symptoms longer than 6 months, and *subacute*was defined as having symptoms for fewer than 6 months. Results of this study demonstrate the importance of having a strong Th1 response for a positive outcome among patients infected with a *Borrelia*spirochete. The results also indicate that an increase in regulatory T cells may cause immunosuppression in patients with chronic disease.

Autoimmunity Involvement

The question of whether long-term exposure to the *Borrelia*spirochete induces chronic autoimmune diseases remains up for debate. Many investigators specifically attribute Lyme arthritis (a commonly reported persistent symptom) to autoimmunity, with T lymphocytes playing a major role (Singh & Girschick, 2004).

A review paper by Bolz and Weis (2004) suggests that treatment-resistant Lyme arthritis might be due to a transition from infection-associated inflammatory arthritis to arthritis mediated by autoimmune T cells. The authors recommend further research into the pathologic potential of T cells that cross-react with human antigens, as such research would establish the importance of molecular mimicry in the development or maintenance of treatment-resistant Lyme arthritis.

Results of a study by Chandra et al. (2010) suggest a differential immune system response occurs in patients who continue to experience symptoms of Lyme disease despite treatment. The investigators used immunoblotting and immunohistochemistry to analyze serum samples from patients with persistent symptoms of Lyme disease, asymptomatic individuals who had been successfully treated for Lyme disease at least 2 years earlier, patients with systemic lupus erythematosus (SLE), and healthy controls.

Levels of antibodies to neural proteins were heightened in approximately half of the patients with persistent symptoms of Lyme disease, compared with 19% of individuals who had been successfully treated for Lyme disease and 15% of healthy controls. Notably, the heightened antibody response level in patients with persistent symptoms was statistically similar to that seen in patients with SLE, a multisystem autoimmune disease.

A more recent European study (Kubánek et al., 2012) highlights a possible link between susceptibility to persistent infection and the presence of organ-specific autoimmune diseases. Researchers hypothesized that infection with *B. burgdorferi sensu lato*was causing dilated cardiomyopathy (DCM) in areas where Lyme disease was endemic. To test that hypothesis, they conducted a comprehensive molecular analysis on endomyocardial biopsy specimens to assess the prevalence of *B. burgdorferi sensu lato*in individuals living in Lyme disease-endemic areas.

The study revealed a higher prevalence of the *Borrelia*pathogens in patients with recent-onset DCM, compared with patients in end-stage heart failure caused by coronary artery disease. Also, evidence of autoimmunity involvement was observed more frequently in patients who had DCM and evidence of infection with *B. burgdorferi sensu lato*, compared with patients who had DCM and no evidence of such infection.

Additionally, patients with DCM who were infected with *B. burgdorferi sensu lato*had a low prevalence of myocardial inflammation. Furthermore, they experienced modest improvement in left ventricular systolic function after treatment with antibiotics, suggesting they had been in the late stage of *Borrelia*infection.

These results suggest autoimmunity and myocardial persistence of *Borrelia*pathogens may be involved in the pathophysiology of DCM in individuals living in Lyme disease-endemic areas. However, as Kubánek et al. (2012) acknowledge, data showing an association between the incidence of Lyme disease and DCM in Europe were unavailable at the time of the study’s publication.

Future Research

Persistent symptoms of Lyme disease cause significant short- and long-term disability. Yet research on the causes of persistent symptoms has been inconclusive.

A 2019 invited review paper by Bhanot and Parveen references the mixed results of studies of antibiotic-refractory Lyme arthritis in mice. The authors also allude to our poor understanding of factors contributing to chronic/treatment-refractory inflammatory Lyme disease. These statements suggest the need for more research. Ultimately, such research will improve outcomes for patients with Lyme disease and decrease the burdens associated with ongoing illness.

Summary of Findings

Appropriateness and Importance

The topic is both appropriate and important.

Duplication

A new review would not be duplicative of an existing product. We found no systematic reviews related to the scope of the nomination.

Impact of a New Evidence Review

There is a large volume of original research on this topic. Most research is inconclusive and calls for additional research. Thus, the impact of a new evidence review is likely to be low.

Feasibility of a New Evidence Review

There is a large volume of original research on this topic; however, the research is inconclusive. A new systematic literature review will have a low impact, but is feasible at this time and may provide some potential direction for future research studies.

References

Bhanot, P., & Parveen, N. (2019). Investigating disease severity in an animal model of concurrent babesiosis and Lyme disease. *International Journal for Parasitology, 49*(2), 145- 151. doi:10.1016/j.ijpara.2018.06.006

Bolz, D. D., Weis, J. J. (2004). Molecular mimicry to *Borrelia burgdorferi:*Pathway to autoimmunity? *Autoimmunity, 37*(5), 387-392. doi:10.1080/08916930410001713098

Chandra, A., Wormser, G. P., Klempner, M. S., Trevino, R. P., Crow, M. K., Latov, N., & Alaedini, A. (2010). Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. *Brain, Behavior, and Immunity, 24*(6), 1018-1024. doi:10.1016/j.bbi.2010.03.002

Ekerfelt, C., Andersson, M., Olausson, A., Bergström, S., & Hultman, P. (2007). Mercury exposure as a model for deviation of cytokine responses in experimental Lyme arthritis: HgCl2 treatment decreases T helper cell type 1-like responses and arthritis severity but delays eradication of *Borrelia burgdorferi*in C3H/HeN mice. *Clinical and Experimental Immunology, 150*(1), 189-197. doi:10.1111/j.1365-2249.2007.03474.x

European Centre for Disease Prevention and Control. Surveillance and disease data. Retrieved from https://ecdc.europa.eu/en/surveillance-and-disease-data

Fleming, R. V., Marques, A. R., Klempner, M. S., Schmid, C. H., Dally, L. G., Martin, D. S., & Philipp, M. T. (2004). Pre-treatment and post-treatment assessment of the C6 test in patients with persistent symptoms and a history of Lyme borreliosis. *European Journal of Clinical Microbiology & Infectious Diseases, 23*(8), 615-618. doi:10.1007/s10096-004-1163-z

Jarefors, S., Janefjord, C. K., Forsberg, P., Jenmalm, M. C., & Ekerfelt, C. (2007). Decreased up- regulation of the interleukin-12Rβ2-chain and interferon-γ secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic *Borrelia-*exposed individuals. *Clinical and Experimental Immunology, 147*(1), 18-27. doi:10.1111/j.1365-2249.2006.03245.x

Kubánek, M., Šramko, M., Berenová, D., Hulínská, D., Hrbáčková, H., Malušková, J., ... & Kautzner, J. (2012). Detection of *Borrelia burgdorferi sensu lato*in endomyocardial biopsy specimens in individuals with recent-onset dilated cardiomyopathy. *European Journal of Heart Failure, 14*(6), 588-596. https://doi.org/10.1093/eurjhf/hfs027

Singh, S. K., & Girschick, H. J. (2004). Lyme borreliosis: From infection to autoimmunity. *Clinical Microbiology & Infection, 10*(7), 598-614. doi:10.1111/j.1469-0691.2004.00895.x

Stricker, R. B., Savely, V. R., Motanya, N. C., & Giclas, P. C. (2009). Complement split products C3a and C4a in chronic Lyme disease. *Scandinavian Journal of Immunology, 69*(1), 64-69. doi:10.1111/j.1365-3083.2008.02191.x

Tjernberg, I., Carlsson, M., Ernerudh, J., Eliasson, I., & Forsberg, P. (2010). Mapping of hormones and cortisol responses in patients after Lyme neuroborreliosis. *BMC Infectious Diseases, 10*(1), 20. doi:10.1186/1471-2334-10-20

U.S. Centers for Disease Control and Prevention. Tick surveillance. Retrieved from https://www.cdc.gov/ticks/surveillance/index.html

Appendix A: Selection Criteria Assessment, Search Strategy

A literature search was conducted using EBSCOhost in August 2019. Keywords and exclusion criteria were derived from the criteria set forth in the PICOTS. Additional articles were excluded when:

the full article was missing or there was not have enough information in the abstract,
	the article was not from a peer-reviewed scholarly journal, or
	the article was not relevant to the topic area.EBSCOhost search terms
			Initial Search Results"persistent symptoms" AND (Lyme OR ticks OR burgdorferi)
			41"autoimmunity" AND (Lyme OR tick OR burgdorferi)
			51("persistent" OR "chronic" OR "prolonged") AND (symptoms) AND (lyme OR ticks OR burgdorferi)
			268(symptoms) AND (lyme OR ticks OR ticks OR burgdorferi)
			681

                    
  


Content created by Office of Infectious Disease and HIV/AIDS Policy (OIDP) Content last reviewed October 29, 2019Back to top
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