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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A
Commissioned Papers

The Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science commissioned 10 papers on range of topics that were not covered in depth at the workshop. The committee felt these papers were necessary for the discussion at the workshop. These papers are reproduced in their entirety in this appendix.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A1
THROUGH A GLASS, DARKLY: THE GLOBAL INCIDENCE OF TICK-BORNE DISEASES

Christopher D. Paddock, M.D., M.P.H.T.M., and Sam R. Telford III, Sc.D.


Infectious Diseases Pathology Branch, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA

Division of Infectious Diseases, Department of Biomedical Sciences, Tufts University Cummings School of Veterinary Medicine

Corresponding author: Christopher D. Paddock


Infectious Diseases Pathology Branch, Bldg 18, Rm. SB 109, Mailstop G-32, Centers for Disease Control and Prevention


The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Introduction

Several events that occurred during the final decades of the 20th Century, and at the cusp of the 21st Century, suggest that increases in the scope and magnitude of tick-borne infections have occurred worldwide. These include recent national and regional epidemics of historically recognized diseases, including tick-borne encephalitis (TBE) in Central and Eastern Europe, Kyasanur forest disease (KFD) in Karnataka state in India, Crimean-Congo hemorrhagic fever (CCHF) in northern Turkey and the southwestern regions of the Russian Federation, and Rocky Mountain spotted fever (RMSF) in Arizona and Baja California (Randolph, 2008; Pattnaik, 2006; Maltezou et al., 2010; McQuiston et al., 2010; Bustamente Moreno and Pon Méndez, 2010a). Globally, the recognized number of distinct and epidemiologically important diseases transmitted by ticks has increased considerably during the last 30 years. By example, >10 newly recognized spotted fever rickettsioses have been identified since 1984 (Raoult et al., 1996; Parola et al., 2005; Paddock et al., 2008; Shapiro et al., 2010). In the United States, only 2 tick-borne diseases, RMSF and tularemia, were nationally notifiable in 1990; by 1998, this list included 3 newly recognized

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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infections: Lyme disease, human granulocytic ehrlichiosis [anaplasmosis] (Anaplasma phagocytophilum infection), and human monocytic ehrlichiosis (Ehrlichia chaffeensis infection), each of which has increased steadily in average annual incidence. Lyme disease is now the most commonly reported vector-borne illness in the United States, with the number of reported cases increasing 101% (from 9,908 to 19,931) during 1992-2006. (Bacon et al., 2008). During 2000-2008, the annual reported incidence of RMSF in the United States also increased dramatically, from 1.7 to 9.4 cases per million persons (Figure A1-1), representing the steepest rise to the highest rate ever recorded (Openshaw et al., 2010). From 2000-2007, the incidence of infections caused by A. phagocytophilum and E. chaffeensis also increased linearly, from 0.80 to 3.0, and 1.4 to 3.0, cases per million population, respectively (Dahlgren et al., in press).

Against this background of rapidly expanding pathogen recognition and escalating incidence have been concerns about the accuracy of case counts that form the basis for these statistics (Mantke et al., 2008; Raoult and Parola, 2008; Paddock, 2009). Many of these agents were catapulted into the realm of human recognition by extraordinary advances in molecular technology; however, epidemiologic tools for capturing cases and calculating incidence have not undergone similar transformative changes. Paradoxically, the discoveries of new pathogens made possible by contemporary diagnostic methods have cast suspicion on certain aspects of the

FIGURE A1-1 Average annual incidence of Rocky Mountain spotted fever and Lyme disease in the United States, 1992-2008 (Bacon et al., 2008; Openshaw et al., 2010).

FIGURE A1-1 Average annual incidence of Rocky Mountain spotted fever and Lyme disease in the United States, 1992-2008 (Bacon et al., 2008; Openshaw et al., 2010).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
×

distribution, frequency, and clinical heterogeneity of some older, historically recognized, tick-borne diseases. In essence, the pace of pathogen discovery has eclipsed fundamental epidemiologic knowledge of many of the diseases caused by these agents.

Incidence rates of tick-borne infections pale in comparison with those of many other arthropod-borne diseases, including malaria, dengue, Chagas’ disease, onchocerciasis, and leishmaniasis. Only Lyme disease, with tens of thousands of new cases each year, distributed across several continents, can be considered as prevalent across a wide distribution (Table A1-1). Lyme

TABLE A1-1 Estimated Global Incidence and Distribution of Major Tick-Borne Infections

Global Incidence and Distribution of Major Tick-Transmitted Infections

Very common (>10,000 new cases each year)

Lyme disease – Holarctic

(Bacon et al., 2008)

Common (1000-10,000 new cases each year)

Tick-borne encephalitis – Holarctic

(www.isw-tbe.info/upload/medialibrary/12th_ISW-TBE_Newsletter.pdf)

Tick-borne relapsing fever – tropical Africa; western United States

(Felsenfeld, 1971; Trape et al., 1996; Vial et al., 2006)

Tick-borne spotted fever group rickettsioses – global

(Rovery et al. 2008; Openshaw et al., 2010)

Ehrlichiosis and anaplasmosis – global

(Demma et al., 2005b)

Masters’ disease – eastern, central, and south-central United States

(CDC, 1990)

Crimean-Congo hemorrhagic fever–southern Europe, Africa, western and central

Russian Federation, North Asia

(www.ecdc.europa.eu/en/Publications/0809_MER_Crimean_Congo_Haemorrhagic_Fever_Prevention_and_Control.pdf)

Moderately common (100-1,000 new cases each year)

Colorado tick fever and other other coltivirus infections–western United States; central Europe

(http://www.cdphe.state.co.us/dc/zoonosis/tick/Colorado_tick_diseases.pdf)

Babesiosis – northeastern United States; Europe

(Telford et al., in press)

Omsk hemorrhagic fever – eastern Russia and Siberia

(Lvov, 1988)

Tick-borne tularemia – eastern and central United States; central Europe; Russian Federation

(CDC, 2002)

Kyasanur forest disease – Karnataka and adjacent states in India; Saudi Arabia; Egypt

(Dandawate et al., 1994; Pattnaik, 2006; Carletti et al., 2010)

Rare (sporadic cases)

Powassan/deer tick virus –Canada; northeastern and north central United States

(Ebel, 2010)

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
×

disease is still less common, by an order of magnitude, than leishmaniasis, represented by 1 million new cases a year among a population at risk of 350 million persons (Anonymous, 1994). Nonetheless, in some regions of the world, such as Europe, tick-borne diseases are the most widespread and medically important of all vector-borne infectious diseases (Randolph, 2010). In addition, some tick-borne diseases are associated with high case-fatality rates or long-term morbidity, and frequently generate considerable fear among the population who reside in areas where these pathogens are endemic; in this context, public health concerns may far exceed actual disease burden. By example, the average annual incidence of Brazilian spotted fever in São Paulo State, Brazil, during 2000-2008 ranged from 0.2 to 1.1 cases per million population, comprising only 285 total cases; however, 89 of these resulted in death, for an average case-fatality rate of 31% (www.cve.saude.sp.gov.br/htm/zoo/fm_i8503.htm). Other tick-borne diseases, including CCHF and KFD, are associated with high case-fatality rates that rival or exceed those of many of the most severe infectious diseases (Hoogstraal, 1979; Swanepoel et al., 1987; Pattnaik, 2006).

This discussion compares the perceived and actual burden of various tick-borne infections suggested by existing surveillance data, evaluates some of the strengths and limitations of current systems that measure incidence, and suggests several approaches for improving the accuracy of incidence determinations for these diseases. While tick-borne infections also pose important veterinary health problems around the world, this synopsis focuses on the occurrence of these diseases in human populations. Although this discussion also incorporates some information that is anecdotal, inferred, or derived from non-controlled circumstances, we hope that a contemporary synthesis of all observations may serve as a guide for subsequent epidemiologic approaches to this remarkably diverse and important collection of zoonotic diseases.

Case Counts, Reporting, and Incidence of Tick-Borne Diseases

Are the global rises in incidence reflective of true events or greater levels of reporting? Simplistically, increased reporting is indeed responsible for these trends; however, this question is somewhat circular, because incidence statistics are obtained principally from reported cases of disease. Incidence rates are dependent directly on the size of the population at risk during a specific interval of time and the number of identified cases of disease; however, from most of the scientific literature, it is difficult to determine whether a change in incidence reflects increased transmission, better reporting, or a change in the population at risk. Ideally, surveillance systems for tick-borne diseases accurately identify rises or declines of the disease in question; however, any of a number of variables may change

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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over time, including ecologic, climatologic, or social variables, case definitions, diagnostic assays, or the appearance or emigration of cognizant and enthusiastic clinicians who actively search for cases and specifically pursue confirmatory tests.

Incidence and Regional Context

Incidence statistics of tick-borne infections, when interpreted flatly as national rates, characteristically lose impact and meaning. These zoonoses are influenced profoundly by a complex mixture of predictable and unpredictable factors that include landscape, climate, wildlife hosts, and tick distributions that coalesce to create regional pockets of intensified risk (Pavlovskey, 1966); in this context, incidence rates for these diseases assume far greater impact when viewed regionally. Because of marked differences in population sizes across regions, it is axiomatic that high incidence does necessarily equate to a large number of reported cases. By example, sparsely populated Cameron County, Pennsylvania, reported only 14 cases of Lyme disease during 2002-2006; however, the county’s average annual incidence rate was greater than the incidence of the more populous Windham County, Connecticut, where approximately 18 × as many cases were reported during the same interval (Bacon et al., 2008). Nantucket County in Massachusetts, reported 151 cases of Lyme disease during 1992-2006, representing only 0.061% of 248,074 total reports received by CDC during this interval; however, it ranked highest in incidence of all U.S. counties during 1992-2001, and third during 2002-2006, with rates of 361 to 755 per 100,000 population (Figure A1-2A). By comparison, the average annual rate of Lyme disease in the entire state of Massachusetts was 14.5 per 100,000 population during the same study period (Bacon et al., 2008).

During 1989-2000, Portugal reported the highest country-wide incidence of Mediterranean spotted fever (MSF) in the Mediterranean basin (9.8 per 100,000 persons); however, the regional incidence in this country ranged markedly, from 3.1 per 100,000 in Lisboa and Vale do Teja, to 31 per 100,000 in the nearby region of Alentejo (de Sousa et al., 2003). During 2000-2007, 11,531 cases of RMSF were reported from 46 states and the District of Colombia; however, approximately two-thirds of these cases originated from only 5 states (Arkansas, Missouri, North Carolina, Oklahoma, and Tennessee), where the incidence ranged from 20.3 to 52.6 per million persons (Figure A1-2B). By comparison, the national incidence of RMSF during the study period was 4.9 per million (Openshaw et al., 2010). These statistics are magnified further when foci of infected ticks overlap rural or undeveloped regions with relatively low population density. During 2003-2009, 88 cases of RMSF were reported from 3 Apache Indian communities in Eastern Arizona that resulted in an average annual incidence of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A1-2 Average annual incidence, by county of residence, of reported cases of Lyme disease, 1992-2008 (a) and Rocky Mountain spotted fever, 2000-2007 (b), in the United States (Bacon et al., 2008; Openshaw et al., 2010).

FIGURE A1-2 Average annual incidence, by county of residence, of reported cases of Lyme disease, 1992-2008 (a) and Rocky Mountain spotted fever, 2000-2007 (b), in the United States (Bacon et al., 2008; Openshaw et al., 2010).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
×

437 /million persons for this 5,000 square mile region, more than 62 times greater than the national average (McQuiston et al., 2010). In some circumstances, regional variation develops when cultural, racial or socioeconomic homogeneity exists among the population at risk. By example, the incidence of RMSF among American Indians has risen dramatically (Figure A1-3), when compared with other racial groups in the United States: during 2001-2005, the average annual incidence among American Indians was 16.8 per 1,000,000 population, compared with rates of 4.2 and 2.6 among white and black racial groups, respectively (Holman et al., 2009).

Trends in Drequency and Distribution

Dramatic shifts in numbers of reported cases of tick-borne diseases over time and space are well-recognized; indeed, such shifts are epidemiologic hallmarks of many of these infections. National or regional trends are best characterized by surveillance systems with sufficient maturity and camber to accommodate for input that might otherwise immediately confound interpretation. The incidence of TBE in the Czech Republic has exhibited at least 4 cycles of rising and declining incidence since 1971, with the greatest upsurge occurring during 1990-1995, when the incidence climbed steadily from approximately 1.7 to 7.2 /100,000 population (Kriz et al., 2004). Similar increases were witnessed in several other eastern European countries

FIGURE A1-3 Annual incidence rates of Rocky Mountain spotted fever, per 1 million population, among American Indians, and the total U.S. population, 1992-2005 (Holman et al., 2009).

FIGURE A1-3 Annual incidence rates of Rocky Mountain spotted fever, per 1 million population, among American Indians, and the total U.S. population, 1992-2005 (Holman et al., 2009).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
×

during this same interval (Figure A1-4) (Šumilo et al., 2007; Randolph, 2008) and more recently, has extended across several countries of Western Europe, including Italy, Germany, and Switzerland, where the incidence of TBE in 2006 exceeded average levels for the previous decade by as much as 183% (Zimmerman, 2005; Randolph et al., 2008; Rizzoli et al., 2009).

In the United States, the annual incidence of RMSF has undergone 3 major shifts (Figure A1-5) since national surveillance for this disease was initiated in 1920 (Childs and Paddock, 2003; Openshaw et al., 2010). While average annual incidence rates of Lyme disease in the United States increased steadily during 1992-2006 (Figure A1-1), at least 88% of all U.S. cases reported in any given year, and 229,782 (92.6%) of the 248,074 cases reported cumulatively during this interval, originated consistently from the 10 states in which Lyme disease is highly endemic (Bacon et al., 2008). During the mid-1970s through the early 1980s, increases in the case numbers

FIGURE A1-4 Incidence of tick-borne encephalitis, per 100,000 population, in Lithuania, Latvia, and Estonia, 1970-2006 (Šumilo et al., 2007).

FIGURE A1-4 Incidence of tick-borne encephalitis, per 100,000 population, in Lithuania, Latvia, and Estonia, 1970-2006 (Šumilo et al., 2007).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A1-5 Average annual incidence of Rocky Mountain spotted fever, per 1 million population in the United States, 1920-2008 (Childs and Paddock, 2002; Openshaw et al., 2010).

FIGURE A1-5 Average annual incidence of Rocky Mountain spotted fever, per 1 million population in the United States, 1920-2008 (Childs and Paddock, 2002; Openshaw et al., 2010).

of reported spotted fever group rickettsioses were documented in several countries bordering the Mediterranean Sea, including Israel, Italy, and Spain (Piras et al., 1982; Segura and Font, 1982; Otero et al., 1982; Gross et al., 1982; Mansueto et al. 1986). Approximately 30 cases of MSF were reported in Italy each year during 1962-1973; however, during the next 6 years, the number of cases identified rose dramatically, to >800 annually by 1979 (Scaffidi, 1981). In the area of the Vallés Occidental near Barcelona, Spain, the incidence of MSF, per 100,000 persons, rose from 3.28 cases in 1979 to 19.05 cases in 1984 (Espejo Arenas et al., 1986). During the mid-1980s through the early 1990s, <20 cases of Japanese spotted fever were reported annually; during the subsequent 15 years, reports climbed steadily to 129 cases in 2009 (Anonymous, 1999; Anonymous, 2006; Anonymous, 2010).

Drivers of Incidence

Unfortunately, the reasons suggested for major periods of increased or diminished incidence of tick-borne diseases have, with few exceptions, been difficult to investigate and even more difficult to corroborate. These infections have circulated dynamically in nature for many thousands of years, and biological equilibria among the pathogen, tick, and vertebrate hosts parasitized by the tick or infected by the pathogen characteristically exist in

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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the absence of humans. Nonetheless, the emergence and flux of tick-borne diseases can most often be traced to specific human activities and behaviours that create disequilibrium in these cycles and position greater numbers of persons into disrupted ecosystems. Outbreaks of tick-borne disease are often linked to ecologic and social upheavals, resulting directly from human influence, that create circumstances advantageous for large numbers of ticks and reservoir hosts. During World War II, following the occupation of Crimea by Axis forces, there was abandonment of agricultural lands and diminished hunting of European hares (Lepus europaeus) because of combat activities. When Soviet troops reoccupied the Crimean steppes in 1944, pastures and farms had become overgrown by weeds, and hares had become extremely abundant and were heavily parasitized with Hyalomma ticks. The combination of these factors is believed to have contributed to an epidemic of CCHF among military personnel during 1944-1945, involving especially signalmen and surveyors, who frequented brushy areas (Hoogstraal, 1979).

A careful analysis of climatic and vegetation features with georeferenced cases of CCHF in Turkey during 2003-2008 identified a recent expansion of extensively fragmented habitats in the Anatolia region as the most important factor for the CCHF epidemic in this region. This process resulted from the loss of mature forests to farming activities, and the reversion of farms to dense undergrowth and subsequent to second growth forest with the emigration of persons from rural to urban areas (Estrada-Peña et al., 2010). In a similar manner, whole-scale clearing of primary old-growth forests by inhabitants in the northeastern United States in the late 18th and early 19th Centuries, followed by the abandonment of farms during the westward expansion of the late 19th Century, and subsequent deciduous successional growth that provided ideal habitats for white-tailed deer (Odocoileus virginianus) and deer ticks (Ixodes scapularis (dammini), fueled the emergence of Lyme disease in the second half of the 20th Century (Spielman et al., 1985). In Italy, changes in forest management practices during the last several decades of the 20th Century transitioned a greater percentage of coppice cover (small areas of broad-leaved forest harvested regularly for firewood) to high-stand forests and improving habitat suitability for small reservoir hosts of Ixodes ricinus ticks. This manipulation of forest structure is believed to have contributed to the steadily increasing incidence of TBE observed in 17 northern alpine provinces since the early 1990s (Rizzoli et al., 2009).

Tick Abundance and Distribution

Environmental disturbance is a frequent trigger for outbreaks of tick-borne infection. The most extensively studied example, Lyme disease in

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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the northeastern United States, resulted from reforestation, increased deer density, and increased development and use of forested sites by humans (Spielman et al., 1985). It is likely that the deer tick vector and its microbial guild survived in relict sites during and after glaciation and through Colonial times (Telford et al., 1993; Hoen et al., 2009). Infestations of the deer tick were first recognized from the terminal moraine areas of southern New England and Long Island as well as northwest Wisconsin; these were also the sites where the first cases of Lyme disease or babesiosis were identified in the United States (Spielman et al., 1985; Scrimenti, 1970; Western et al., 1970). In the mid-1980s, Ipswich, Massachusetts represented the northernmost established infestation in the Northeast (Lastavica et al., 1989). Within a decade, the distribution of the deer tick expanded on a northsouth axis to the Bar Harbor region in Maine and the coastal peninsula of Delaware, Maryland, and Virginia (Rand et al., 1998). Infestation of migratory birds by deer tick larvae and nymphs served as the primary mode of introduction (Battaly et al., 1993; Ginsberg, 1993). Transport of adult ticks by deer along major waterways also contributed to a rapid spread, particularly in the Hudson River Valley (Chen et al., 2005).

Other recent examples of range expansions of medically important tick species include the establishment of Amblyomma americanum (a vector of E. chaffeensis and Ehrlichia ewingii) in the northeastern United States (Paddock and Yabsley, 2007) Amblyomma maculatum (a vector of Rickettsia parkeri) throughout Arkansas (Trout et al., 2010), I. scapularis across the lower peninsula of Michigan (Hamer et al., 2010), and Dermacentor reticularis (a vector of Rickettsia raoultii) in western Germany and the Netherlands (Dautel et al., 2006; Nijhof et al., 2007).

Conversely, loss of habitat or a host species may reduce the abundance of a historically dominant tick species. From a tick surveillance program in Ohio during 1984-1989 D. variabilis ticks accounted for 13,351 (97%) of 13,764 ticks submitted to the Vector-Borne Disease Unit of the Ohio Department of Health by the general public, physicians, and local health departments from every county in the state; fewer than 1% of the ticks submitted during this period were A. americanum (Pretzman et al., 1990). However, during 1994-1999, only 3,841 (62%) of 6,234 of the submitted ticks were D. variabilis, with 1,351 (22%) now comprising A. americanum (Scott Odee, Richard Gary, pers. comm.). From 1978-1981, 1,342 adult D. variabilis ticks were collected during a mark-and-release survey of ticks at Panola Mountain State Park in Georgia (Newhouse, 1983); however, D. variabilis was only rarely encountered when extensive tick surveys were conducted at this same park approximately 20 years later (Michael Levin, pers. comm.). The causes of these apparent shifts remain speculative; however, a hypothesis to explore is the effect of periodic scarcity of keystone hosts for D. variabilis, i.e., skunks and raccoons, from repeated

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
×

rabies epizootics in certain areas of the eastern United States (Anthony et al., 1990; Guerra et al., 2003).

Changes in Vertebrate Host Abundance and Distribution

The anthropogenic nature of tick-borne infections is considerable and sustained human activities that deplete or amplify the vertebrate host populations can manifest as surges of disease incidence in human populations. In Brazil, capybara (Hydochoerus hydrochaeris) are important hosts to the tick Amblyomma cajennense, a vector of RMSF, and an effective amplifying host for R. rickettsii (Souza et al., 2009). The resurgence of RMSF in many areas of São Paulo State in Brazil during 1998-2007 coincides with explosive increases in the numbers of capybara, and a broadening distribution of these rodents into urban areas of this region (Verdade and Ferraz, 2006). Collectively, these data suggest that dramatic increases in the numbers of RMSF in São Paulo State (www.cve.saude.sp.gov.br/htm/zoo/fm_i8503.htm), and other areas of southeastern Brazil, may be linked closely to a rapidly expanding population of a tick host species that is well adapted to anthropogenic habitats (Labruna et al., 2004; Angerami et al., 2006).

Several arguments document the role of white-tailed deer in the emergence and expansion of Lyme disease, babesiosis, ehrlichiosis, and anaplasmosis (Piesman et al., 1979; Spielman et al., 1993; Paddock and Yabsley, 2007). These 4 diseases were identified and characterized during the last 3 decades of the 20th century, following a period of near-exponential growth of white-tailed deer populations in multiple regions of the eastern United States. At the end of the 19th Century, following several decades of overhunting and habitat loss, an estimated 300,000-500,000 deer existed in the United States. Intensive conservation efforts, coupled with expansive environmental changes that inadvertently provided ideal habitats for these animals to proliferate, caused an eruptive increase of the numbers of deer to approximately 18 million animals by 1992. Because these animals serve as keystone hosts for I. scapularis and A. americanum ticks, the extraordinary increase in range and numbers of white-tailed deer also contributed to increases in these vector tick populations. Because O. virginianus is also an important reservoir host for E. chaffeensis and E. ewingii, this remarkable increase in numbers also expanded considerably the reservoir pool of these pathogens (Paddock and Yabsley, 2007). In a similar manner, roe deer (Capreolus capreolus) were nearly extirpated from the Italian Alps by the end of World War II; however, changes in wildlife practices during the last 50 years enabled a dramatic rebound of this species, by as much as 2000% in some provinces. Because roe deer are also considered crucial in maintaining and amplifying I. ricinus tick populations, an upsurge in deer denisty in northern Italy is likely to have contributed to the rapid and

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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steady rise in TBE incidence witnessed in this same region since the early 1990s (Rizzoli et al., 2009).

Mediterranean spotted fever all but disappeared from the Côte Varoise of France during 1952-1966, a period that closely approximated the disappearance wild rabbits (Oryctolagus cuniculus) following an epizootic of myxomatosis along the Mediterranean coast. In 1967, a dramatic resurgence of MSF in the region occurred simultaneously with the recovery of the wild rabbit population, suggesting to some investigators that these two events were linked ecologically and epidemiologically (Le Gac et al., 1969). Disequilibrium among domesticated animals may create drastic changes as well. More than 90 cases of RMSF, including 11 deaths, have been reported from several small communities in the White Mountain area of eastern Arizona since 2003. This outbreak appears to be linked directly to enormous numbers of R. rickettsii-infected R. sanguineus ticks in the peridomestic environment that resulted from unchecked populations of stray and free-ranging dogs in the community (Demma et al., 2005; Nicholson et al., 2006). During the 1940s, investigators in Mexico reported a similar occurrence in states of Sonora, Coahuila, Durango, Nuevo León, and San Luis Potosí (Bustamente and Varela, 1947).

Climate Change

Direct effects of climate change on the incidence of tick-borne infections remain largely speculative; (Šumilo et al., 2007; Rizzoli et al. 2009; Randolph, 2009a; Randolph, 2010; Randolph et al., 2008). Many transmission models have been developed, but the lacuna in virtually all of these systems is a quantitative assessment of the “zoonotic bridge,” i.e, biological events that introduce the pathogen from the natural enzootic cycle into the realm of human health (Spielman and Rossignol, 1984). Risk factors for human exposure to vectors, and human-associated factors that modify this risk, including activity patterns and the use of personal protection, remain poorly studied. In addition, incidence data of sufficient duration and at the appropriate temporal and spatial scales are often not available to validate existing quantitative models. Accordingly, if one cannot accurately predict incidence for a site over a short interval of time, despite readily measured surveillance variables, then any long-term prediction for the results of climate change remain conjectural. Nonetheless, climate change has been implicated frequently as an important driver of incidence. The spread of tick-borne borreliosis in West Africa is possibly linked to a sub-Saharan drought that allowed the tick vector, Alectorobius sonrai, to colonize new savannah areas (Trape et al., 1996). It has been suggested that warmer weather increases the frequency with which R. sanguineus will bite humans and thereby transmit its associated pathogens (Parola et al., 2008).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Of the tick-borne diseases, TBE perhaps has the best incidence data across a range of scales, as well as ecological data, that permit detailed examination for causality. For several years, rising incidence of TBE throughout central Europe was attributed by many investigators to climate change (http://www.ecologyandsociety.org/vol2/iss1/art5/). During the mid-1980s, the incidence of TBE in Sweden increased from 2 to 5 per 100,000 population, and two opposing factors confounded epidemiologic analyses: an increase in roe deer density, to suggest a greater abundance of I. ricinus ticks and increased transmission, and the introduction of a TBE vaccine, suggesting greatly diminished risk. Even with confounding, a multiple regression analysis of meteorological data and TBE incidence suggested that a milder winter in the previous year, with 2 consecutive mild spring and fall seasons, predicted increased incidence.

However, climate change alone does not adequately explain the remarkably rapid increase in the incidence of TBE across much of Europe during the last few decades, particularly in the Baltic States (Figure A1-4); the factors that influence changes in TBE transmission, and ultimately human risk, appear to be more numerous and complex. What is known is that the risk of TBE in humans is dependent on the frequency of exposure to bites by infected ticks, which is dependent on human behaviour and on various biotic and abiotic factors, including climate (Rizzoli et al., 2009). Starting in 1989, mean springtime temperatures increased across the Baltics; however, the change in TBE incidence among these counties was spatiotemporally heterogeneous and inconsistent with regional weather phenomena (Sumilo et al., 2007). Simultaneously, a decline of collective farming in the post-communism Baltic States conceivably induced successional growth that promoted landscape changes, altering the fauna associated with I. ricinus ticks. In addition, berry picking, mushroom gathering, and other socioeconomically related food-seeking activities placing individuals in more frequent contact with tick-infested habitats are believed to have increased during this same period, as a result of economic changes associated with the fall of the Soviet Union. In this context, short-term climate changes that provided optimal growing conditions for mushrooms and berries in Baltic forests may indeed have been a driver for risk, but only in direct association with human behaviors that resulted in increased exposure to tick-infested habitats (Figure A1-6) (Randolph, 2008; Randolph et al., 2010).

Changes in Funding and Scientific Interest

Scientific, medical, or veterinary interest in a particular pathogen, or changes in the epidemiologic programs or organizational frameworks used to survey for a particular disease, may have enormous impact on the recorded incidence. By example, only 27 cases of Powassan encephalitis were

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A1-6 Hypothetical explanation for the upsurge in cases of tick-borne encephalitis in Estonia, Latvia, and Lithuania, following the end of Soviet rule (Šumilo et al., 2007)

FIGURE A1-6 Hypothetical explanation for the upsurge in cases of tick-borne encephalitis in Estonia, Latvia, and Lithuania, following the end of Soviet rule (Šumilo et al., 2007)

reported in North America during the 3 decades after its discovery in 1958; however, the introduction of West Nile virus to the continent in the late 1990s stimulated enhanced surveillance for arthropod-borne encephalitis by state and local health departments, and is believed to be the major factor in the recognition of 20 U.S. cases of this disease during 1999-2009, including identifications from 4 northeastern and upper Midwestern states that had never previously reported the disease (Hinten et al., 2008; Hoang Johnson et al., 2010).

Prior to the early 1980s, research in tick-borne infections focused largely on RMSF, TBE, and diseases associated directly with animal health, such as babesiosis and theileriosis. The emergence of Lyme disease in the northeastern United States during the late 1970s, particularly at sites where an affluent population lived or vacationed, stimulated a renaissance in tick biology and ecology that was driven, in part, by increased availability of state and federal funds for Lyme disease research. A single individual with interest in a specific disease, particularly one that is otherwise infrequently diagnosed and seldom reported, can have tremendous impact on the incidence of that disease. By example, no cases of MSF from Algeria were documented in the medical literature until 1 clinician identified 93 cases during

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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a 4-month interval in 2004 (Mouffok et al., 2006). Austria and Slovenia have among the highest reported rates of Lyme disease in Europe, with an average annual incidence of 135 and 206 per 100,000 population, respectively (Smith and Takkinen, 2006); however, reporting in these countries is likely enhanced because of particularly energetic Lyme disease researchers who work in this region (Stanek and Strle, 2009). Conversely, it has been suggested that the precipitous drop in reported cases of RMSF witnessed in the United States during the 1950s might be attributable, in part, to the death in 1949 of R. R. Parker, who had been the driving force behind U.S. RMSF surveillance activities for more than 3 decades (Burgdorfer, 1975).

Active and Passive Surveillance

In the United States, surveillance data for tick-borne diseases are acquired voluntarily through separate but complementary reporting instruments that collectively comprise a national system of passive surveillance. The National Electronic Disease Surveillance System (NEDSS), (formerly the National Electronic Telecommunications System for Surveillance [NETSS]) represents the primary reporting instrument. Incidence statistics for all U.S. tick-borne diseases are calculated from electronically reported data; however, these systems acquire relatively limited supplemental information, so that detailed clinical data must be gathered by using other collection instruments, including an extended NEDSS record for Lyme disease, and a standardized case report form (CRF) for RMSF, ehrlichiosis, and anaplasmosis. State or local health departments are responsible for ensuring that cases reported to CDC through NEDSS meet the case definition for these diseases, while CRF data are generally screened at CDC for accuracy and consistency. Understandably, compliance with requests to physicians and state and local health department staff to provide supplemental data is problematic. By example, only 61% of Lyme disease cases reported to CDC during 1992-2006 contained data for reported signs and symptoms (Bacon et al., 2008). During 2000-2007, the number of CRFs submitted for RMSF was approximately 68% of the 11,531 cases reported through NETSS (Openshaw et al., 2010). Submitted CRFs often lack requested information necessary to confirm the diagnosis approved by the Council of State and Territorial Epidemiologists (CSTE) and CDC. Indeed, only 6% of RMSF CRF cases could be classified as confirmed during 2000-2007 (Openshaw et al., 2010). The non-submission of CRFs and the incompleteness of supplementary data collection suggest that a considerable percentage of cases tick-borne disease in the United States are unavailable for detailed analyses, including analysis of risk factors that determine severity (Childs and Paddock, 2002).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Case Definitions

Establishing an accurate and specific case definition that couples well-defined clinical characteristics with specific laboratory confirmation is fundamentally important in all forms of surveillance and provides the foundation from which subsequent epidemiologic parameters are derived. The absence of standardized case definitions for tick-borne diseases that cross regional or national borders remains a crucial problem in the accumulation of broad scale incidence data for many of these infections. Despite a system of mandatory reporting for TBE in Poland since 1970, no standardized case classification for this disease existed until 2005, creating a mix of confirmed, probable, or possible cases that were defined by clinical or laboratory criteria that differed among the county’s multiple provinces. When a national working group created a uniform case definition and retrospectively evaluated data from 1999-2002, they determined that only 25% of cases reported during this interval had sufficient laboratory testing to be classified as confirmed (Stefanoff et al., 2005).

Case definitions are not immutable, and as clinical knowledge about a particular disease expands and evolves, the case definition may be remodeled to include clinical or laboratory data specific to the disease. Because so many tick-borne infections are relatively new to science and medicine, it is not surprising that case definitions and surveillance systems for several of these diseases have required years or decades of refinement (Table A1-2). In this context, incidence statistics, particularly early in the evolution of these systems, should be interpreted cautiously, and comparisons of data from year-to-year, or even decade-to-decade, may be misleading. While passive surveillance requires a reasonably high level of stability to maintain its effectiveness, it must also remain malleable, and responsive to new information gained about a particular disease. By example, the nationally notifiable disease category of “Rocky Mountain spotted fever” was modified in 2010 to a less specific, but more inclusive and more accurate designation of “Spotted fever rickettsiosis, including Rocky Mountain spotted fever,” to adjust to recent data identifying causes of spotted fever group rickettsioses in the United States other than R. rickettsii (Council of State and Territorial Epidemiologists, 2009a).

A well-crafted case definition provides more robust surveillance for the recognized disease and better positions investigators to detect clinically or epidemiologically similar diseases that otherwise might be embedded in data gathered by using a non-specific case definition. Erythema migrans rashes were noted on many patients in the southern and southcentral United States during the late 1980s (Masters et al., 1998), and in 1989, 715 cases of ‘Lyme disease’ were reported from Georgia (CDC, 1990), placing this state among the top 7 in the country for reporting Lyme disease. In the

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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TABLE A1-2 Changes in Case Definitions of Selected Nationally Notifiable Tick-Borne Diseases in the United States, 1996-2008

Disease (year of first case definition)

Year of change(s) in case definition

Change(s)

Reference

Lyme disease (1990)

1996

Recommendation of 2-tiered approach for serologic confirmation.

CDC, 1996a

2008

Inclusion of western blot testing as a single confirmatory assay; addition of probable and suspect categories to case classification.

CDC, 2008a

Ehrlichiosis (1996)

2000

Inclusion of Ehrlichia ewingii as an agent of ehrlichiosis; distinction between laboratory assays for Ehrlichia chaffeensis and Ehrlichia phagocytophila (Anaplasma phagocytophilum); formation of new reporting category, ehrlichiosis/anaplasmosis, human, undetermined.

CDC, 2000

2008

Nomenclature change from human monocytic ehrlichiosis to E. chaffeensis infection; from ehrlichiosis (unspecified, or other agent) to E. ewingii infection; from human granulocytic ehrlichiosis to Anaplasma phagocytophilum infection; inclusion of ELISA format as laboratory criterion for diagnosis of probable infection.

CSTE, 2009a

Rocky Mountain spotted fever (1990)

1996

Inclusion of PCR testing for laboratory confirmation; single titer of greater than or equal to 64 defined as laboratory criterion for a probable case.

CDC, 1996b

2004

Inclusion of ELISA format as laboratory criterion for diagnosis of confirmed or probable case; inclusion of immunohistochemical staining of tissue specimen as confirmatory laboratory criterion; cutoff titers used to determine probable cases defined by individual laboratories; elimination of Proteus OX-2 and OX-19 agglutinin titers as supportive laboratory criteria for a probable case.

CDC, 2004

2008

Confirmation by serologic testing defined as fourfold change in IgG antibody titer; single elevated IgG or IgM titer sufficient for a probable case; ELISA format sufficient only to determine probable cases; inclusion of suspect case classification.

CDC, 2008b

2010

Change of disease category from “Rocky Mountain spotted fever” to “Spotted fever rickettsiosis”; inclusion of an eschar as clinical evidence of disease; requirement of PCR or cell culture isolation as laboratory confirmation of Rocky Mountain spotted fever.

CSTE, 2009b

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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following year, however, only 161 cases were reported from Georgia (CDC, 1991), and even fewer cases in subsequent years. The decline in reported cases reflected the adoption of the CDC surveillance case definition in 1990 by the Georgia Department of Public Health. The abundance of cases reported during 1989 most likely reflected a Lyme disease mimic, associated with bites of lone star ticks, now recognized as Masters’ disease, or southern tick-associated rash illness (Felz et al., 1999; Wormser et al., 2005).

In a similar scenario, investigators in southern Spain identified several patients with atypical ‘Lyme borreliosis,’ who were serologically reactive with Borrelia burgdoreferi antigens, but who lacked classical erythema migrans skin lesions and who originated from a region of the country where the recognized tick vector of Lyme borreliosis was distributed sparsely. Indeed, blood cultures subsequently revealed a relapsing fever Borrelia sp., genetically distinct from B. burgdorferi and transmitted by an entirely different tick species. In this case, discovery of a novel disease agent occurred because these patients did not meet the established case definition for Lyme borreliosis (Anda, et al., 1996; Guy, 1996). Recent discoveries of novel rickettsioses in the United States caused by R. parkeri and Rickettsia sp. 364D were precipitated by reports of atypical ‘RMSF,’ associated prominently with eschars, which are characteristically absent in the great majority of cases of classical RMSF (Paddock, 2008; Shapiro et al., 2010).

The efforts required to verify that reported data comply with an established case definition are considerable and are magnified further when clinical data and exposure history are uncoupled from laboratory results. Electronic laboratory reporting, used increasingly by states to expand case identification of Lyme disease, captures positive test results, but does not provide supportive information about clinical findings or exposure history. Instead, these data must be collected by public health personnel, creating added burden to surveillance endeavors that often exceeds investigative capacity (Kudish et al., 2007; CDC, 2008c). In response, CSTE Epidemiologists modified the national surveillance case definition for Lyme disease in 2007 to allow reporting of probable cases, i.e., those diagnosed by a health care provider and supported with laboratory evidence of infection (CDC, 2008a).

Strengths and Limitations of Passive and Active Surveillance

The most accurate incidence rates are obtained through active surveillance, but these apply to relatively small catchment areas defined for the investigation, and typically provide a snapshot of incidence in a specified region during a relatively short interval of time. This process allows greater control in the selection of clinical specimens and data collected, but is labor-intensive and requires a level of funding that is prohibitive to sustain

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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indefinitely. Indeed, most contemporary active surveillance endeavors are supported by federal grants and have a defined period of patient enrollment that spans, at most, only a few years (IJdo et al., 2000; Olano et al., 2003). In contrast, passive surveillance systems provide data that define endemicity and provide long-term trends over larger geographic regions; however, there is generally less control over the quality and quantity of the acquired data, and this activity requires sustained commitment and appropriate infrastructure at local, state, and national levels to collect, collate, and analyze data collected over broad intervals of time and space.

Inherent differences between these systems preclude direct comparisons of the data generated by each method. By example, prospective active surveillance for ehrlichiosis in southeast Missouri identified 29 confirmed and probable cases from 1997-1999, for a calculated average annual incidence of 3.2 cases per 100,000 population during this 3-year interval (Olano et al., 2003). By comparison, the average annual incidence of ehrlichiosis for the entire state of Missouri, determined by passive surveillance, was only 0.52 cases per 100,000 during 1997-2001 (Gardner et al., 2003), and 0.68 cases per 100,000 during 2001-2002 (Demma et al., 2005b). The nature of active and passive surveillance explains these marked differences in incidence rates. Catchment areas for active surveillance are not chosen at random; rather, these are selected by investigators using passive surveillance estimates that indicate the disease exists in relative abundance in that region (Wilfert et al., 1984; IJdo et al., 2000). In the case of the Missouri investigation, patient ascertainment was facilitated by a motivated clinician who was skilled at identifying potential cases of ehrlichiosis. Additionally, national surveillance for ehrlichiosis was initiated only in 1997, and several years of maturation may be required before passive surveillance systems reach a level of familiarity and frequent use by clinicians and epidemiologists.

Underreporting of true cases is a problem inherent to all passive surveillance systems and can be substantive: in the Marshfield Clinic Epidemiologic Research Study Area, only 34% of the identified Lyme disease cases were reported to the Wisconsin Department of Public Health during 1992-1998 (Naleway et al., 2002). Even for epidemiological statistics that document outcomes as important as death, there is considerable underreporting to public health authorities. From a capture-recapture study evaluating deaths caused by RMSF in the United States during 1983-1998, approximately 64% of fatal RMSF cases identified by death certificate data were not reported to state health departments or to CDC (Paddock et al., 2002)

Prospective cohort studies provide the best estimates of incidence but the resources that are needed to undertake such research preclude their use over larger scales. A good example of the value of a prospective study is that of the clinical trials for SmithKline Beecham’s Lymerix Lyme disease vaccine during 1994-1998. Phase II dose-ranging studies were done during

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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1994-1995 in coastal New England with 353 enrolled subjects. A conservative case definition was adopted, with definite Lyme disease comprising compatible clinical manifestations and laboratory confirmation. Cases of suspected symptomatic Lyme disease comprised erythema migrans without laboratory confirmation and compatible clinical manifestations without other plausible explanation. Such active case finding demonstrated an incidence of 3.4% (95% CI, 1.2-9.5) for either confirmed or suspected Lyme disease among the placebo subjects. This study cost $250,000 (Telford et al., unpublished). Starting in 1995, 10,936 subjects were enrolled in a controlled, double-blind, multicenter Phase III trial in 31 sites in 10 northeastern and mid-Atlantic states from Maine to Maryland (Steere et al., 1998). In the placebo group, the incidence of Lyme disease was 1.5% (95% CI, 1.2-1.9) during the first year, and 2.0% (1.6-2.4) in the second year. Of particular interest were the percentages of asymptomatic seroconversion (16% and 14%, respectively) (Smith et al., 2002). This expensive (>$5,000,000) trial provided our best estimates for Lyme disease incidence, as well as data on the asymptomatic to symptomatic ratio, a critical statistic to help define burden of disease.

Accuracy of Surveillance Data

Underreporting is invariably cited as a limitation to surveillance activities, but over-reporting may be even more damaging to epidemiologic assessments. One of the greatest obstacles to surveillance is ensuring that the data collected represent the disease under consideration. Blended data arise when a single common diagnosis is used to identify multiple related diseases caused by distinct pathogens. This process ultimately creates epidemiological havoc by producing incorrect distributions, hospitalization rates, and case-fatality rates, based erroneously on amalgamated characteristics of several individual diseases.

Most diagnoses of tick-borne infections are diagnosed, and subsequently categorized as ‘confirmed cases’ for epidemiologic analyses, by detecting antibodies in the serum of patients in whom the disease was suspected. Unfortunately, the antibodies generated by humans to specific pathogens often react with other closely related agents that are similar antigenically, but may cause illnesses that differ considerably in disease severity and clinical outcome. Overreliance on serologic methods is also the basis for many non-confirmed cases of tick-borne diseases. It has been demonstrated repeatedly that antibody responses for many of these diseases, including ehrlichiosis and RMSF, often require 7-10 days before a diagnostic titer is detected. Most patients may appear for care during the first few days of the illness, and may never return for subsequent evaluation. From 1 study, approximately two-thirds of culture-confirmed patients infected with

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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E. chaffeensis lacked diagnostic IgG titers, as measured by IFA, when they initially presented for care (Childs et al., 1999). Because diagnostic levels of IgG and IgM antibodies are frequently absent from the serum of patients who die from RMSF, fatal cases of this disease are often not confirmed if appropriate samples are not collected for immunohistochemical, molecular, or culture-based diagnotics (Paddock et al., 1999).

Diagnostically relevant levels of antibodies reactive with R. rickettsii have been detected in approximately 5%-10% of the U.S. population (Wilfert et al., 1985; Graf et al., 2008; Marshall et al., 2003; Taylor et al., 1985; Hilton et al., 1999). Even more troubling are the frequent descriptions of seroconversions to spotted fever group (SFG) Rickettsia and Ehrlichia spp. antigens that occur among as many as a 33% of healthy asymptomatic individuals following exposure to tick bites and tick-infected habitats. (Sanchez et al., 1992; Yevich et al., 1995; Hilton et al., 1999; McCall et al., 2001). Nonetheless, serology is used increasingly to diagnose cases of RMSF; as a result, fewer cases are confirmed and a far greater percentage of cases are considered probable (Figure A1-7). The impact of diagnostic inaccuracy upon epidemiologic observations may be considerable. During 2000-2007, the reported case fatality rate for RMSF in the United States was 0.5%, based on CRF denominator data comprising 7,796 cases, or approximately 1000 cases each year (Openshaw, 2010). The validity of this statistic is unreasonable when considered with historical U.S. case-fatality rates of RMSF that typically approach 10%. One explanation

FIGURE A1-7 Reported cases of Rocky Mountain spotted fever in the United States, by case classification status, 1992-2007 (Openshaw et al., 2010).

FIGURE A1-7 Reported cases of Rocky Mountain spotted fever in the United States, by case classification status, 1992-2007 (Openshaw et al., 2010).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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for this estimate lies in the composition of the denominator, which is likely populated with patients with milder infections, caused by SFG Rickettsia species other than Rickettsia rickettsii (Paddock, 2009).

Under some circumstances, serological methods may produce results that divert attention from the true arthropod vector, creating a false portrait of the disease ecology. In this situation, a ‘tick-borne’ disease may in fact be something altogether different. By example, patients infected with Rickettsia felis, a flea-borne pathogen, generate antibodies that react with various SFG Rickettsia species. Because R. felis has a cosmopolitan distribution and commonly infects multiple species of wild and commensal human-biting fleas, (Reif and Macaluso, 2009), the potential for human infections is enormous. Recent studies in Kenya and Senegal revealed a prevalence of infection with R. felis in approximately 4% of 297 febrile patients from rural areas of these countries; only 1 patient from either series was infected with a tick-borne Rickettsia sp. (Socolovschi et al., 2010; Richards et al., 2010). To place these results in context, it is important to recognize that at least 7 pathogenic, tick-borne SFG Rickettsia species have been detected in ticks or human patients from the immense and ecologically diverse continent of Africa (Cazorla et al., 2008). If these researchers had not used molecular techniques to correctly identify R. felis as the causative agent, and relied only on serologic methods (as many investigators have done for >50 years), the etiology of the disease in these patients could have been ascribed erroneously to any of multiple tick-borne SFG rickettsial pathogens endemic to this continent. Broader use of similar techniques around the world might change considerably existing notions about the ecology, epidemiology, and clinical presentations of tick-borne rickettsioses.

Network Approaches for Detecting Shifts in Incidence and Disease Severity: Challenges, Prospects, and New Rubrics for Surveillance

Any form of surveillance requires sustained and coordinated efforts to provide meaningful data. As with all regional and national services, these programs require continuous funding and prospective governmental commitment, based on public health priorities defined by that state or country. Coordinated national efforts that track these diseases are notably absent in many developed countries. In Germany, an estimated 60,000 new cases of Lyme borreliosis occur each year; however, Lyme borreliosis is not a nationally notifiable disease in this country and precise incidence data do not exist (Mehnert and Krause, 2005). Many countries with active, internationally recognized research programs in rickettsioses, including Australia and France, lack formal national surveillance for tick-borne rickettsioses (Stephen Graves and Philippe Parola, pers. comms). Even in countries

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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where national surveillance exists for one or more of these diseases, the systems are often porous or lack the discriminatory power needed to epidemiologically characterize individual infections. In Italy, tick-borne rickettsioses are lumped in the general category of “rickettsiosis,” without respect to specific disease or arthropod vector species (Ciceroni et al., 2006). In Norway, only cases of disseminated or chronic Lyme borreliosis are notifiable to the Norwegian Institute of Public Health; the majority of infections, represented by erythema migrans, are not tabulated (Nygård et al., 2005).

Not surprisingly, tick-borne diseases are seldom included as nationally notifiable conditions in developing countries with considerable and diverse infectious disease burdens. In the southern Indian state of Karnataka, approximately 400-900 cases of KFD were reported annually during 2001-2004 (Pattnaik, 2006); however, the lack of national surveillance for this potentially lethal hemorrhagic fever has contributed to a belief that this disease is confined to a few small districts of a single state in this vast country. This seems highly improbable, considering that the virus as been isolated from or transmitted experimentally by at least 16 species of hard and soft ticks (Boshell, 1969; Pattnaik, 2006), and strains of the flavivirus responsible for the disease have been isolated from patients as far away as Saudi Arabia and Egypt (Mehla et al., 2009; Carletti et al., 2010), suggesting that variants of KFD might be found in other parts of India or other countries.

Expanding and Unifying Epidemiologic Coverage

More countries need to adopt national surveillance for tick-borne infections, and work to better harmonize and coordinate case definitions of diseases that cross national borders. Meaningful comparisons of incidence across broad geographical expanses are compromised when a melange of independent and varied case definitions exist for the same disease. Currently there are no standardized case definitions for CCHF notification or contact tracing in European countries, despite a vector tick (Hyalomma marginatum) that is distributed broadly across southern and southeastern Europe, and epidemic disease occurring in neighboring parts of Turkey (Figure A1-8), and in several Territories and Republics of the Russian Federation (Maltezou et al., 2010). From a recent survey of 21 European countries that compared national surveillance efforts for TBE, it was determined that case definitions differed widely across these countries, and for 6 countries where the disease is endemic, there was no officially or clearly formulated case definition (Mantke et al., 2008).

The European Union Concerted Action on Lyme Borreliosis (EUCALB) was established in 1997 to provide information on all aspects of Lyme disease, obtained from peer-reviewed literature and edited by a committee of experienced researchers and clinicians. Despite the intent to provide

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A1-8 Spatial distribution of reported cases of Crimean-Congo hemorrhagic fever in Turkey, 2003-2008 (Estrada-Peña et al., 2010).

FIGURE A1-8 Spatial distribution of reported cases of Crimean-Congo hemorrhagic fever in Turkey, 2003-2008 (Estrada-Peña et al., 2010).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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guidance for obtaining and disseminating the highest standard of information, EUCALB has not been able to standardize surveillance across the European Union, and the compilation of European Union case definitions (http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:159:0046:0090:EN:PDF) does not have an entry for Lyme borreliosis. Few European countries have made Lyme disease a compulsorily notifiable condition. Estimates of incidence for this and other tick-borne diseases in many countries are derived from laboratory-based reporting which typically lacks sufficient clinical information to integrate into a robust case definition. Accordingly, many of the same problems for Lyme disease surveillance in the United States are also seen for the European Union as a whole and for most of the member states.

Applying Species-Specific Diagnostics

Robust and predictive epidemiology is predicated on the use of sensitive and specific diagnostic assays. Currently, molecular techniques represent the most widely available standard for species-specific diagnosis. Whenever possible, culture isolation, the microbiological reference standard of diagnosis, should also be attempted to compliment molecular assays. Repeatedly, these methods have leveraged the discovery of novel tick-borne infections and clarified long-standing epidemiologic concerns regarding atypical clinical manifestations, unusual geographic distributions, or exaggerated or diminished severity of diseases that were incorrectly diagnosed. Diligent use of molecular and culture-based diagnostics during a study of 140 Portuguese patients with MSF enabled investigators to identify specifically a strain of R. conorii that was more frequently associated with severe disease in this patient population (de Sousa et al., 2008). The case-fatality rate in this series, determined by using accurate and specific diagnostic assays, was 21%, more than 8 times greater than the previously recognized lethality of this disease (Parola et al., 2005). Molecular techniques were used recently to identify infections with E. ewingii and E. chaffeensis in dogs and R. sanguineus ticks in Cameroon (Ndip et al., 2005: Ndip et al., 2010). These findings provided impetus to search for cases of ehrlichiosis in humans; surprisingly, 12 (10%) of 118 Cameroonian patients with undifferentiated febrile illnesses in whom malaria and typhoid were excluded showed PCR evidence of infection with E. chaffeensis (Ndip et al., 2009).

In Missouri, investigators used molecular methods to discriminate infections caused by E. ewingii from those caused by E. chaffeensis (Buller et al., 1999). Their discovery unveiled a second, clinically and ecologically similar illness, the identity of which was previously obscured because of sufficient overlap of disease manifestations and a shared tick vector. Indeed, surveys examining the relative prevalence of Ehrlichia spp. in reservoir

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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hosts and lone star ticks in the United States suggest that E. ewingii occurs in these species at frequencies similar to, or in some cases greater than, infection with E. chaffeensis (Paddock et al., 2005). However, E. ewingii appears to cause a milder illness, and most commonly causes disease in immmunosuppressed patients. Without molecular methods, these infections would have remained submerged among those caused by E. chaffeensis, contributing to a falsely heterogeneous portrait of E. chaffeensis ehrlichiosis. More recently, an Ehrlichia muris-like agent, identified by molecular methods from the blood of 4 patients in Minnesota and Wisconsin, is likely responsible for many other serologically diagnosed cases of ehrlichiosis in the upper Midwestern United States, where neither E. chaffeensis nor E. ewingii are endemic (McFadden et al., 2010).

Repeatedly, patients with antibodies reactive to multiple SFG Rickettsia spp. are found ultimately to be infected with unexpected agents when PCR and cell culture methods are used. In these circumstances, the diagnosis sheds light on clinical or epidemiologic characteristics not conventionally associated with the presumed pathogen, including occurrence of disease in a different geographical region, greater or lesser severity of illness, or presence or absence of prominent cutaneous manifestations. Just a few of the recent discoveries that exemplify the utility of these assays include Rickettsia heilongjiangensis in Japan, R. parkeri in the southeastern United States, Rickettsia sp. 364D in California, Rickettsia massiliae in Argentina, and Rickettsia sibirica mongolotimonae in southern France (Raoult et al., 1996; Paddock, 2009; Shapiro et al., 2010; Ando et al., 2010; Garciá-Garciá et al., 2010). Each of these diagnoses provides a foundation to explain more accurately the epidemiology of the historically recognized SFG rickettsioses for which these were initially confused.

Improved Integration of Entomologic and Veterinary Sciences

For decades, epidemiologists have integrated surveillance of non-human sources, such as mosquitoes, birds, and domesticated animals, in the detection of arboviruses. Similar efforts must be considered with tick-borne infections. Entomologic expertise ensures correct species identification of tick vectors, defines appropriate ecologic associations, and most importantly, provides data otherwise missing that establish the zoonotic bridge and better define incidence.

Epidemiological Entomology

Robust programs in medical entomology at state and national levels are essential to predict and respond to issues relating to tick-borne infections. In 2003, investigators in Mexicali, Mexico, conducted an entomologic

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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survey to determine the prevalence of R. sanguineus among 94 stray and privately owned dogs in the city, and determined that 60% of these animals were infested with R. sanguineus, a prevalence far greater than reported in other areas of Mexico and other parts of the world (Tinoco-Gracia et al., 2009). In retrospect, these results served as a tocsin to an epidemic of RMSF that occurred in Mexicali and other areas of Baja California during 2009, resulting in 275 confirmed and 734 probable infections (Bustamente Moreno and Pon Méndez, 2010a). In 2009, surveys for R. sanguineus identified these ticks in all 14 districts of Mexicali, where 96% of the cases occurred (Sanchez et al., 2009; Bustamente Moreno and Pon Méndez, 2010b). A survey for ticks on dogs from a small community in São Paulo, Brazil, in 2005, identified R. sanguineus-infested animals at approximately one-third of the households, including specimens infected with R. rickettsii. A canine serosurvey conducted in the same community one year later revealed that 70% of the sampled dogs showed high levels of antibodies reactive with R. rickettsii, and that human cases were also occurring (Morares-Filho et al., 2008).

Even in the absence of accurate incidence data, entomologic studies can provide objective and quantifiable data to reconcile a real or perceived public health burden. By example, a coastal Maryland community determined by questionnaire that Lyme disease afflicted more than 15% of their residents each year, creating apprehension among residents and local public health officials. Entomologic surveillance, in conjunction with a cross-sectional epidemiologic study, provided objective evidence that Lyme disease was actually rare, and disproportional to the perceived risk. In fact, the community did not know that it was plagued by an infestation of A. americanum ticks, that accounted for >90% of all ticks saved by residents, and the majority of ticks collected from vegetation (Armstrong et al., 2001).

Tick-borne infections may be thought of as guilds, or a group of species, not necessarily related, that utilize a common resource. The best example of a tick microbial guild may be found within deer ticks, comprising B. burgdorferi, Babesia microti, A. phagocytophilum, and deer tick virus (Telford et al. 1997). Globally, wherever there are related ticks from the Ixodes persulcatus complex, Lyme disease spirochetes, babesiae, Anaplasma sp., and a TBE- group virus may be found. Indeed, detecting one member of the guild is cause for search for all of the others (Telford and Goethert, 2008). Because concurrent or sequential infection with more than one agent is not infrequent (Krause et al., 1996) the guild model has epidemiologic implications. Accordingly, when a patient is diagnosed with Lyme disease, evidence of babesiosis and anaplasmosis should also be sought. When Nantucket Cottage Hospital started using a clinical laboratory

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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that automatically tested for direct molecular evidence of infection with B. burgdorferi, B. microti, and A. phagocytophilum of all patients with a suspected tick-borne illness, the number of confirmed cases of babesiosis and anaplasmosis immediately doubled (T. J. Lepore, pers. comm.).

Natural cycles of known pathogens do not necessarily imply a zoonotic risk to humans. By example, Ixodes dentatus feeds primarily on rabbits, and only rarely bites humans, yet maintains a diverse guild of pathogens and potential pathogens comprising Borrelia andersoni, B. microti, a Babesia divergens-like parasite, A. phagocytophilum, Anaplasma bovis, and a Kemerovo-group orbivirus in northeastern U.S. sites (Telford and Spielman 1989; Goethert and Telford, 2003 a, b, c). However, this guild has minimal epidemiological importance, even when sympatric with human-biting deer ticks, because deer ticks rarely feed on rabbits. Ticks, similar to all multicellular organisms, harbor a diverse array of microbes, and novel high-throughput DNA amplification and sequencing techniques are unveiling the complex microbiome of ticks (Benson et al., 2004; Clay et al., 2008); however, and public health relevance of an agent detected in a tick should never be assumed a priori.

Currently applied entomological risk indices include only the prevalence of infection in host-seeking ticks and the number of ticks collected in an hour (Piesman et al., 1987). However, an epidemiologically predictive risk index will require information on the species of ticks infesting humans, how frequently these attach, and the actual duration of attachment. Although B. burgdorferi typically infects 20% of host-seeking nymphal deer ticks in northeastern United States, the median annual incidence of Lyme disease from 9 prospective studies in the most intensely enzootic communities is only 2% (range, 0.4%-4.0%) (Hanrahan et al., 1984; Steere et al., 1986; Lastavica et al., 1989; Alpert et al., 1992; Shapiro et al., 1992; Krause and Telford, unpublished; Wormser et al., 1998; Steere et al., 1998; Sigal et al., 1998). In addition, fewer than 10% of all Lyme disease cases in the northeastern United States are reported during the fall or winter months when adult deer ticks are most active, even though as many as 50%-75% of host-seeking adult ticks contain spirochetes (Piesman et al., 1986). These apparent paradoxes can be answered by entomology: most tick-borne bacterial pathogens require a period of ‘reactivation’ before they attain infectivity (Spencer and Parker, 1923; Piesman et al. 1987; Katavolos et al., 1997). The probability of infection is directly proportional to the duration of feeding and may differ by life stage of the tick, so that 24-48 hours of attachment are generally required for B. burgdorferi to be transmitted by nymphal deer ticks; in contrast, adult deer ticks require approximately 3-5 days of attachment to transmit B. burgdorferi to a susceptible host (Telford, unpublished).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Sentinel Species for Tick-Borne Disease

Despite repeated successes using wildlife and domesticated animals as sentinel species for tick-borne infections, these resources remains under-utilized in formal surveillance programs around the world. Because domestic dogs are frequently parasitized by human-biting ticks, develop robust antibody titers to most agents, are closely associated with human habitation, and are easily sampled, these animals represent exceptional sentinel species for tick-borne pathogens. This technique has been used effectively to predict or corroborate the occurrence, or in some cases, relative absence, of disease burden in human populations, including spotted fever group rickettsiosis in southeastern Australia (Sexton et al., 1991), and Lyme disease and anaplasmosis in the United States (Guerra et al., 2001; Hinrichsen et al., 2001; Duncan et al., 2004; Bowman et al., 2009).

With respect to infections caused by SFG rickettsiae, canine antibodies typically show greater specificity to the infecting agent than to other, antigenically related Rickettsia spp. (Nicholson et al., 2006; Demma et al., 2006; Piranda et al., 2008), and may provide greater accuracy than results of human antibody assessments in serologic surveys. Retrospective analysis of 329 archival canine serum specimens, collected from dogs in a community in the White Mountain region of eastern Arizona during 1996, revealed epidemiologically relevant titers of antibodies reactive with R. rickettsii in only 2 (0.6%). When dogs were tested 7 years later, following recognition of an RMSF epidemic in this community, 70 (72%) of 97 animals demonstrated epidemiologically relevant antibody titers, and the geometric mean titer was > 84 times higher than observed in 1996 (Demma et al., 2006). Of even greater interest, high antibody titers were also detected in 8 (57%) of 14 dogs sampled at a second community, 60 miles distant, where no cases of RMSF had been reported; however, the following year, an outbreak of RMSF occurred in the second community, involving 9 residents and causing 2 deaths. This approach was later applied to serosurvey of dogs in counties adjacent to the outbreak communities, where approximately 6% of animals demonstrated antibodies to R. rickettsii, primarily among R. sanguineus-infected dogs, suggesting future cases of human disease outside of the recognized boundaries established during the initial outbreak (McQuiston et al., 2009).

Because white-tailed deer are important hosts for several species of ticks that transmit infectious agents to humans, these animals have been used effectively in the United States as sentinels for multiple tick-borne infections, including E. chaffeensis ehrlichiosis and Lyme disease. Among the advantages cited for this species include an extensive and inclusive distribution throughout the range of these diseases, the relatively sedentary nature of deer, rates of exposure to ticks that far exceed those of human

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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exposures, and regulated harvests in all states that facilitates collection of samples from hunter-killed animals (Yabsley et al., 2003; Gill et al., 1994).

Prospecting Other Databases

Tick-borne infections can mimic many other infectious diseases, including meningococcemia, leptospirosis, hantavirus pulmonary syndrome, dengue, and malaria. Recent investigations in Senegal and Togo suggest that tick-borne relapsing fever may be a common cause of fever in many parts of West Africa; however, the diagnosis is seldom considered, because many cases are misdiagnosed with malaria. Indeed, several studies have identified infections with Borrelia spp. in as many as 10% of febrile patients (Vial et al., 2006; Nordstrand et al., 2007).

From a 1993 study of dengue fever in Yucatan and Jalisco states of Mexico, 50 patients with a recent compatible illness had no serologic evidence of infection with dengue virus. Of these, 20 had high levels of antibody reactive to SFG rickettsiae (Zavala-Velazquez et al., 1996). A similar approach was used for a study in Colombia, when 158 serum samples collected from febrile patients during 2000-2004 as part of national or regional surveillance for malaria, dengue, or yellow fever were evaluated for SFG rickettsiae and 21% showed antibodies suggesting recent infection with a Rickettsia species (Hildago et al., 2007).

Evaluations of databases comprising those patients negative for a particular tick-borne disease of interest may be especially fruitful, as many of these patients have been bitten by ticks, reside in tick-infested areas, or present during periods of peak tick activity. From a study conducted by investigators at CDC, paired serum samples collected from 3 (10%) of 29 patients for whom RMSF was suspected, but subsequently showed no serologic evidence of acute disease, were determined retrospectively to have seroconversions to Ehrlichia antigens, and corroborative clinical evidence of ehrlichiosis (Fishbein et al., 1987). A novel bunyavirus, transmitted by Haemaphysalis longicornis ticks, was recently identified as the cause of a life-threatening disease (severe fever with thrombocytopenia syndrome), confirmed in 171 patients from six provinces in Central and Northeast China. Clinical similarities with human anaplasmosis, and an assosciation with tick bites, focused initial investigations on A. phagocytophilum as the suspect pathogen; however, when molecular and serologic assays failed to identify this agent with the outbreak, culture of clinical specimens in multiple permissive cell lines, eventually yielded isolates of a previously undescribed phlebovirus (Yu et al., 2011).

Every year, spider bite statistics are collected by poison control centers across the United States; however, the accuracy of these data have been questioned by prominent arachnologists, who argue that hundreds

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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of reports of necrotic arachnidism attributed to the brown recluse spider (Loxosceles reclusa) originate from areas where these spiders are absent (Vetter and Furbee, 2006), including much of Georgia, Florida, and South Carolina (Vetter et al., 2004; Vetter et al. 2009). Because necrotic arachnidism is occasionally considered by physicians as a diagnosis for patients with eschar-associated rickettsioses (Paddock et al., 2008) and Lyme disease (Rosenstein and Kramer, 1987; Osteroudt et al., 2002), closer inspection of these databases could uncover many previously undiagnosed and uncounted cases of tick-borne disease. This approach could also yield interesting results in other parts of the world, including Australia and Brazil, where necrotic skin lesions are also often attributed to bites from spiders that do not exist in the reporting area (Ibister, 2004).

Extracting New Data from Existing Surveillance Systems

Increasingly, physicians and scientists are identifying specific genetic characteristics and co-morbid or infectious conditions in patients that predispose these individuals to particularly severe forms of certain tick-borne infection. These include life-threatening disease in HIV-infected patients who become co-infected with E. chaffeensis, fulminant R. rickettsii and R. conorii infections in patients with glucose-6-phosphate dehydrogenase deficiency, fatal MSF in alcoholics, and increased severity of TBE in patients with a specific deletion in the chemokine receptor CCR5 (Walker et al., 1983; Raoult et al., 1986; Paddock et al., 2001; Kindberg et al., 2008; de Sousa et al., 2008). These observations have been identified in relatively small cohorts of patients who have been evaluated by relatively few clinicians who become cognizant of a specific characteristic that places these patients at increased risk for more severe infection; to identify similar characteristics among the total number of counted cases in a state or country poses a great challenge for future surveillance efforts (Childs and Paddock, 2002).

Age-specific incidence data gained from the first several years of national surveillance (Demma et al., 2005b; CDC, unpublished data) for ehrlichiosis and anaplasmosis show a striking age-related increase in frequency of these infections among older persons (Figure A1-9). One plausible hypothesis for this observation suggests that cholesterol dependence by E. chaffeensis and A. phagocytophilum may correlate with greater disease severity in older patients, because cholesterol levels typically rise with increasing age, and these bacteria lack all of the genes necessary for the biosynthesis of lipid A (Lin and Rikihisa, 2003). A direct association between cholesterol levels and the clinical severity of other forms of gram-negative sepsis add support to this hypothesis (Ayyadurai et al., 2010); in this context, serum cholesterol levels, collected as supplemental data on CRFs, could ultimately provide important clues to the pathogenesis of these diseases.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A1-9 Age-specific incidence of human ehrlichiosis (n = 3,104) and human anaplasmosis (n = 4,134) in the United States, 2000-2007 (Dahlgren et al., in press).

FIGURE A1-9 Age-specific incidence of human ehrlichiosis (n = 3,104) and human anaplasmosis (n = 4,134) in the United States, 2000-2007 (Dahlgren et al., in press).

In Silico Analytic Methods

Molecular phylogenetic tools have refined our understanding of the etiology of tick-borne infections. Advances in data analysis, made possible by tremendous computing power, should provide similar refinement of our understanding of transmission dynamics and environmental correlates of risk. Predictive models for guiding intervention and proactively studying new zoonotic sites are currently untenable. Validation of these models would require incidence data at the same scale as that for enzootic parameters; it is not axiomatic that the case counts for an entire state would be predicted by regressors, such as an entomological risk index, estimated from solely one town in that state. Although some analyses demonstrate correlations between measured tick density and Lyme disease case reports (Stafford et al., 1998; Mather et al., 1996), a priori predictions are not currently possible.

Vector-borne infections are complex to model. Sir Ronald Ross initiated mathematical modeling for malaria risk in 1909, but it was not until coordinated efforts in the 1950s (MacDonald, 1957) promoted enough quantitative understanding of malaria epidemiology that the effects of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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interventions such as vaccination could be predicted (Molineaux, 1985). In this respect, considerably more attention needs to be directed toward studies that provide data for quantitative models of tick-borne diseases. These efforts could also help develop testable hypotheses on critical aspects of tick life cycles or pathogen transmission cycles. Given the difficulty of finding study sites for longitudinal ecology study of R. rickettsii, for example, the role of transovarial transmission in perpetuating this agent in nature could be explored by modeling (Telford, 2009).

Great advances in remote sensing of environmental parameters and data analysis algorithms such as Geographic Information Systems (GIS) may allow prediction of the distribution of infection, or even incidence. However, given the extremely focal nature of transmission for most tick-borne infections, the utility of GIS would be a function of the scale of the analyses, which would depend on the availability of satellite data of a useful scale. For GIS analyses, as with mathematical models, the bridge from nature to human risk requires the filter of human behaviors; in the absence of this filter, associations of environmental variables with incidence data, even when available at the correct scale and duration, are less robust. In this context, GIS analyses are potentially powerful tools, whose practical utility are currently limited by our understanding of the basis for and measurement of human risk.

Summary and Perspective

Tick-borne diseases are the Cinderella of vector-borne disease (VBD) systems: always beautiful, but for so long over-shadowed by the big ugly sisters of insect-borne malaria, trypanosomiasis, dengue, etc. In traditional happy-ending style, they are now emerging as the princess of VBDs, their full significance appreciated: as important in temperate as tropical regions, as much a veterinary as a medical problem to fit neatly into the ‘one world, one health’ maxim, and with an exquisite complexity to keep many a scientist fully occupied over a lifetime.

S. E. Randolph, 2009b


Predicting the future is an imprecise science; nonetheless, a clear association exists between human disturbance of natural habitats and the emergence and expansion of tick-borne diseases, and it is precisely this link that portends important increases in the scope and range of these zoonoses in the years to come. Remarkable scientific and medical discoveries during the last several decades have expanded considerably the known spectrum of tick-borne infections. Fundamental surveillance efforts for these infections, curiously, have not made similar strides. There are many practical reasons

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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to explain the paucity of effective surveillance systems for tick-borne diseases around the world, including perceived need, long-term interest, and monetary commitments necessary to sustain these programs. These factors affect the longevity necessary for fine-tuning of case definitions and collection instruments, and ultimately, meaningful interpretations of the collected data; however, as more unique pathogens are identified, distinctions among the diseases caused by these agents may become increasingly subtle. In the end, the effort required to discover a new disease is generally far less than the subsequent endeavors required to establish and maintain long-lasting and accurate surveillance for that disease.

The measurement of incidence is important because it can be used to quantify and rank the causes of ill health so that scarce resources may be allocated. Incidence is critical to refine and validate predictive or explanatory models, which help develop new testable hypotheses or identify critical breakpoints. Changes in incidence may point to fundamental alterations of ecology or human behavior. Measuring incidence accurately, however, can be prohibitively expensive, as seen with the Lymerix Phase III trials. Indeed, surveillance will become increasingly important in the places that have the least existent infrastructure and the fewest resources to devote to establishing such programs. In Africa, scientific and medical concerns for tick-borne diseases are vastly overshadowed by other arthropod-borne infections; nonetheless, the unrecognized burden of these infections could be considerable. By example, the incidence of tick-borne relapsing fever in Senegal has been estimated at 5.1% (Trape et al., 1996), and the spread of infections with Ehrlichia spp. among an expanding and highly vulnerable HIV-infected cohort on this continent could have devastating consequences (Ndip et al., 2009).

Our challenge is to improve the measurement of incidence within the limits of available resources and capacities. With technological advances, global disparities in the capacity to collect this information may lessen; today, even the poorest countries are rapidly gaining access to thermal cyclers and the Internet, and the coverage of such critical technology will only increase. In the interim, our use of the currently available data—a dark glass—can be enhanced if we understand its limitations and frame our interpretations accordingly.

Acknowledgments

We thank the following individuals who generously provided data and input to this work: Marcelo Labruna (Cidade Universitária São Paulo, São Paulo, Brazil); Elba de Lemos (Instituto Oswaldo Cruz, Rio de Janeiro, Brazil); Rita de Sousa (Instituto Nacional de Saúde Dr Ricardo Jorge, Lisboa, Portugal); José Oteo (Hospital San Pedro, Logroño, Spain); Shuji

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Ando (National Institute of Infectious Diseases, Tokyo, Japan); Agustín Estrada-Pena (University of Zaragoza, Zaragoza, Spain); Claudia Colomba (Universita di Palermo, Palermo, Italy); Philippe Parola (Université de la Mediterannée, Marseille, France); Robert Swanepoel (National Institute for Communicable Diseases, Sandringham, South Africa); Stephen Graves (Hunter Area Pathology Service, New South Wales, Australia); Scott O’Dee and Richard Gary (Zoonotic Disease Program, Ohio Department of Health), and; Scott Dahlgren and Robert Holman (Division of High Consequence Pathogens and Pathology, CDC). We are indebted to Paul Mead and Jennifer McQuiston (Division of Vector-borne Diseases, CDC) for their thoughtful review and invaluable comments to the manuscript. SRT is supported by NIH R01 AI 064218.

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A2
GLOBAL ENVIRONMENTAL CHANGE AND TICK-BORNE DISEASE INCIDENCE

Sarah H. Olson, Ph.D., and Jonathan A. Patz, M.D., M.P.H.

Introduction

The diverse and complex ecology of tick-borne diseases (TBDs) is exceptional among vector-borne diseases. Today it is estimated that tick species exceed 850 and inhabit every continent (Dennis and Piesman 2005, Benoit et al 2007). Their resilience and persistence in the environment can be traced back in the fossil record, which suggests that they originated 65-146 million years ago (Fuente 2003). The Swiss Army knife of disease vectors, ticks generate a neurotoxin and they can host bacterial, viral, and protozoan pathogens as well, a greater variety of disease agents than any other arthropod vector (Sonnenshine 1991).

Grouped into Ixodidæ and Argasidæ families, or hard- and soft-bodied ticks respectively, all ticks are obligate blood-suckers and undergo three stages of development: larval, nymphal, and adult. The life cycle of ticks starts when, “larvæ seek hosts, attach, feed, detach, and develop in sheltered microenvironments where they molt to nymphs; nymphs follow the same pattern and molt to adults (except argasids, which first molt into further nymphal stages); adults seek hosts, mate, feed, and in the case of engorged females, drop off to deposit eggs” (Dennis and Piesman 2005). Tick hosts are terrestrial vertebrates, and host-seeking activity is called questing. Ticks may have vastly different host preferences, among species and at different developmental stages, as well as seasonal questing that depends on climate and environmental conditions (Dennis and Piesman 2005). See Table A2-1 for an overview of major tick-borne diseases, their vectors, endemic areas, and studies relevant to global environmental change.

Global environmental change is the cumulative effect of climate change, the changing built environment and landscape, and evolving biodiversity (MEA 2005). This review will emphasize these three elements. In the context of disease ecology, climate change encompasses abiotic risk factors of temperature, precipitation, and the intensity and frequency of extreme weather events. Globally these events are shifting climatic zones and influencing seasonality. Landscape risk factors include observations of the amount and arrangement of land cover types and uses, from native land cover to urban development. Landscapes provide both the habitat for host and tick vector populations and set the stage for human behavioral risk factors. The presence of host and vector populations are key biodiversity risk factors in TBD ecology, but a less obvious risk factor is the biodiversity of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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TABLE A2-1 Major Tick-Borne Diseases, Their Vectors, Endemic Areas, and Studies Relevant to Global Environmental Change

Disease

Vector

Research

Effects

Tick-borne paths

[Anaplasma phagocytophilum, Ehrlichia caffeensis

Wimberly et al 2008

Climate: Habitat (bkwrds finding) biodiversity

TBE

Ixodes ricinus

Perkins et al 2006

Biodiversity

TBE

Ixodes ricinus

Gilbert et al 2010

Climate: habitat

TBE

Ixodes ricinus

Ogden et al 2008

Climate: Habitat

TBE

Ixodes ricinus

Randolph and Rogers 2000

Climate: Habitat

TBE

Ixodes ricinus

Lindgren and Gustafson 2001

Climate: Seasonality

TBE

Ixodes ricinus

Lindgren et al 2000

Climate: Seasonality

TBE

Ixodes ricinus

Carpi et al 2008

Climate: Seasonality and habitat

TBE

Ixodes ricinus

Estrada-Peña et al 2003

Habitat

TBE

Ixodes ricinus

Halos et al 2010

No climate habitat/built enviro

TBE

Ixodes ricinus

Vanwambeke et al 2009

No climate habitat/built enviro

Lyme

Ixodes ricinus TBEV B. burgdorferi sensu lato

Danielová et al 2010

Climate: Habitat

Lyme

Ixodes scapularis

Brisson et al 2008

Biodiversity

Lyme

Ixodes scapularis

Brunner et al 2008

Biodiversity

Lyme

Ixodes scapularis

Giardina et al 2000

Biodiversity

Lyme

Ixodes scapularis

Keesing et al 2009

Biodiversity

Lyme

Ixodes scapularis

Ostfeld and Keesing 2000

Biodiversity

Lyme

Ixodes scapularis

Ostfeld and Keesing 2000

Biodiversity

Lyme

Ixodes scapularis

Ostfeld and Keesing 2006

Biodiversity

Lyme

Ixodes scapularis

Schauber et al 2005

Biodiversity/Climate-weather mice acorns

Lyme

Ixodes scapularis

Brownstein et al 2003

Climate: Habitat

Lyme

Ixodes scapularis

Ogden et al 2005

Climate: Habitat

Lyme

Ixodes scapularis

Jones and Kitron 2000

Climate: Seasonality

Lyme

Ixodes scapularis

Kitrone and Kazmierczak 1997

Climate: Seasonality

Lyme

Ixodes scapularis

Prusinski et al 2006

Habitat

Lyme

Ixodes scapularis

Wilder and Meikle 2004

Habitat (bkwrds finding)/biodiversity

Lyme

Ixodes scapularis

Bunnell et al 2003

No climate habitat

Lyme

Ixodes scapularis

Allan et al 2003

No climate habitat/built enviro

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Disease

Vector

Research

Effects

Lyme

Ixodes scapularis

Brownstein et al 2005

No climate habitat/built enviro

Lyme

Ixodes scapularis

Cromley et al 1998

No climate habitat/built enviro

Lyme

Ixodes scapularis

Das et al 2002

No climate habitat/built enviro

Lyme

Ixodes scapularis

Frante et al 1998

No climate habitat/built enviro

Lyme

Ixodes scapularis

Horobik et al 2006

No climate habitat/built enviro

 

Mix

Cumming and Van Vuuren 2006

Climate: Habitat

 

Multiple

Altizer et al 2006

Climate: Seasonality

Rickettsioses

Rhipicephalus sanguineus

Parola et al 2008

Climate: Seasonality

 

Dermacentor andersoni, Ixodes ricinus

Eisen et al 2008

Climate: Seasonality

other vertebrate species in the community. Predation and competition may affect host densities, depending on the species composition of biodiversity changes. Lastly, just as the elements of global environmental change range from local to worldwide (Patz and Olson 2006, Patz et al 2008), temporal and spatial scale effects of global environmental change on vector-borne diseases are anticipated (Kovats et al 2001, Patz et al 2005, Plowright et al 2008).

Tick vector species are often vectors for multiple disease-causing microorganisms (Table A2-1), so our approach allows generalization of changing environmental effects on pathogens not yet studied. Other important elements of disease emergence, including genetic, biological, social, political and economic factors, are included when available, but in-depth analysis of these risk factors is beyond the scope of this paper (IOM 2003).

Climate Change

Research on climate change and TBD is directed toward three areas of investigation. First, the fundamental question is how climate change will impact the tick vector and microbial agent. In vitro observations allow us to understand precisely how temperature and humidity affect tick and pathogen development, behavior, and survival. The second question is where will climate change affect the transmission of TBD. Use of information from in-vitro studies can be used (directly or in simulation models) to identify current and future projected climate-based geographic ranges (Ogden et al

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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2005, 2006). Alternatively (and particularly useful where detailed information on climate effects on vector biology are not available) correlations between observed current distributions of vectors and climate (accounting for other important variable such as habitat) are generalized to large areas using simulations of projected climate change. Finally, when may TBD be altered under future climate change scenarios, or more specifically changes to transmission intensity and duration, including patterns of tick, host, and microbe seasonality and synchrony? For this question, data-rich longitudinal field studies are particularly useful to sort out the integrated impact of climate change on disease ecology.

Methodological approaches are implicit to the framing of each question and the different approaches provide varied perspectives of climate change impacts on TBD. A severe lack of long-term data on coupled disease and environmental systems restricts integrated assessment of all three questions (Pascual and Bouma 2009). So uncertainty grows between the research gaps, but taken together, a mosaic is slowly taking shape of how, where and when TBD will be modulated by climate change.

How Will Climate Affect Tick-Borne Diseases?

Many dimensions of tick development and behavior and TBD transmission are directly linked to climate cues. Higher temperatures yield faster development rates of larvae, nymphs, and adults, with the precise rate of development varying between stages and species. Diapause, or a period of rest between stages, has latitudinal relationships corresponding to photoperiod (tropical species) and temperature-linked physiological aging (temperate species). Together photoperiod and temperature also influence host questing. “At the end of each year, decreasing day length reduces the probability of questing and low temperatures may inhibit activity altogether while at the start of each year, increasing day length is permissive, but only if temperatures are high enough” (Randolph 2004). Of particular note are species and stage specific temperature thresholds for tick activity (3.9–9.8°C), coordinating host seeking activity (7.2–13.9°C), and cold temperature survival (−18.5 – −11.6°C) (Clark 1995, Vandyk et al 1996, Schulze et al 2001). Slight temperature changes around thresholds can have a large impact on tick survival and host-seeking behavior. Beyond temperature in the tropics, Rhipicephalus appendiculatus female to larvae survival drops under conditions of high rainfall but low humidity (Randolph 1994, 1997). At local scales, there are exceptions to these climate maxims (Schulze et al 2009, Hubalek et al 2003). Lastly, there is some evidence for direct effects of climate on the pathogen. The rate of parva transmission to cattle increases at higher temperatures but the development of Theileria parva

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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requires a specific temperature range (18–28°C) (Ochanda et al 1988, 2003; Young and Leitch 1981).

Dichotomous habitat and host-seeking behavior define two distinct groups of ticks. Exophilic or nonnidicolous species live in the open environment, whereas nidicolous ticks live in the nests and burrows of host species. Since non-nidiculous ticks spend nearly 90% of the life off the host, they are consequently sensitive to external conditions caused by climate change. In contrast, nidiculous ticks are dependent on the presence of host-related microhabitats (e.g., nests, burrows) and are thus sensitive to species distributions, which may change as a result of climate change.

“Nidicolous ticks exhibit behavioral patterns that restrict their distribution to these cryptic microhabitats, avoiding bright sunlight and low humidity. Under these conditions nidicolous ticks can wait for months or even years until hosts arrive and take up residence in these shelters. For the nonnidicolous ticks, survival in the open environment depends upon many factors, among the most important of which is tolerance to desiccation. Ticks adapted to the cool, humid arboreal and deciduous forests of northern Europe and North America typically have only limited tolerance of desiccation. After brief periods of questing on vegetation for passing hosts where they are exposed to subsaturated air, the loss of body water overwhelms their hunger and induces them to retreat to saturated atmospheres in the rotting meadow vegetation or damp leaf litter on the forest floor.” (Sonenshine 2005)

Climate, along with other biotic factors such as host availability, is strongly connected to the population density of nonnidicoulous ticks, which transmit the majority of human TBDs. Primarily, this is because climate factors, such as cumulative degree-days and humidity, affect tick survival and longevity (McEnroe 1977, McEnroe 1984, Lindsay et al 1995). In Illinois, Jones and Kitron report severe drought in the previous year significantly lowers Ixodes scapularis larval density on Peromyscus leucopus mice. There are also positive correlations between larval density and cumulative rainfall and degree-days (2000). In fact, climate is thought to be the major factor controlling Lyme disease occurrence, stronger even than host factors (Randolph 2000). And the importance of climate extends from macro down to micro scale, as survival strongly depends on narrow microclimatic conditions found on the ground, which may be very different even from local ambient conditions (Daniel and Dusbabek 1994, Bertrand and Wilson 1996). When ambient air temperature (measured 50cm above ground) is substituted for ground air temperature, a model of I. ricinus development erroneously predicts nymphs emerge 2–3 weeks earlier than observed in southern UK (Randolph 2004). Sensitivity analyses of a population-based

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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land use and land cover physiological tick model of the cattle-tick species Boophilus spp confirmed bi-hourly temperature and relative humidity strongly affect tick population dynamics (Corson et al 2004). Landscape and soil conditions will need to be integrated with high-resolution climate projections in order to model tick emergence effectively.

Altitudinal gradients are useful to study the specific mechanisms of climate change on TBDs (Eisen 2008). An altitude gradient creates a linear temperature gradient that represents different climate scenarios while holding other environmental factors relatively constant. Across a difference of 380m and a temperature loss of 0.72°C per 100m gained in elevation, Jouda and colleagues show annual questing nymph and adult I. ricinus density and the spring onset of questing is negatively associated with changes in elevation or positively associated with warmer temperatures (2004). A follow-up study between earlier years and more recent times on these same slopes attributed a significant increase in tick density and phenology at higher elevations to recent warmer summers and falls in the higher elevations as measured by saturation deficit (the drying ability of the atmosphere). They also observed an increase in the density of nymphs infected with Borrelia at the highest elevation, but overall Borrelia infection prevalence dropped with altitude (Cadenas et al 2007, Burri et al 2007). While this study was not able to adjust for differences in host populations across the elevation gradient, another study in Scotland showed Ixodes ricinus tick abundance decreases with altitude, again as higher elevations are cooler, even after controlling host (deer) abundance. The authors conclude, “It could be inferred that ticks may become more abundant at higher altitudes in response to climate warming. This has potential implications for pathogen prevalence such as louping ill virus if tick numbers increase at elevations where competent transmission hosts (red grouse Lagopus lagopus scoticus and mountain hares Lepus timidus) occur in higher numbers” (Gilbert 2010). However, the authors fail to consider how climate change may shift the abundance of grouse and hare hosts at the higher elevations. In Colorado, Eisen observed Dermacentor andersoni (Stiles) along an altitudinal gradient and projected a 1 to 2°C increase in mean maximum April-September temperature would generate the same peak tick abundances at 2390 to 2480m that currently occur at 2290m (2008). Adaptation to specific local conditions may also influence future patterns of TBD, as Eisen also observed a site-specific positive correlation between daily maximum temperatures during peak tick host-seeking activity and mean daily maximum temperatures (2007). In sum, the literature consistently shows warmer temperatures increase tick abundance but cautions against assumptions that host distributions will remain relatively constant.

Just as climate influences overall tick population dynamics, evidence suggests biting rates of ticks also are affected by climate. A fascinating epidemiological detective story began in May 2007 when two patients

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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presented with Rickettsia massiliae and R. conorii infections in southern France. In April, both patients had visited the residence of a mutual friend. An entomological survey of the residence in July found 218 adult Rhipicephalus sanguineus ticks in just one hour, of which roughly one-fourth were positive for rickettsia. The authors point out that April 2007 was the warmest since 1950, and they also performed a healthy volunteer human biting study with pathogen-free Rh. sanguineus to test affiliations between aggressive tick biting behavior and temperature. Surprisingly, between 27-67 percent of larvae incubated at 40°C attached to the skin where only 0-6 percent of larvae incubated at 25°C attached successfully. Known commonly as the dog tick, Rh. sanguineus transmits dog pathogens but also vectors important and emerging human rickettsioses (Parola et al 2008). Few studies have investigated temperature and I. scapularis biting affinity, but McCabe and Bunnell attribute greater numbers of Lyme disease cases to increased survival and tick activity in the northeastern United States brought about by above average rainfall in May and June (2004).

How climate change will impact TBDs is further complicated by the way it alters host diversity, abundance, dispersal, the development cycle of the pathogen, and the suitability of habitat for both tick and hosts (Schulze and Jordan 1996, Gubler et al 2001). Using structural equation modeling, Cumming and Guegan show climate will have a greater direct influence on community richness of the tick vectors than on the pathogens themselves, but that alterations in tick biodiversity will then affect pathogen diversity (2006). In addition to direct effects of climate change on tick and pathogen populations, routes and species of migratory birds transporting Crimean-Congo haemorrhagic fever virus (CCHFV) may change under future climate scenarios. In fact, climate is interwoven into multiple elements of CCHFV zoonotic transmission, from the risk of dispersal by changing migration patterns and bird species to shifting livestock and small vertebrate reservoirs (Gale et al 2009). There may be complicated interactions between temperature, host behavior, and tick population dynamics (Craine et al 1995). A study found when temperatures exceeded 40°C, radio-tracked Australian lizards were more likely to seek out microhabitats or dens where they became infested with high numbers of ticks (Kerr and Bull 2006). Researchers anticipate weather will also affect human behavior in TBD transmission. Randolph et al point to climate influences on cultural practices and socioeconomic conditions as a more critical pathway than climate influences on tick abundance for a tick-borne encephalitis (TBE) epidemic in Europe in 2006. “An alternative explanation, supported by qualitative reports and some data, involves human behavioural responses to weather favourable for outdoor recreational activities, including wild mushroom and berry harvest, differentially influenced by national cultural practices and economic constraints” (Randolf 2008).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Where Might Climate Change Affect Tick-Borne Diseases?

Just as there are multiple factors that contribute to TBD risk, there may be more than one factor that limits the geographic range of a tick-borne disease. At regional and national scales the spatial area of Lyme disease risk has been documented to correlate with annual precipitation, temperature, and drought events (Estrada-Peña 2002; McCabe and Bunnell 2004; Jones and Kitron 2000). Therefore, why is Lyme disease not more prevalent in the southern United States where ideal climate conditions already occur? Ostfeld and Keesing suggest that higher species richness, and especially those of ground-dwelling birds, reduces transmission probabilities, or in other words, creates a protective dilution effect (2000a). Therefore, in the south Lyme disease is restricted by biodiversity and species assemblages that limit its ability to spread. Other tick-borne pathogens reveal similar limitations from other factors. The joint distribution of Ehrlichia chaffeensis and Anaplasma phagocytophilum, the agents of human monocytotropic ehrlichiosis and human granulocytic anaplasmosis, respectively, is bounded in range by climate in the southeastern United States and by the forest fragmentation and cover of the Great Plains (Wimberly et al 2007). While the likelihood of whether climate or land use has a greater effect on tick abundance is an interesting question, it overlooks the dynamic balance of joined climate and land use systems. Land use may be a dominant factor in one year and one location, followed by climate the next. More likely both may limit the geographic extent of TBDs.

The relative dominance of climate or land use on the tick vector of Lyme disease, Ixodes scapularis, will depend on the location, the rate of change of climate, the rate of change of land-use conditions, and scale. To forecast tick distribution 40 years hence requires an understanding of both current and projected trends of land use and climate. Climate projections for 2050 from B1-low and A2-high scenarios estimate 1.0-3.7°C warming for mean temperatures in Dec/Jan/Feb and June/July/Aug over the present range of Lyme disease transmission (Hulme and Sheard 1999). Generally, earlier spring and warmer winters are positively associated with tick abundance and Lyme disease incidence. Land-use patterns in the last 50 years in the United States reveal exurban development leading to habitat fragmentation changed 20-60 percent for much of the range of Lyme disease (Brown et al 2005) (see Figure A2-1).

Recent research shows that at present climate is limiting the migration of Ixodes ticks into eastern Canada and that under several climate change scenarios this migration is anticipated to spread to the southeastern corner of Alberta and across to the eastern tip of Newfoundland by 2050 or 2080 (Ogden et al 2005; Ogden et al 2006) (see Figure A2-2). The rate of climate change is relatively assured, compared to the rate of land-use change, which

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A2-1 Land-use patterns in the last 50 years in the United States.

FIGURE A2-1 Land-use patterns in the last 50 years in the United States.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A2-2 Land-use change in rural America.

FIGURE A2-2 Land-use change in rural America.

varies with economic, social, and political institutions. As Ixodes is new to this environment all predictions are uncertain. Knowledge of land use and tick habitat suitability is still emerging. Unlike climate, land use is not readily quantifiable. For example, it is difficult to state that 10 ha of type A landcover relates to a given degree of risk. Over the next century, climate is a good bet to be the dominant driver that spreads Lyme disease into Canada (Ogden et al 2010). Land-use change may influence the intensity of the initial epidemic and persistence of endemicity that follows this expansion. In the Northeast, to the extent that climate and forests are linked ecosystems,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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there may be synergistic effects of climate and land-use change. Deforested and fragmented lands may not be able to support historical tick densities under different climate regimes. We are only beginning to quantify the consequences of land-use and climate patterns on biodiversity, vector-borne diseases and human health (Hansen 2005).

The complex dynamics of climate and land use patterns are underscored by a debate on the rising incidence of tick-borne encephalitis (TBE) in Central Europe that began in the mid-1990s. A survey of dogs carrying ticks and tick collections were performed in 2001 and 2002 and compared to a 1957 survey of small terrestrial vertebrates. The authors conclude I. ricinus tick habitat encroached up to around 1000m from 700m in elevation as a result of climate change since the 1950s (Daniel et al 2003, 2006). Another research group that included landscape in a more comprehensive analysis of risk factors found that “there was little evidence for the role of climate change in the increase in infections … in northern Italy from 1996 to 2006. However, support was found for the influence on TBE increases due to changing forest landscapes and that both red and roe deer, essential hosts in maintaining and amplifying tick populations, had increased 10% from 1996 to 2000 in the region and over 300% in the last 50 years” (Rizzoli et al 2009). The large influence of the host population in this case study underscores the importance of gestalt in disease ecology systems.

Despite this cautionary tale, geographic areas of TBD risk are projected to change globally. An expert panel concluded climate change would have the greatest impact on the distribution of ticks that transmit two of the top three vector-borne viruses in the EU, African horse sickness virus (AHSV) and Crimean-Congo haemorrhagic fever virus (CCHFV) (Gale et al 2010). Increases in the density and geographic range of I. ricinus in the mid-1990s is attributed to milder winters compared to the early 1980s (Lindgren 2000). Further research in Sweden found a correlation between increased TBE, transmitted by I. ricinus ticks and global warming trends that led to earlier onset of spring and milder winters (Lindgren and Gustafson 2001). It remains unclear why the UK is experiencing a large increase in the distribution and abundance of this tick (Kirby et al 2004; Scharlemann et al 2008). A rising number of TBE cases reported in Slovakia since 1980 appears to reflect a migration of the disease to submountainous habitat as a response to a warming climate (Lukan et al 2010). Yet this relationship may not directly translate to entomological risk (Zeman and Bene 2004, Danielová et al 2010). Scientists using a global habitat suitability model for 73 African tick species predict that over the next 100 years the habitat area will increase 1-9 million square kilometers. “If this is also typical of other invertebrates, then climate change will disrupt not only the geographic location of [their] communities but also their structure. Changes in tick

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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communities are also likely to influence tick-borne pathogens” (Cumming and Van Vuuren 2006).

When Will Climate Change Affect Tick-Borne Diseases?

The significance of climate change on TBDs goes beyond the debate of shifting distributions of ticks (Pascual and Bouma 2009). “Seasonal patterns are one major pathway for the subtle but potentially drastic effects of climate change on disease dynamics” (Pascual and Dobson 2005). Further, “empirical evidence points to several biologically distinct mechanisms by which seasonality can impact host-pathogen interactions, including seasonal changes in host social behaviour and contact rates, variation in encounters with infective stages in the environment, annual pulses of host births and deaths and changes in host immune defenses” (Alitzer et al 2006). Seasonal patterns of host pathogen prevalence also need to be considered. Sero prevalence of Anaplasma phagocytophilum, an emerging pathogen in roe deer in Denmark, was nearly two times higher in the summer versus the fall hunting season (Skarphédinsson et al 2005). The challenge of monitoring these dynamics is further complicated by adaptation and evolution (Tabachnick 2010). Simulations done by Ogden and colleagues demonstrate different seasonal patterns predicted by climate change will select for I. scapularis-borne pathogens that are “shorter-lived, less efficiently transmitted, and more pathogenic to their natural hosts, i.e. altered frequency distribution and evolution trajectories” (Ogden et al 2008a).

Climate Caveats

The narrow focus of this section on climate change (or the focus of the following section) should not dismiss the critical role of human behavioral factors along with social and political changes (Randolph 2008, 2010; Vanwambeke et al 2010).

Biodiversity, the Landscape, and Built Environment

“Epidemiological models should consider not only the demographic structure of the host population, but its spatial structure as well, and this can in some cases be effectively inferred from landscape structure.” (Langlois et al 2001)

The complex interwoven ties between disease ecology and biodiversity, landscape, and the built environment were first elucidated for Lyme borreliosis in the northeastern United States. It was observed that small mammal reservoir competency, or the ability of a species to infect a biting larva,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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varies from species to species. In the northeast, white-footed mice (Peromyscus leucopus), eastern chipmunks (Tamias striatus), and short-tailed or masked shrews (Blarina brevicauda or Sorex cinereus) are the reservoir for 80-90 percent of infected nymphs (Brisson et al 2008). Because the tick is a nonspecific feeder, diverse community assemblages effectively decrease disease spread by reducing the number of blood meals taken from more competent reservoirs. So in high biodiversity settings, this phenomenon, called the “dilution effect,” decreases the likelihood that larval blood meals are taken from mice, an animal with high reservoir competence, while increasing the likelihood that larval blood meals are taken from species with lower reservoir competence, such as raccoons or squirrels (Norman et al 1999; Schmidt and Ostfeld 2001; LoGuidice et al 2003; Brisson et al 2008).

Research suggests the dilution effect is an ecological disease process related to forest fragmentation and that landscape metrics can detect this process. Landscape metrics quantify the amount and arrangement of landscape components. Following the theory, in smaller forest patches the population density of white-footed mice, a highly competent reservoir of Lyme disease, nymphal infection prevalence (NIP), and density of infected nymphs increase exponentially (Nupp and Swihart 1998; Allan et al 2003). Diverse communities of small mammals and birds (lacking in small forest fragments) limit disease spread by reducing the number of blood meals taken from mice, which have the highest reservoir competency (Ostfeld and Keesing 2000a, b). Landscape patterning is important because the disease-buffering ability of an ecosystem may decline with reduced species richness, which often results from decreasing habitat patch size.

Notably, the universality of the dilution effect is being challenged. Recent modeling suggests changing host abundance may also amplify pathogen transmission, “with the outcome depending precisely on mechanisms of competition, host contact rates with ticks, and acquired host resistance to ticks” (Ogden and Tsao 2009; Salkeld et al 2010). Further, the emerging infectious disease, enzootic granulocytic anaplasmosis seroprevalence was greatest in habitats with high biodiversity (ticks, rodents and vegetation) (Foley et al 2009). Bottom line, depending on locality, biodiversity can increase or decrease TBD transmission.

In addition to the dilution effect, other environmental and ecological processes may relate Lyme disease to specific landscapes. Habitat fragmentation can alter host movements and disease transmission dynamics. Micro-infestations or dense patches of I. ricinus in a habitat mosaic landscape are critical nodes in a host movement network that sustain the permanent tick population on 1,400 km2 in northern Spain (Estrada-Peña et al 2003). Lyme disease is linked to numerous environmental and ecological systems. Soil characteristics (including order and texture), bedrock, land cover and forest type, sandy soil, low elevation, and deciduous forests have

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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all been implicated (Bunnell et al 2003; Jones and Kitron 2000; McCabe and Bunnell 2004). Deciduous forests have edaphic characteristics that support higher levels of ticks than coniferous forests (Guerra et al 2001; Bunnell et al 2003). In townships surrounding Lyme, Connecticut, landscape metrics of fragmentation are positively associated with tick density and NIP (Brownstein et al 2005). Smaller deer exclosures (less than 2.5 ha) had greater tick densities and within those exclosures, greater densities in the center (Perkins et al 2006). These varied findings suggest that there may be multiple forest fragmentation-linked ecological processes related to Lyme disease.

Tick habitat suitability, a common surrogate estimate of Lyme borrelosis risk, is defined by landscape characteristics across spatial scales. In the North Central United States, Guerra et al (2002) demonstrate tick presence or absence depends on soil order and texture, bedrock, land cover and forest type. In Maryland, agricultural land use has lower tick abundance than forested land cover (Das et al 2002). And along the East Coast, climate, sandy soil, low elevation, deciduous forests, soil characteristics and water availability are all related to elevated abundance of adult ticks (Bunnell et al 2003). In Wisconsin, vegetation detected by satellite—the spring and autumn normalized difference vegetation index (NDVI)—helped distinguish agricultural from forested areas and was significantly associated with human disease cases and tick distributions (Kitron and Kazmierczak 1997). In between this patchwork of regional scale analyses, a lack of uniform surveillance and environmental data limit the understanding of landscape characteristics and tick habitat suitability. Even the fine scale structure of understory vegetation may drive tick density and infection prevalence (Prusinski et al 2006).

Landscape ecology studies provide a powerful reminder that in addition to landscape composition, its configuration plays an important roll in biodiversity and TBD risk. Indices of landscape configuration suggest underlying biological relationships depend on the arrangement of the natural and built environments (Turner 2005). Fragmentation, edge and patch landscape metrics can help describe risks in the built environment, host abundance and distribution, vector abundance, and pathogen prevalence. Jackson et al show high incidence rates of Lyme borrelosis in Maryland are best explained by the amount of edge between forest and herbaceous land cover (2006). The configuration of the built environment, specifically the density and size of residential settings, defines the greatest variation of Lyme cases in a hyperendemic community in Connecticut (Cromley et al 1998). The dilution effect, noted above, is directly connected to the arrangement of the forest; the density of a highly competent Lyme reservoir, the white-footed mouse, is closely associated with the size of forest fragments (Nupp and Swihart 1998). Yet, fragmentation-related entomological risk may or may

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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not necessarily translate into human risk (Brownstein et al 2005, Wilder and Meikle 2004, Horobik et al 2006).

The survivability and stability of ticks in a world of declining biodiversity is not well understood. Biodiversity loss is a silent endpoint of global environmental change. “For the past 300 years, recorded extinctions for a few groups of organisms reveal rates of extinction at least several hundred times the rate expected on the basis of the geological record. The loss of biodiversity is the only truly irreversible global environmental change the Earth faces today” (Dirzo and Raven 2003). Studies of the dilution effect show higher rates of TBD transmission occur when vertebrate biodiversity that effectively buffers pathogen prevalence is reduced (Schmidt and Ostfeld 2001, LoGuidice et al 2003). However, TBD transmission may decline if just the highly competent pathogen reservoirs are absent (Giardina et al 2000). Kessing et al recently proposed another perspective on biodiversity in an ecological disease system. They find hosts, by killing ticks, can act as “ecological traps,” and the removal of these hosts may elevate TBD risk, “by increasing both vector numbers and vector infection rates with a zoonotic pathogen” (2009).

Biodiversity plays an important but unassuming role in controlling ticks. There are numerous “natural enemies” of ticks, including mammals and birds, parasitoid wasps, nematodes, bacteria, and fungi proposed to be used as bio-control agents (Ostfeld et al 2006a, Samish et al 2004). For instance, “fire ants” (Solenopsis invecta) are thought to have reduced populations of the tick Amblyomma americanum in southern US, while spiders are thought to have reduced populations of the tick Rhipicephalus sanguineus in Corsica (Wilson 1994). Another biodiversity-linked method of tick control is the exploitation of host pheromones and immunology. These natural organic compounds stimulate tick assembly, dispersal, attraction, attachment and mating behavior (Sonenshine 2006). Micro-infestations of ticks can emerge from pheromonal feedback loops (Yoder et al 2008). And natural systems of biodiversity are critical in identification of pheromones that may support future tick control. For instance, recently penguins in the Antarctic Peninsula were found to provide an assembly pheromone (via guano) of the seabird tick, Ixodes uriae (Benoit et al 2008). Another discovery shows the blood of a lizard host of I. pacificus blood contains an anti-bacterial agent that effectively eliminates Borrelia burgdorferi s.l. from its blood stream (Lane and Quistad 1998).

Given the historical resilience and persistence of ticks through the millennium, their expanding geographic range at the very least introduces a powerful vector of infectious disease and the impact of that introduction depends on local biodiversity. Tick distributions and tick-borne disease transmission potential have localized dependencies on biotic diversity (Ogden and Tsao 2009). In alpine regions in Italy the increased abundance

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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of roe deer is a strong predictor of resurgent TBE, along with changes in forest structure (Rizzoli et al 2009). But locally in the same region deer exclosures were found to have greater nymphal tick abundance on rodents (Perkins et al 2006). As another example, when deer density in a New Jersey township with endemic Lyme borrelosis was reduced, transmission appeared to increase the population of host-seeking ticks (Jordan et al 2007). Anticipating future transmission risk is challenging in a static environment, and even more so under scenarios of tick migration, as the spatial habitats of key reservoir species, which may also vary by locality, are also shifting (Jannette et al 2007, Brisson et al 2009, Surgeoner et al 1997, Sutherst et al 2007). The gross impact of tick expansion into new areas will be mitigated by local relationships of species richness and diversity and new adaptations within the community (Ogden et al 2008b, Frank et al 1998).

Integration on Environmental Determinants

The study of TBDs is uncovering dynamic ecological disease processes. One classic and elegant study tells the story of how Lyme disease risk in Dutchess County, New York, is embedded in an oak forest system, and connected to masting and rodent, deer, and gypsy moth abundance (Ostfeld et al 1996). But ecological disease processes cannot always be isolated from anthropogenic processes. Vanwambeke et al tracked TBE incidence in Latvia from 1999–2003, and found it was related to land cover, but also patterns of land use and ownership (2009). Further, at a regional scale the TBE increase in Central and Eastern Europe is attributed in part to “human behaviour determined by socio-economic conditions” that followed the collapse of the Soviet Union (Randolph 2007).

Scientists continue to move ahead with studies of global environmental change and the complex disease ecology of TBDs turning research gaps into challenges:

“The emerging research field focusing on climate-driven change in spatial and temporal patterns of arthropod vectors, vector-borne pathogens, or incidence of vector-borne diseases is characterized by a plethora of models based on empirical data of variable quality and a disturbing lack of empirical long-term studies that will allow us to demonstrate that future change was in fact driven by climate factors.” (Eisen 2008)


“[There is] a need for a more standardized and comprehensive approach to studying the spatial dynamics of the Lyme disease (LD) system…. Significant progress in identifying the determinants of spatial variation in LD risk and incidence requires that: (1) existing knowledge of the biology of the individual components of each LD system is utilized in the development of spatial models; (2) spatial data are collected over longer periods of time;

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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(3) data collection and analysis among regions are more standardized; and (4) the effect of the same environmental variables is tested at multiple spatial scales.” (Killilea et al 2008)


“Improved methods for collection and presentation of spatial epidemiologic data are needed for vectorborne diseases in the United States. Lack of reliable data for probable pathogen exposure sites has emerged as a major obstacle to the development of predictive spatial risk models…. New methods are urgently needed to determine probable pathogen exposure sites that will yield reliable results while taking into account economic and time constraints of the public health system and attending physicians. Recent data demonstrate the need for a change from use of the county spatial unit for presentation of incidence of vectorborne diseases to more precise ZIP code or census tract scales.” (Eisen and Eisen 2007)

Added to these challenges is the need for comprehensive transdisciplinary approaches to risk assessment, disease surveillance, and treatments (Patz et al 2004). This need requires collaboration among academics and practitioners of public health to join epidemiological, environmental and social determinants, and it must cross political boundaries (AagaardHansen et al 2009, Ahmed et al 2009, Hui 2006). The best science on global environmental change TBD ecology will need to reflect the complex and dynamic ecological connections driving them.

Acknowledgements

The authors greatly appreciate the comments and feedback from Dr. Nicholas Odgen and Dr. Jack Teng, as well as editing by George Allez. We also thank the Robert Wood Johnson Working Group on Interdisciplinary Perspectives on Health and Society (based at the University of Wisconsin) for a Graduate Research Award to Dr. Olson to address land-use change and Lyme disease risk.

References

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A3
THE HUMAN DIMENSION OF LYME AND OTHER TICK-BORNE DISEASES: THE PATIENT PERSPECTIVE

Submitted by: The National Capital Lyme & Tick-Borne Disease Association

“Courage is what it takes to stand up and speak; courage is what it takes to sit down and listen.”

Winston Churchill


When one family member is infected with Borrelia burgdorferi (Bb), the entire family is affected. Life as previously lived comes to a screeching halt. The focus of the family turns to survival of a disease that drains the energy, ability and hope from the patient and replaces it with pain, weakness and helplessness.

The unfortunate patients who fail the 2-4 week course of antibiotics are often reassured by their doctor they need no further treatment. They fall further into the progressive illness that includes facial paralysis, cognitive processing delays, difficulty walking, slurred speech, pain, and the loss of their former life and self. Prescription bottles and IV poles become the norm in the home. The roles of parent and spouse disappear as the victim of the disease can no longer fulfill responsibilities that once had been second-nature. Child patients often require individualized education plans, accommodations and special education. Some children must be home-schooled because they cannot get out of bed to participate in a regular classroom curriculum.

Months and years of illness march on and the patient grows wearier of any possibility of recovery. While the medical community spends its time arguing over whether to provide promising additional treatment, the patient faces a daily battle alone with the medical safety net stretched thin. Doctors, family and friends, who long since have had no viable answers, continue to be at a loss to know how to help and stop communicating. The fortunate patients who respond to aggressive antibiotic treatment face a slow climb back to their former life and health. Extensive treatment, however, comes with a price tag that for most patients means the obliteration of their retirement plans and, for some, becoming a financial burden to their children. When the IV pole has been moved from the bedroom to the garage, the question remains: “Do we give it away, or might we need it again?” Tick populations and their related illnesses are increasingly creating epidemics in neighborhood after neighborhood. Each year, more and more new cases are tabulated, documented and stored somewhere … and the band plays on.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Overview

Lyme borreliosis, commonly referred to as Lyme disease, alone or concurrent with other tick-borne infections, can be a debilitating illness that severely diminishes a person’s health and quality of life. The more inclusive term “Lyme borreliosis” is used in this paper, rather than Lyme disease, to include patients with persistent and relapsing infections of the Borrelia burgdorferi bacterium after initial therapy. This paper documents the impact of tick-borne infections on patients and their families. It draws on survey data, patient testimonies, and scientific research to examine symptom manifestation, chronicity of illness, and the human and economic costs of tick-borne infections. Children account for a significant number of Lyme borreliosis cases, and this paper examines how tick-borne infections disrupt their development into productive adults. Despite years of research on Lyme borreliosis, understanding of this infection and its impact on patients remains inadequate. This paper identifies gaps in research and medical care. The overwhelming consensus of Lyme patients and their families is that neither the government research community nor the medical community gives sufficient credibility to this disease or devotes adequate resources to combating it. The paper concludes with recommendations that include future research and policy changes needed to combat the serious and growing problem of tick-borne diseases in the United States.

Onset of Illness and Problems of Diagnosis

The beginning of patients’ struggle with Lyme borreliosis can be confusing and frightening. Misperception about tick bites, tick-related rashes, and the variety of symptoms leaves the patient feeling bewildered with a medical system that does not produce answers. As the mother of a 15-year-old patient from New Jersey described the situation, The most worrisome thing was not knowing what was afflicting my daughter—not knowing who the enemy was for lack of a diagnosis.” Worry returns when doctors offer no explanation for the recurrence of symptoms after a short course of treatment.

Patients are fortunate if they observe the telltale erythema migrans (EM) or bull’s-eye rash at the time of their tick bite, which alerts them to seek immediate antibiotic treatment. As few as 44 percent of Lyme patients with chronic illness recall seeing a rash and only 29 percent recall seeing a tick bite (Donta, 1997). Unfortunately, many of those patients who do seek care for a rash do not always receive accurate or appropriate medical advice. Physicians unfamiliar with the many variations of EM rashes may miss the diagnosis of Lyme disease. Only 19 percent of rashes resemble a classic bull’s-eye rash (Tibbles and Edlow, 2007), and as many as 15 percent

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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of EM rashes were misdiagnosed, most often as spider bites but also as cellulitis and shingles (Aucott et al, 2009).

Sister of Patient A from Virginia, ill for 6 years:1

“She told the doctor of her fear of Lyme and showed him the bull’s-eye rash and she was ignored. We went to doctors located in Virginia where my sister resides and was bitten who said, ‘Lyme doesn’t exist here. We will not treat.’ My beloved twin began a horrible spiral that has gone downhill ever since. She, a woman who worked in healthcare 17 years helping people with HIV, became a victim of a system she used to believe in.”

One of the most common patient experiences is the misuse of the Centers for Disease Control and Prevention’s (CDC) Lyme disease surveillance case definition for diagnostic purposes. Many doctors are not aware that the CDC’s case definition opens with the warning, “This surveillance case definition was developed for national reporting of Lyme disease; it is not intended to be used in clinical diagnosis” (CDC, 2010a). Despite such admonitions, many doctors refuse to diagnose and treat unless the patient meets the CDC’s recommended two-tier testing criterion which requires a positive enzyme-linked immunosorbent assay (ELISA) or IFA before use of the Western blot. When the ELISA is negative, patients are routinely refused the more specific Western blot test. As a patient from New Hampshire reports, All of my five Elisa tests were negative. I was sick with fatigue, headaches, and cognitive issues for a year and a half and missed a whole year of school. When a Western blot was finally done it was CDC positive for Lyme disease.”

Moreover, the tests for Lyme disease are notoriously unreliable due to the lack of sensitivity and specificity. Studies have found the sensitivity of the ELISA test for Bb infection to vary from 59 to 95 percent (Depietropaolo et al, 2005), meaning that tests can miss up to two-in-five of all cases. The authors found that two-tier testing further decreases test sensitivity, resulting in more missed diagnoses. Unreliable testing hampers both surveillance and patient care when the CDC criteria, designed for patient surveillance purposes, are being misused to deny treatment to patients.

The two-tier testing for Bb infection is not recommended since testing is unreliable until several weeks after the onset of illness as the test reflects antibodies in the blood that are not produced until that time (Aguero-Rosenfeld et al, 2005; Depietropaolo et al, 2005). Many patients report that they are tested prior to 4-6 weeks; and when their ELISA comes back

1

Patient testimonies were obtained from various sources, including email requests from various Lyme support patient groups, stories collected by Lyme advocates, and published sources. To ensure patient anonymity, patients are identified only by their state of residence and years of illness.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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negative, they are not re-tested, and their infection goes undiagnosed. Since early diagnosis and treatment greatly improve outcomes, it is a tragedy that so many patients do not receive a timely diagnosis.

Patient B from North Carolina, sick for unknown years:

“I continue to deteriorate, now so weak I couldn’t go any real distance without a wheelchair … I experienced violent muscle jerks that left me sore afterwards, as if I had been beaten up. I went into long coma-like sleep lasting 20 hours a day, waking up lethargic, as if I never slept. I started to have impaired short term memory loss, difficulty multitasking or concentrating and forgetting how to do the simplest tasks, like how to take off my seatbelt. As I’m knee deep in this hell, my dogs start to get sick one right after the other. Their tick titers came back positive for ehrlichiosis, Lyme, and Rocky Mountain spotted fever. It was then I researched Lyme for myself and found all my seemingly unrelated symptoms. Excited I had found the answer, I went back to my doctor and told him to test me for Lyme. We did the Elisa which was negative, so he confidently proclaimed, ‘You do not have Lyme. We do not have it in North Carolina.’”

Even positive test results are sometimes dismissed by doctors as irrelevant without additional investigation into the cause of their illness. As one Virginia patient states, “Even with a positive ELISA and Western Blot and 23 symptoms I am being told by Infectious Disease [doctor] I am negative. I am being told we are not sure what you have had for 7 years but it is not Lyme.” This common experience indicates a perception of unreliability of Bb tests in the medical community, and therefore Lyme borreliosis should remain a clinical diagnosis. Far too many patients never hear about the possibility of Lyme borreliosis. A Johns Hopkins study found that 54 percent of patients were misdiagnosed when they did not present with a rash (Aucott et al, 2009). Other patients see a number of specialists who are unable to determine the proper diagnosis.

Mother on behalf of Patient C from Illinois, sick for 10 years:

“He saw 21 doctors who ran numerous tests. He was getting sicker, missing school and no one was putting it all together … the contact with friends diminished. At times he wondered what he has to live for.”

Lyme borreliosis is often not considered in the differential diagnosis of a patient’s worsening symptoms. Rather, patients are offered a diagnosis such as chronic fatigue syndrome or fibromyalgia, conditions for which there is no known cause or cure. Eventually, depression may also be diagnosed and antidepressants prescribed. Rarely do antidepressants relieve symptoms that Lyme patients experience.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Patient D, sick for more than 5 years:

“Sometimes I wonder if things would have been different had I been diagnosed earlier and received treatment at a younger age. This illness has destroyed my quality of life. Before my illness, I was a very active person capable of working long hours, jogging, tennis, running a household, and active in my church and community activities. It destroyed 2 marriages and I was not able to have children. It is not only costly, it is demoralizing to not be able to take care of yourself on a daily basis.”

Some patients with enough observable signs and symptoms are diagnosed with multiple sclerosis, lupus, or amyotrophic lateral sclerosis (ALS). Steroids are prescribed, which have the effect of worsening the Lyme patient’s infection through immune suppression, a finding reflected in rhesus monkey studies (Pachner et al, 2001). While the possibility of Lyme borreliosis is overlooked or outright rejected, patients are given seemingly unrelated diagnoses as varied as postural orthostatic tachycardia syndrome (POTS), gastroparesis, autonomic dysfunction disorder, hypoadrenalism, sleep apnea, obsessive compulsive disorder, Aspergers, Tourette syndrome, blood clotting disorders or cyclic vomiting syndrome.

Patient E from California, sick for 7 years:

“My father had unknowingly contracted Lyme, Babesia, and Bartonella. Six years later, he began to lose strength and felt like he was losing muscle. His HMO doctor ignored his complaint for over a year. A neurologist diagnosed him with ALS. My brother urged our father to pursue Lyme testing and a Western blot came back positive. The HMO agreed to put him on IV antibiotics for one month. After thirty days, Dad could stand up again but [the HMO] refused to continue IV antibiotics citing IDSA treatment guidelines. The HMO insisted Dad had ALS not Lyme Disease, ignoring the fact Dad gained back the use of his legs. [The HMO] also insisted that he had tongue atrophy and put him on a feeding tube. We were told to take Dad home to die and call Hospice. We chose to take our father out of [the HMO hospital] and put him in a nursing home under the care of a physician who would treat him for advanced Lyme Disease. An occupational therapist found that our father did not have tongue atrophy and he began to eat three meals a day. In the next eight months, my father was walking, off the ventilator, and off the feeding tube.”

Reaching the correct diagnosis of Lyme borreliosis can be a long and arduous process. A survey of patients conducted by the California Lyme Disease Association (CALDA) in 2009 found that 35 percent of patients consulted 10 or more doctors before receiving the diagnosis of Lyme borreliosis and 36 percent reported a delay of six years or more between onset of illness

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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and diagnosis. Lack of public and physician awareness leads to significant diagnostic delays. Like the correct diagnosis itself, the search for a knowledgeable physician proves extremely difficult for 58 percent of patients surveyed.

Mother on behalf of Patient F from Virginia, sick for 13 years:

“My son was diagnosed with chronic Lyme at age 18 after being misdiagnosed with chronic sinus infections and Chronic Fatigue Syndrome. He started having chronic headaches, fatigue and low fevers at age 9, and would improve on antibiotics, but then relapse a couple months after discontinuing them. He saw a CFS/FM specialist and was treated symptomatically for 5 years. He had to be home schooled the whole time due to his severe fatigue. He also acquired a severe sleep disorder, severe POTS, tremors, sound and light sensitivity, and severe cognitive issues (primarily brain fog, concentration problems and word retrieval difficulty.) He lost 35 lbs. At age 18, he was diagnosed with chronic Lyme disease. At age 22 after long-term Lyme treatment, he is improved enough to attend college part-time.”

Other Tick-Borne Infections

Joseph Piesman, who oversees the tick-borne disease program at the CDC, notes that, “The more people study ticks, the more new pathogens are discovered” (Landro, 2010). More than a dozen tick-borne diseases have been documented to cause serious illness in humans. “Ticks can be infected with bacteria, viruses, or parasites. Some of the most common tick-borne diseases in the United States include: Lyme disease, babesiosis, ehrlichiosis, Rocky Mountain Spotted Fever, anaplasmosis, Southern Tick-Associated Rash Illness, Tick-Borne Relapsing Fever, and tularemia. Other tick-borne diseases in the United States include Colorado tick fever, Powassan encephalitis, and Q-fever” (CDC, 2010b). A tick study from southern Connecticut found that 20 percent of the 230 Ixodes scapularis ticks collected were infected with Bb, and of these ticks 68 percent were co-infected with one or more additional pathogens (Sapi et al, 2009). Consequently, a person bitten by a tick is at risk for being infected with multiple tick-borne diseases.

The National Capital Lyme and Tick-borne Disease Association (NatCapLyme) conducted an online survey in July 2010 on Lyme disease for 10 days.2 A total of 1,438 subjects, elicited via e-mail from patient

2

The survey was an Internet survey, conducted from July 9 to July 19, 2010. Subjects from the United States, Canada and Europe were recruited by email. Announcements about the survey were posted on Lyme patient support websites. The reported data are for the United States only (1,438 respondents). Respondents who reported that they were infected outside the United States were not included in the analysis (121 respondents). Duplicate response entries were also excluded.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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support groups across the country, participated in the survey. Such a large response in so short a time demonstrates that those affected with tick-borne infections want serious consideration and recognition of the impact of the disease.

The NatCapLyme survey found that 46 percent of the respondents had been diagnosed with two or more tick-borne infections. Babesiosis is the most common co-infection, with 41 percent of respondents afflicted. Patients who are co-infected with Lyme borreliosis and other tick-borne infections experience more symptoms and more persistent illness than those with only Bb infection (Krause et al, 1996). Because symptoms for other tick-borne infections can be similar to those of Lyme borreliosis, these infections may go undiagnosed, contributing to ongoing illness despite treatment.

Patient G from Virginia, sick for 13 years:

“After my initial two and a half years of ‘lyme’ treatment, it was believed the lyme was ‘cured.’ Unfortunately, after a couple months, not only did all my symptoms come back, but, I had developed cardiac issues. Sadly, at this time, I was also diagnosed with Babesia and Bartonella by a specialty lab which verified IgG and IgM for Babesia. The physician believed the initial regional test he had performed earlier for Babesia did not include the strain I had, which was WA-1. If the co-infection testing had been accurate back in early 2004, I may not have had the struggle I still face with cardiac issues due to years of infection with Babesia and Bartonella.”

Lyme patients frequently suffer from other infections. The NatCapLyme survey found that fully 39 percent of respondents had been diagnosed with bartonellosis in addition to Lyme borreliosis. The tick study from southern Connecticut found the Bartonella henselae bacterium to be present in 30 percent of ticks, suggesting an association with ticks as a vector.

The exact role that other tick-borne diseases and opportunistic illnesses play in the disease course is poorly understood, suggesting the need for more research. Researchers have found that spirochete DNA remains in the circulation longer in subjects co-infected with both Lyme disease and babesiosis, compared to patients with Lyme disease alone, leading them to speculate that “babesial infection may impair human host defense mechanisms, as it does in cattle and mice” (Krause et al, 1996). Tick-borne infections can overwhelm the immune system, making the patient vulnerable to other infections, such as mycoplasma, Epstein Barr virus, yeast, H. pylori and Chlamydia pneumoniae, etc. Consequently, a downward spiral of health problems may consume the patient’s life and resources.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Ongoing Illness

Some patients report a full or nearly complete recovery following a month or less of antibiotic treatment for Lyme borreliosis. Receiving early treatment is critical, because left untreated, Lyme borreliosis can become a debilitating disease. When ticks transmit B. burgdorferi to humans, a rash develops where the spirochetes enter the skin. Several days to weeks later, there may be symptoms elsewhere in the body, where the spirochetes have spread. The symptoms are more likely to appear in the joints, the nervous system, and the heart than anywhere else in the body. When the symptoms of Lyme disease appear in these parts of the body, the person may be considerably disabled. It is this potential for disability that, understandably, makes people so afraid of the disease” (Barbour, 1996).

Early treatment often fails when medication is discontinued prior to full recovery. Some patients experience a slow, insidious deterioration, while others report an abrupt return of former symptoms as well as new, disturbing ones. A literature review on treatment failure of antibiotic therapy found that after a 2-4 week course of treatment, 10 to 61 percent of patients relapse with debilitating symptoms that are indistinguishable from those of late Lyme borreliosis (Green, 2009). Further delay in treatment comes when patients wait to call their doctors during the initial relapse because they do not want to complain after being treated with what they have been told should be sufficient treatment. They are naturally bewildered that the therapy ceases before they feel better, since it is common for doctors to repeat a course of antibiotics when a throat or ear infection persists. In the case of Lyme disease, the end of treatment is often dictated by treatment guidelines rather than the resolution of symptoms.

It is well-documented that Bb can infect most parts of the body, producing different symptoms at different times (Steere, 1989; Duray, 1989). Early symptoms are easily mistaken as aches and pains attributable to the common flu, stress at work, over-exercising, or simply the natural aging process. The initial dismissal of possible Bb infection allows an otherwise more easily treated infection to develop into a full-blown central nervous system infection which is difficult to treat.

One of the more perplexing dimensions of untreated or under-treated infection is the multiplicity of symptoms that seem to change, appear and disappear suddenly, only to reappear. In patients with Lyme meningitis, Pachner (1995) notes that, “Symptoms can be surprisingly variable, so that days of near normality can alternate with days of profound debility.” Symptoms can include, but are not limited to, fever, chills, fatigue, body aches, headaches, rash, swollen lymph nodes, stiff neck, pain, meningitis, neurological problems, poor motor coordination, cognitive impairment, heart problems, eye inflammation, skin disorders, gastrointestinal issues,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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and general weakness. The great range of symptoms can make disease recognition difficult.

Mother of Patient H from Florida, sick for 15 years:

“One of her doctors told us that if one doesn’t want to be bored in the medical profession, one should focus on Lyme disease since every organ in the body is affected. Our daughter has had brain encephalitis, arthritis, vision problems, sporadic rashes, extreme fatigue, a headache that has lasted 11 years, photosensitivity, hyperacusis, tinnitus, skin sensitivity, carditis, autonomic nervous system dysautonomia and much, much more.”

Patients choosing to continue their search for a treating physician often report great difficulties finding a doctor who has experience in treating persisting infection. Many patients report that the specialists they consult are focused on their chosen field of medicine and miss the multi-system nature of the disease. When this multi-system concept is understood and patients receive long-term antibiotic therapy, they report benefits. A patient survey found that between 72 and 78 percent of respondents experienced improvement in neuropathy, joint pain, concentration difficulties and fatigue with additional treatment beyond 2-4 weeks (CALDA, 2009).3 Also, two NIH-funded studies on re-treatment of patients with persistent Lyme borreliosis found a statistically significant improvement in symptoms. A study found that 64 percent of patients in the treatment group, versus 19 percent in the placebo group, showed substantial and sustained improvement in fatigue (Krupp et al, 2003). Another study found that patients with more severe symptoms who received an additional 10 weeks of antibiotics reported sustained improvement in pain and physical functioning (Fallon et al, 2008). Although there are treatment failures, long-term, combination antibiotic therapies do return many patients to functional and rewarding lives.

Patient I:

“After 10 weeks of Rocephin therapy, I had regained about 80% of my previous health, and most significantly, the return of my intellect and termination of my depression…. Now after 6 weeks on oral antibiotics, I’m approximately at 90% recovered…. And the big question: will my improvement hold with the eventual ending of antibiotics?”

A common theme in the patient stories we collected was that patients asked for more effective treatment. More research is needed regarding treatment failures in order to meet the needs of those Lyme borreliosis patients who continue to be ill. Lyme borreliosis can lower the quality of

3

The percentages were determined from the survey subsample with the given symptom.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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life dramatically. Chronic Lyme borreliosis patients experience deficits in health status of someone with congestive heart failure or osteoarthritis and suffer more impairment than someone living with type 2 diabetes or a recent heart attack (Klempner et al, 2001). A more recent study found the fatigue level in patients with chronic Lyme disease equals that of multiple sclerosis (Fallon et al, 2008).

Impact on Work

Quality of life for adults with Lyme borreliosis is marked by major declines in vocational, social and recreational functioning, as well as overall deterioration in cognitive and neuropsychiatric impairment. Persistent Lyme borreliosis severely impacts patients’ abilities to function in the workplace. A James Madison University survey (Wilcox and Uram, 2009) on the impact of persistent Lyme disease on workplace performance found that patients experience difficulties working. Prior to their illness, all the respondents had been working full-time (a selection criterion), whereas only 28 percent were still working full-time at the time of the survey.

Cognitive impairment, memory, attention deficiencies, and lack of word fluency interfere with Lyme disease patients’ work performance. Eightynine percent of the 315 respondents said that their symptoms had either a “moderate impact” or a “severe impact” on their ability to remember facts and details. Moreover, 75 percent said that Lyme disease impacted their ability to understand complex concepts and analyze information. More than half of the respondents reported an adverse impact on their basic skills of reading, writing, and math. Such impaired employees are not the only ones affected. When they cannot fulfill their duties, their colleagues are forced to pick up the slack, which has a complex, negative impact on the workplace itself.

Fatigue, pain and dizziness also negatively affect Lyme patients’ ability to work. A study of Lyme patients with persistent symptoms found that 90 percent suffered from fatigue and malaise (Klempner et al, 2001); and nearly all of the respondents (95%) in the work performance survey reported that fatigue made it difficult, and in many cases impossible, to maintain a full-time workload (Wilcox and Uram, 2009). Connecticut biologist Joe Dowhan conducted tick research and brought the first Ixodes scapularis ticks to Dr. Allen Steere in 1976. Dowhan struggled to keep up with his work as he developed chronic Lyme disease:

“By the beginning of July (of 1976), I was crawling up the stairs to get home. The other biologists were finally telling me to just stay in the car because it was slowing everyone down. I was incapacitated with the disease…. In 1990, I started feeling a generalized malaise, a real fatigue,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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headaches, neck aches … I just had overwhelming fatigue, unrelated to exercise. I would find myself at two in the afternoon absolutely needing to drop my head on the desk. I just couldn’t move. I’d come home. My pockets would be stuffed with notes (to myself); I was having a difficult time remembering things and getting dinged by my bosses for not following through with things, not even remembering phone conversations with them” (Edlow, 2003).

Dowhan’s story is repeated in workplaces across the country. Many Lyme patients struggle to adequately fulfill the requirements and responsibilities of their jobs. More than half (52%) of the respondents in the work performance survey changed jobs, usually for a less challenging and less stressful job (Wilcox and Uram, 2009). Many Lyme patients eventually became too disabled to work as their health deteriorated. Half (51%) of the respondents had left the workforce, and 55 percent of those who stopped working were receiving disability benefits.

Patient J from Maryland, sick for 6 years:

“In 2004, I developed severe left-sided head pain and pressure, and eventually migraine headaches. In November 2006 I collapsed at my job where I was working as a surgical nurse in open heart surgery. I had no feeling from the neck down. I have been on disability since. I had a constant ‘buzzing’ or ringing in my ears, with occasional loud blasts of sounds. Extreme fatigue, blurred vision, floaters in my eyes were next. Tingling and numbness in my legs and eventually my arms. Balance problems were next, stumbling and falling also. I eventually walked with a cane…. I could have avoided all of this if I had been treated with oral Doxycyline for 28 days. I would still be working as a registered nurse, a job that I loved. I have been disabled since I was 52…. After 3 years of treatment for Lyme Disease, I am better, but very different from a high functioning nurse that I was. I am mentally challenged and every day is a struggle, but I am thankful that I am alive.”

Functionality at Home

Many Lyme patients have to cut back on usual everyday activities. Cooking, cleaning, and other household tasks become arduous, if not impossible, to perform due to cognitive problems, pain and fatigue. Fifty-six percent of respondents to the NatCapLyme survey said that their ability to cook a meal was “moderately impacted” or “severely impacted” by their illness, and 70 percent said that cleaning the house was nearly impossible.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Patient K from Maryland, sick for more than 10 years:

“Despite [my husband’s] long work days, he was now in charge of meals and most everything else. I was rarely able to do the shopping. I no longer cooked. One morning I decided I wanted scrambled eggs for breakfast. I remember standing at the stove, spatula in hand, looking down at these yellow things in a pan, and very clearly thinking: I DON’T KNOW WHAT THESE ARE.”

Many patients have to curtail driving due to dizziness, vision problems and/or cognitive problems. Forty-six percent of the respondents in NatCapLyme’s survey said that their driving was impaired. Lyme patients have reported that they have become lost just blocks from their own home, as they are unable to recognize familiar landmarks. One Lyme patient from Maryland wrote, “Cognitive function declined rapidly … I would get lost less than a mile from my home that I lived at for thirty years.” Consequently, patients become dependent on family and friends for transportation or otherwise find themselves homebound and isolated.

Social Impact

Interpersonal relationships are strained to the breaking point by the challenges of Lyme borreliosis. Sometimes family and friends are sympathetic to the initial illness, assuming that it will pass like the flu. Patience wears thin, however, when a patient cannot resume normal vocational and recreational activities. Being part of a school, work, sports or social event requires accommodations for the patient. Only the immediate family members, who witness the planning required to get ready for simple daily activities, understand the extent of the efforts required to maintain some normalcy. Everyday grooming requires effort. Acting normal requires stamina. Showing up requires mobility. Patients must adopt a “one day at a time” philosophy and have to cancel vacations and other important events at the last minute due to flaring symptoms. Patients feel that repeated comments from family and friends ranging from “You look fine” and “Do you still have Lyme?” to “Why don’t you take some energy pills and get back into life?” invalidate their illness.

Patient L from Virginia, sick for unknown years:

“At first my children told me that I didn’t have Lyme disease, that it was all in my head, and then they began to make fun of me, and finally, now that I have a doctor and have been under treatment, they tell me I spend too much time focusing on my Lyme disease, that I need to stop thinking about it…. I have learned, over the years, to keep it hidden as much as

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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possible, to say nothing, to never ask for help, because when and if I try to talk to them about it, I am quickly silenced or humiliated. Their lack of compassion and understanding is what hurts the most.”

The patients’ testimonies frequently speak about broken engagements, divorces and abandonment by loved ones who have difficulty accepting that the person they once knew has unnaturally changed. Meanwhile, patients suffer a loss of self-esteem due to the burden of their illness being imposed on the family. Marriages are understandably strained. Spouses may be frustrated by their partner’s sudden inability or unwillingness to have children. Disagreements erupt over the patient’s inability to work and care for their children as well as the drain of life savings to pay for treatment. Parents may differ about how to treat an ailing child, and adult children can underestimate the depth of their parents’ suffering.

Mother on behalf of Patient M from Virginia, sick for 8 years:

“It’s rough on a marriage to have a child sick without a diagnosis for a long period of time. And, it’s even more difficult once there’s a controversial diagnosis that is very expensive to treat. Add to that a sick spouse and the opportunities for implosion are everywhere. Our life turned from activities, work, vacations, individual pursuits, hobbies and pleasures to pain, isolation, pressure to make treatment decisions based on limited understanding, and total exhaustion.”

Many times Lyme borreliosis infects multiple family members. If one or both parents are affected, children reverse roles and become caretakers to their parents at the expense of their own social lives and with undue stress on their personal development. The focus of the entire family is redirected toward daily survival of new and variable symptoms, the reduction of pain, and the potential for emergency room visits. The healthy family members feel the full weight of being the caregivers. Some have to start working multiple jobs to compensate for the patient’s lost income and the added financial burden.

The patient’s personality may undergo significant changes due to the illness. Previously vibrant people become confused, scared, and angry. A mother from New Jersey wrote: “In his teen years his health and personality changed. He was having problems with anger that were uncharacteristic for him. Over several years he became homicidal, suicidal, and was in jail.” Patients who were independent before their illness become dependent on family and friends for everything. Friendships are hard to maintain, and many patients feel isolated and alone. Feeling they are a burden to their loved ones makes it difficult to face another day of suffering. Seven percent of the respondents in the NatCapLyme survey said they had attempted suicide after contracting Lyme disease and 42 percent had suicidal thoughts.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Patient N from Kansas, sick for 9 years:

“Last September, I tried to commit suicide. I ended up in the hospital due to my wounds for two weeks. Everyone thought I just had a bad case of post-partum depression. But I knew the truth, I wasn’t depressed, I was absolutely terrified about how lyme was destroying my body, and I just could not take the pain anymore. Slowly I have gotten better on antibiotics. It has almost been a year … I have come a long way from where I was, and I am able to function as wife and mother again.”

As patients seek understanding on how to deal with the multi-faceted issues related to having Lyme disease, support groups can play an important role in helping patients regain their health. Struggling with bewildered family members and the lack of support from physicians and insurance companies, they turn to Lyme disease support groups to learn more about their illness and how to cope. Support groups provide life skills in how to deal with daily challenges, illness-related social problems, and disability and insurance issues. As former U.S. Surgeon General, C. Everett Koop, MD, explained: “I believe in self-help as an effective way of dealing with problems, stress, hardship and pain…. Mending people … is no longer enough; it is only part of the total health care that most people require.”

Financial Impact

As the illness stretches into months and then years, health care costs accumulate. NatCapLyme’s survey asked respondents for their “best estimate” of the total costs of their Lyme-related treatments. Forty-six percent said that they and their insurance company paid $50,000 or more for treatment. Many patients find their insurance coverage is inadequate to cover their growing health care needs (Jorgensen, 2010). Patients also report that their health insurance company has denied coverage of antibiotic therapy for persistent Lyme borreliosis based on the Infectious Diseases Society of America’s (IDSA) 2006 treatment guidelines on Lyme disease. A patient from Virginia, sick for over a year, explains, “Not only do Lyme patients have to battle the medical community for a proper diagnosis, but they are forced to battle the insurance companies for treatment.” Treatment that falls outside the guidelines is deemed “to exceed the standard of care” or is considered “experimental” and therefore is not covered. Thirty-five percent in the NatCapLyme survey responded that they were denied either insurance coverage or treatment due to IDSA treatment guidelines. A husband of a patient from Virginia who has been sick for 3 years states, “I have paid medical insurance premiums for more than 50 years but today’s medical system allows my insurance carrier to deny coverage of lyme treatment. Big insurance is allowed to practice medicine without a license.” Insurance

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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denial leaves Lyme patients with the choice of either paying for treatment out of pocket or being condemned to a life of persistent illness.

Patient O from Iowa, sick for 6 years:

“Our insurance company to this date refuses to pay for the treatment and antibiotics citing them to be experimental and not medically necessary. We exhausted all appeals with the insurance company, put a mortgage on our home and cashed out our retirement funds to pay for the medical bills. We currently have a case pending before the Supreme Court of Iowa pertaining to medical coverage denied by our health insurer.”

Most health care costs could be avoided if the infection were diagnosed in a timely manner and treated aggressively. According to a CDC study on the economic impact of Lyme disease, the estimated average annual costs, both medical and non-medical, per patient with late-stage Lyme disease are $18,880 (in 2009 dollars). That amount is 10 times higher than the per patient costs for early-stage Lyme disease (Zhang et al, 2006).

Lyme borreliosis poses a serious financial strain on families. Numerous patients with persistent Lyme borreliosis are forced to cut back on work, modify their career goals, or stop working altogether. Parents may have to curtail work hours to care for a sick child. According to the JMU work performance survey, 37 percent of the respondents had lost $100,000 or more in income and wages from onset of illness to the time of the survey. Job loss usually means health insurance coverage is lost as well. Families often deplete savings accounts, run out of personal resources, and lose their homes to pay for medical care. Many patients must depend on government assistance. Twenty-five percent of respondents in the CALDA survey had been on public support or received disability benefits for their illness.

The loss of income has a staggering effect on Lyme patients and represents a burden on our economy. The CDC estimates the national annual economic impact of Lyme disease to be $295 million (in 2009 dollars) (Zhang et al, 2006).4 This figure underestimates the true economic impact for several reasons. First, the CDC acknowledges significant underreporting (by a factor of 6 to 12) in the number of Lyme disease cases under their case definition (CDC, 2004). This means that the actual number of new Lyme disease cases could be over 300,000 per year. Secondly, the CDC’s economic impact study looked at a narrow set of economic variables. It excluded the costs of loss in productivity resulting from spouses and parents taking time

4

The total economic costs figure was based on the CDC’s estimate of $203 million (in 2002 dollars) by Zhang et al, converted into 2009 dollars, using the Consumer Price Index (CPI-U) and adjusted for the increase in the number of reported cases from 23,763 in 2002 to 28,921 in 2008.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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off from work to care for a family member. Other economic costs, such as those associated with childcare services and adults needing in-home or assisted living services also were not included. A 2007 study on the economic burden of persistent disease found that caregivers’ lost productivity can add fully 7 percent to economic costs (DeVol and Bedroussian, 2007). Not only does the disease affect patients’ financial stability, it has the potential to impact the financial security of generations to come.

Patient P from Maryland, sick for more than 20 years:

“If the doctors had met their most basic obligations, or cared at all, I would have been cured decades ago…. They have decided I do not have value as a human being and am not worthy of a healthy, happy life.”

Youth

According to the CDC, children 5 to 14 years of age face one of the highest risks of Bb infection (CDC, 2006). This risk is likely due to the amount of time children spend playing outdoors, and a lack of awareness of the importance of finding and removing ticks. While children experience the same range of symptoms as adults, they often do not have the capacity to express and understand what they are feeling. Parents and doctors often dismiss non-specific symptoms of headaches, fatigue, gastrointestinal issues, and behavioral changes as a part of growing up. Such dismissal often results in delayed diagnosis, thereby allowing dissemination of the infection and consequent long-term illness.

Studies have revealed a long-term impact of Lyme borreliosis on a child’s physical and intellectual functioning. Researchers at Columbia University found “deficits in visual and auditory attention, or in working memory and mental tracking” in children with cognitive problems associated with Lyme disease. They concluded that their study demonstrates that children whose diagnosis and treatment are delayed may suffer considerable impairment (Tager et al, 2001).

The education of children with persistent Lyme borreliosis becomes compromised, leading to inconsistent school attendance and performance. According to the NatCapLyme survey, 45 percent reported that their children with Lyme borreliosis missed school more than one day a week, and 42 percent reported that their children were tardy more than once a week. Studies on the long-term impact of Lyme borreliosis on children’s physical and intellectual functioning have documented behavioral changes, forgetfulness, cognitive deficits, and partial complex seizure disorder (Bloom et al, 1998; Tager et al, 2001). Teachers notice changes in play behavior, declining school performance, excessive sleepiness and frequent trips to the school

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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nurse. At home, parents notice that some children present with cognitive and behavioral issues, nightmares, trouble falling asleep, difficulty concentrating and learning difficulties.

Adolescents present special diagnostic and treatment challenges, since their new-found desire for privacy, normalcy and independence may prevent full-body tick checks by parents and compliance with keeping doctor appointments and taking prescribed medications. Lyme borreliosis can cause symptoms including fatigue, slurred speech, and confusion which can be misinterpreted as resulting from illegal drug or alcohol use. Although some school districts offer generous support through Individualized Educational Plans and home instruction, others resist. Sadly, some teenagers do turn to street drugs and alcohol to self-medicate unmanaged neurologic and rheumatologic pain.

Many teenagers, overwhelmed by the illness and socially isolated, find it increasingly difficult to cope with life. Parents of children 8 to 16 years old reported in the Columbia University study that 41 percent of their children had expressed suicidal thoughts and 11 percent had made a suicidal gesture (Tager et al, 2001). Among the most disturbing results of the NatCapLyme survey were that 54 percent of the respondents reported that their children with Lyme borreliosis suffered from depression and 13 percent reported that their children had attempted suicide. Such suicidal ideation arises from an understandable weariness from chronic illness. Most poignant is the simple statement from a Lyme-infected child, “I just don’t want to live anymore.”

Patient Q, age 13 from Missouri, sick for 4 years:

“The kids at school pick on me because I am now in a wheelchair. I have a pic line in my arm … I am very sad. I can’t play sports and I am very tired all the time. Sometimes I wish I were not alive. I really have no friends. Who wants to be a friend of someone in a wheelchair or with an illness like mine?”

Relationships with friends and family become strained for some young people with Lyme borreliosis. Some children are confined at home by their illness. Their participation in normal activities, such as athletics or hobbies, becomes a vague memory. Persistent illness affects youths’ ability to participate in normal rites of passage.

Mother on behalf of Patient R from Florida, sick for more than 10 years:

“Since R was not able to attend school for so many years, receiving home-bound tutoring through the school, she missed out on the normal social growth of a teenager. I think one of the most difficult moments for

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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me was the night her only two friends brought their dates over to show off their prom finery, with the limo waiting outside. I thought my heart would break when my Cinderella ran upstairs after the kids left.”

Parents understandably suffer along with their children. During periods when symptoms abate, hope of recovery rises, only to be dashed when symptoms return. Parents must make unimaginable decisions about putting their children on powerful painkillers or pursuing experimental treatments. They spend sleepless nights weighing the risks and benefits of committing their own child’s life to one of the opposing treatment philosophies.

Mother of Patient S from Virginia, sick for more than 8 years:

“The treatment decisions often boil down to the lesser of two evils. I worry constantly about the potential long-term effects of all of these medications on her developing body, her reproductive capacity.”

Parents wonder why there is a narrow focus of concern from physicians regarding the dangers of curative antibiotics while little concern is expressed regarding the dangers of all the other medications including painkillers and “black-box” medications for the treatment of symptoms. As the mother of an 8-year-old Maryland patient states, “There is also, as a parent, guilt … tremendous guilt if we make what later turns out to be the wrong choice.”

Most parents share the goal of guiding their children to a happy, healthy, productive adulthood. To that end, many parents of children suffering from Lyme borreliosis stretch their resources of time, energy and money to the limit. When young adults expect to launch their independence via college and career, ongoing illness interferes with this natural process. As the years of illness accumulate, hopes of becoming a productive adult and having a family fade. Too many of these young people are forced to create new life plans, but how does one plan for life under these circumstances?

Patient T, young adult from Virginia, sick for more than 10 years:

“Lyme has taken what was supposed to be my decade of life, promise, and opportunities and turned it into a decade of intense struggle, betrayals, and constant disappointment. While I once celebrated the highest academic achievements, strove to draw that perfect sound from my instrument, and worried which boys’ words rang true, I now celebrate making it to the bathroom, strive for ways to diminish my ever growing medical costs, and worry this time the insurance company will reject my claim because I’m too expensive and growing too weak to fight back. And when Lyme traps me in a twitching body that gasps for air, tries to vomit and feels crushed by an elephant all at the same time, I remember my past filled with promise,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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ponder my present filled with doctors who say if they can’t figure out what’s wrong it doesn’t exist and family that says if you just try hard enough all problems will disappear, and then contemplate my future—wondering if there is still any hope left in it. They say that adversity builds character, but Lyme weaves darker paths in life that I hope my friends will never need to travel.”

Conclusion

Lyme borreliosis erodes every facet of an individual’s life, decimates marriages, and causes children to leave the educational system. Life never returns to normal for many patients, as they must accommodate activity restrictions and ongoing health concerns. Recovery is further complicated by physicians who do not acknowledge the possibility of ongoing illness, and medical policymakers who do not consider additional avenues worthy of scientific exploration, in spite of mounting evidence of persistent infection.

Research remains inconclusive about optimal treatment. Yet state medical boards routinely penalize doctors for deviating from the Infectious Diseases Society of America’s (IDSA) guidelines for treatment of Lyme disease (Wormser et al, 2006) by subjecting them to investigations and disciplinary procedures rarely visited on physicians treating other diseases. Consequently, a growing numbers of patients lose their doctors, who stop treating Lyme disease in fear of losing their licensing. Physicians are reluctant to treat Lyme and other tick-borne infections in a manner that contradicts the IDSA guidelines. This phenomenon appears to be unique to Lyme borreliosis. The government-sanctioned medical society favoring one treatment philosophy over another places an unnecessary burden on patients who are left to fend for themselves. In an ironic twist of the medical axiom “First do no harm,” patients are left to wonder why the harm they endure from failure to receive treatment is not a rejection of that cherished standard.

The patient testimonies submitted illustrate that the conventional medical wisdom is seriously disserving Americans with tick-borne infections. They also support the frequent allegation that Lyme and associated tick-borne infections are major life-debilitating diseases that should be taken very seriously. Disease manifestations and treatment responses vary among patients. Some patients who are diagnosed and treated early respond well to IDSA-recommended treatment. Patients, whose diagnosis and treatment are delayed, often benefit from long-term or intermittent antibiotic therapy, which is why patients should have the right to pursue all treatment options.

Lyme patient support groups are encountering a growing number of people who were healthy prior to contracting Lyme borreliosis and have not returned to their former level of functioning after treatment. Patients across the United States report innumerable treatment failures. Worse yet, some

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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people never receive treatment. It is unconscionable that so many people suffer for lack of an accurate diagnosis or effective treatment.

A recent study on the use of guidelines in medical negligence litigation in England and Wales concluded that, “there is a danger in applying the generalized prescription of guidelines in a rigid fashion to every patient” (Samanta et al, 2006). The authors noted that this interference with clinical freedom can result in “cookbook medicine.” “In medical practice, many situations arise where the art of identifying patient problems and the application of clinical acumen to individual patient’s needs remain removed from the science and technological advances of the discipline. Evidence-based medicine cannot fully capture the art of medical practice, and there remains a need for clinical judgment and discretion” (Samanta et al, 2006). Weak research data undermine the validity of treatment guidelines.

Clearly a serious gap between the conventional medical community’s acknowledgment and patient reality is evident. Harvard Medical School professor Dr. Jonathan Edlow states in his book, Bull’s-Eye, “We still have a lot to learn about Lyme disease, and more importantly, we still have a lot to learn about the scientific process” (Edlow, 2003). Patients hope that the Institute of Medicine’s (IOM) Workshop will lay the foundation by bringing university and private-sector scientists and practicing physicians from different viewpoints together to collaborate on solving the problems of treatment failures and persistent illness. We must utilize the scarce resources available to reach out to new thinkers, to explore fresh approaches that will give us the answers to find a cure for all victims of Borrelia burgdorferi.

“The controversy in Lyme Disease research is a shameful affair. And I say that because the whole thing is politically tainted. Money goes to people who have, for the past 30 years produced the same thing…. Nothing.”

Willy Burgdorfer, Entomologist who first identified the bacterial spirochete responsible for causing Lyme disease (Wilson, 2009).

Recommendations

The National Capital Lyme and Tick-borne Disease Association recommends:

  1. Improve surveillance by effective, thorough national oversight of tick-borne infections. Tick-borne infections are a serious health concern, and effective national surveillance of these diseases is needed in order to improve public awareness, prevention and diagnosis. Develop a more inclusive surveillance case definition that reflects the actual experiences of practicing physicians confronted with patients presenting with symptoms consistent with Lyme borreliosis. Suggestions to accomplish this are:

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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  • Broaden the case definition for surveillance to include advanced late-manifestations of Lyme disease.

  • Abandon the two-tier testing approach by eliminating the ELISA as a prescreening requirement before advancing to the Western Blot. The ELISA is too unreliable to be used as a preliminary screening test, given its extremely low sensitivity.

  • Standardize national reporting forms by issuing brief, automated forms that will enable treating physicians to report cases easily. Re­ports should be held confidential and not disclosed to state medical boards or insurance companies and their service organizations in order to remove the physicians’ fear of adverse consequences from treating patients with Lyme borreliosis.

  1. Differentiate between the criteria for surveillance and clinical diagnosis. Once sufficient data have been gathered to form valid conclusions with respect to symptoms of Lyme borreliosis, develop a working clinical case definition for broad application within the medical community. Immediately, the CDC should inform all health service providers and health departments that the surveillance case definition is not intended to be used in clinical diagnosis.

  2. Improve diagnostics by developing definitive, reproducible tests with a sensitivity of 95% or higher, that can detect active and latent infec­tion of Bb and other tick-borne infections. The test should be reliable enough to be part of an annual physical examination.

  3. Design a national survey. While both NatCapLyme and CALDA have conducted informal surveys which yielded useful information, their results point to the need for an unbiased national scientifically valid survey that collects reliable data on the experience of those suffering from Lyme and other tick-borne infections. Include the patient com­munity in designing the survey.

  4. Broaden clinical trials to include patients with persistent Lyme borreli­osis. These patients are at the heart of the Lyme controversy. Broaden the entrance criteria for government-funded clinical trials to include entire classes of Lyme patients, whose disease expression and treatment response are poorly understood.

  5. Base research grants for tick-borne infections on a non-biased ap­proach. Given the recognized controversy over treatment of Lyme and other tick-borne infections, priority should be given to fund new researchers with innovative ideas and methods that would help to settle this controversy.

    • Many in the Lyme community believe that the Bayh-Dole Act of 1980 ultimately hindered advancement in Lyme disease research. Notably, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) researchers recently discovered significant new biomarkers. Under

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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  • the ADNI, researchers agree to share all data, make every finding public immediately, and renounce ownership and patent rights accru­ing to any individual researcher. According to Dr. John Trojanowski, a researcher at the University of Pennsylvania, “… we all realized that we would never get biomarkers unless all of us parked our egos and intellectual-property noses outside the door” (Kolata, 2010). NatCapLyme strongly advocates adoption of this model in the field of Lyme disease research.

  • Conduct treatment trials that better mirror the variety of treatment regimens actually used by treating physicians.

  • Research the unique attributes of Bb including multiple life forms and the incredible survivability of this organism in the host, genetic complexity, cell-wall deficient forms, its capacity for intercellular sequestration, antigenic variation, immune suppression, and the pos­sible role of borrelial colonies and biofilms.

  • Research the complex disease resulting from multiple tick-borne infections.

  1. Create dialogue among the scientific research community, health agen­cies, medical societies, and the full spectrum of treating physicians, including those who view Lyme borreliosis and tick-borne diseases as a potential persistent and infectious process. NatCapLyme encourages all parties interested in Lyme and tick-borne diseases to work together to find solutions. NatCapLyme believes that true solutions to the dilemma of Lyme and tick-borne infections may be found only when all parties are willing to consider the views that each seeks to contribute.

  2. Respect patients’ right to choose treatment. Medical guidelines are de­signed to provide recommendations and not mandates. No monolithic treatment solution should be offered for such an unresolved area of medical research. While the overuse of antibiotics is a concern to all, some Lyme patients are reporting benefit from longer-term and combi­nation antibiotic therapy.

  3. Design a National Informed Consent Form to protect the patients’ right to choose as well as protect the doctors’ right to treat. The consent form should reflect fair and balanced treatment options and the ben­efits and risks of both short-term and long-term treatment choices. The committee that writes this should include medical and legal profession­als who hold varied and conflicting points of view. This consent form must not favor any single treatment protocol. It should only include information necessary for fully informed patients to exercise their right to choose treatment.

  4. Conduct Institute of Medicine Workshop on tick-borne infections, Part II. This workshop should address effective treatments for persis­tent and assimilated Lyme disease.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Our committee would be happy to discuss further these recommendations and the experiences of Lyme and tick-borne disease patients that led to our conclusions. We were asked to provide the IOM committee with insight into the patient experience. We concluded that a simple cathartic expression of the angst and suffering of patients and their families would be useless, unless it was combined with insights into the research and science that further illuminates that experience. There is an urgent need to broaden our understanding of tick-borne infections. It is our hope that the scientific community will address the chronic forms seriously and effectively, so that many more of Lyme victims will be able to return to useful, productive lives and the pursuit of happiness.

The National Capital Lyme and Tick-borne Disease Association thanks the Institute of Medicine committee members for allowing us to offer you the experience, thoughts, concerns, and needs of Lyme patients. Our hope is that the work of this committee will result in better care for patients and continued research to find a cure for this disease. We look forward to continuing to work with all governmental agencies and the medical community in hopes of finding successful treatment for all patients with tick-borne diseases.

The NatCapLyme Working Group: Monte Skall, Executive Director, NatCapLyme; Don Boileau, Professor; Barbara Cohen, Psychologist; Cindy Eisenhart, School Librarian; Susan Green, Attorney; Janis Ivicic, School Teacher; Helene Jorgensen, Economist; Linda Lobes, Advocate; Bill Merrigan, Legislative Attorney; Mimi Segal, Clinical Social Worker; Gregg Skall, Attorney; Lisa Torrey, Tick-Borne Disease Advocate; Joy Walker, Law Student; Judith Weeg, former CDC Health Educator; Sharon Whitehouse, Editor; Diane Wilcox, Professor.

Acknowledgment: We would like to thank the following organizations for their contributions to this paper: Lyme Disease United Coalition, Judith Weeg, President; Michigan Lyme Disease Association, Linda Lobes, President; National Tick-borne Disease Advocates, Lisa Torrey, President; and Parents of Children with Lyme.

Correspondence: Monte Skall, Executive Director, National Capital Lyme and Tick-borne Disease Association; phone: 703-821-8833; e-mail: Natcaplyme@natcaplyme.org.

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Wilcox, D. M., and C. Uram. 2009. The impact of chronic Lyme disease on workplace performance: A survey of chronic Lyme patients. (Addendum of tables and charts). Paper presented at the International Lyme and Associated Diseases Society Conference 2009, National Harbor, MD.

Wilson, A. A. 2009. Under Our Skin. Open Eye Pictures, Inc. http://underourskin.com/blog/?p=191 (Accessed August 5, 2010).

Wormser, G. P., R. J. Dattwyler, E. D. Shapiro, J. J. Halperin, A. C. Steere, M. S. Klempner, P. J. Krause, J. S. Bakken, F. Strle, G. Stanek, L. Bockenstedt, D. Fish, J. S. Dumler, and R. B. Nadelman. 2006. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical practice guidelines by the Infectious Diseases Society of America. Clinical Infectious Diseases 43:1089-134.

Zhang, X., M. I. Meltzer, C. A. Pena, A. B. Hopkins, L. Wroth, and A.D. Fix. 2006. Economic impact of Lyme disease. Emerging Infectious Diseases 12(4):653-60.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A4
DIAGNOSIS OF TICK-BORNE DISEASES: BORRELIA BURGDORFERI, BABESIA MICROTI, AND ANAPLASMA PHAGOCYTOPHILUM

David H. Persing, M.D., Ph.D.

Chief Medical and Technology Officer

Cepheid

Sunnyvale, CA

Consulting Professor of Pathology

Department of Pathology, Stanford University School of Medicine

Abstract

Lyme disease is the most common tick-borne zoonotic infection in the northern hemisphere. It is a complex multisystem disorder that may involve single or multiple organ systems. Infection with the causative agent, the spirochete Borrelia burgdorferi, may involve the skin, central and peripheral nervous systems, as well as targets within the cardiovascular and musculoskeletal systems. Patients at risk for Lyme disease are also at risk of acquiring infection or coinfection with other agents transmitted by the same tick vector, including Babesia microti and Anaplasma phagocytophilum. Since infection with all three agents can manifest initially as a nonspecific febrile illness with or without specific organ system involvement, the clinical diagnosis of a presenting patient can be challenging. Laboratory methods for detection of and discrimination among these infections are of significant value in the clinical evaluation of such patients. This review will describe the curious convergence of these tick-borne infections and the diagnostic challenges they pose, and will detail the laboratory procedures that can be used to decipher the complex array of diagnostic possibilities.

Introduction

Although significant progress has been made over the past several decades in understanding the immunobiology of Lyme disease and in increasing awareness that this disease is an important public health problem, much about the disease still remains puzzling. Its pathogenesis is still poorly understood, and the interdependent problems of diagnosing the disease accurately and assessing therapeutic outcomes confound one another. One of the most curious aspects of Lyme disease in humans has been its inconsistent presentation, in terms of both disease severity and organ system involvement (Malawista and Steere, 1986; Rahn, 1991; Steere, 2001). By far, the most consistent finding is erythema migrans, often accompanied by

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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a nonspecific febrile illness. However, even these findings may be absent or unrecognized in many cases, and subclinical or self-limiting infections may occur in a substantial proportion of exposed persons. Within a few weeks to months of infection, a wide array of signs may appear that affect certain subsets of infected patients. These signs (in roughly descending order) include arthritis, lymphadenopathy, meningitis, cranial neuritis (including Bell’s palsy), myopericarditis, nonexudative sore throat, mild transient or recurrent hepatitis, and, less commonly, pancarditis, ocular involvement, and adult respiratory distress syndrome. Years after the onset of disease, occasional patients may develop migratory musculoskeletal disorders along with persistent malaise and fatigue or chronic encephalomyelitis (Logigian et al., 1990). These complications usually respond to therapies directed against Borrelia burgdorferi, but some patients have delayed responses and others do not respond at all.

In the United States, the apicomplexan blood parasite Babesia microti and the more recently recognized agent of human granulocytic anaplasmosis (HGA) are also transmitted by the deer tick (Pancholi et al., 1995; Spielman, 1976; Spielman et al., 1979; Telford et al., 1996). Both infections appear to be most intensely enzootic in established Lyme disease-endemic habitats, and Lyme disease coinfection with one or both of these organisms has been described in most of these areas in the upper Midwest and northeastern United States. In general, cardinal symptoms of babesiosis and anaplasmosis are often absent in co-infected patients, such that coinfected patients can be difficult to distinguish objectively from patients with uncomplicated Lyme disease. However, because the three infections may require different approaches to treatment, an understanding of the natural history of infection with Babesia and Anaplasma may become critical for understanding the biological variation of human Lyme disease and determining optimal medical management for affected patients. For these and other reasons, considerable effort in several laboratories has gone into further defining the transmission cycles of these agents, developing serological and molecular markers of infection for all three pathogens, propagating all three pathogens from human sources, and defining the extent of human exposure to these pathogens (Reviewed in Persing, 1997).

Several other tick-borne pathogens have been described in recent years, including the agent of human monocytic ehrlichiosis (reviewed in Bakken and Dumler, 2000) (Dumler et al., 2007; Thomas et al., 2009) and a novel babesia species (B. duncani) which is found primarily in the western U.S. (Persing et al., 1995; Quick et al., 1993). However, these organisms do not appear to be enzootic with Lyme disease and are not part of the Lyme disease transmission cycle. As a result, coinfection of these organisms with B. burgdorferi, though not impossible, is much less likely. The diagnosis of infection with these organisms should be considered on the basis of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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likelihood within their respective endemic areas, but the focus of this review will be on agents that are proven to be part of the Lyme disease ecology.

B. microti Infection

B. microti infection has been diagnosed in residents of many areas in the northeastern and northern midwestern United States where Lyme disease is prevalent (Homer et al., 2000a; Krause et al., 2003; Pruthi et al., 1995; Vannier and Krause, 2009). It is interesting to note that B. microti was once considered to be a possible agent of Lyme disease, since many patients with babesiosis presented with an erythema migrans-like rash at the site of a deer tick bite. The initial symptoms of both illnesses somewhat overlap: like Lyme disease, babesiosis in humans often presents with nonspecific symptoms including fever, fatigue, and other flu-like symptoms. Hemolytic anemia, which lasts from several days to a few months, may occur in patients with clinically severe cases, most commonly asplenic or elderly patients. However, most cases of human babesiosis in normosplenic, immunocompetent patients are probably subclinical and occur as a self-limiting illness (Krause et al., 1996d; Ruebush et al., 1977).

Seroepidemiological data suggest that ~10% of Lyme disease patients in Connecticut and perhaps even higher proportions of such patients in other areas have been exposed to B, microti (Filstein et al., 1980; Krause et al., 1991). However, these two studies did not provide proof of coinfection (vs. sequential infection) with both agents, because they were conducted retrospectively, and specimens for the direct demonstration of both pathogens were not collected. A prospective study by Krause et al. (Krause et al., 1996d) provided more convincing evidence of simultaneous infection with B. burgdorferi and B. microti in substantial numbers of patients with presumptive Lyme disease from coastal New England. Although not usually recognized as coinfected on clinical grounds, patients harboring both organisms often had more severe disease and a higher likelihood of persistent post-infectious fatigue.

Since antibiotic therapy for early Lyme disease is unlikely to be effective against coinfection with B. microti, it is easy to envision a scenario in which underlying babesiosis is responsible for the persistence of symptoms after therapy for early Lyme disease. However, since the clinical presentation is nonspecific, it will be difficult to know at the time of presentation whether a patient would benefit from therapy targeting babesial coinfection. The risks associated with antibabesial therapy such as atovaquone plus clindamycin are not insignificant, and given a low probability of coinfection, presumptive diagnosis and therapy would not appear to be warranted even in the most heavily endemic areas. It is important to note

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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that the converse scenario does not appear to be true: among patients with case defined chronic fatigue syndrome and no history of antecedent Lyme disease, there is no evidence supporting a major role of coinfection with B. burgdorferi and/or B. microti (Macdonald et al., 1996). A more conservative approach would employ selective testing of patients, who based on clinical, epidemiological, and initial laboratory evaluations, may be at higher risk of coinfection (see below).

Human Granulocytic Anaplasmosis

In 1994, Bakken et al. (Bakken et al., 1994) described a nonspecific febrile illness among patients in the Upper Midwest that was characterized by, thrombocytopenia, and neutrophilic inclusions (morulae). Genetic and serological analyses of patients’ blood samples indicated that the agent of human granulocytic ehrlichiosis was closely related to Ehrlichia equi and Ehrlichia phagocytophila. Infections caused by a similar or identical agent were subsequently described in many states including New York, Connecticut, Massachusetts, Rhode Island, Minnesota, Wisconsin, and California (reviewed in Bakken and Dumler, 2000) (Dumler et al., 2007; Thomas et al., 2009). Since then, phylogenetic analyses have determined that the agent of human granulocytic ehrlichiosis is more closely related to the genus Anaplasma and the infection is now referred to as human granulocytic anaplasmosis (HGA) (Dumler et al., 2007).

The report of a case of HGA that occurred following a deer tick bite (Pancholi et al., 1995), together with recognition of the apparent overlap between areas where Lyme disease and HGA are endemic, prompted an investigation into whether the deer tick could also transmit HGA. Ixodes ticks collected from fields in several locations in Wisconsin where HGA cases have been described were analyzed retrospectively; the collection obtained from Wisconsin in 1993 and an earlier collection stored in alcohol since 1982 both contained A. phagocytophilum-infected PCR-positive specimens. Just as retrospective epidemiological studies of B. burgdorferi demonstrated the presence of pathogen DNA in suitable vectors (Persing et al., 1990b) or reservoirs (Marshall et al., 1994a) from historic specimens, the existence of the agent of HGA clearly preceded the first descriptions of the disease itself. Indeed, the increased incidence of HGA is likely to be due, in part, to the emergence of its recognition. In a subsequent study, Telford et al. (Telford et al., 1996) showed that the deer tick is competent to transmit an agent of HGA that was recovered from a patient on Nantucket Island. Ixodes pacificus may be the vector of HGA in the western United States; this tick is the primary vector of E. equi, which is the agent of HGA.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Immunomodulatory Effects of Babesia and Anaplasma: Impact on Diagnostic Markers?

The elucidation of the immunologic interplay of the microbial agents that exist with the transmission cycle of Lyme disease is likely to yield a better understanding of what can be expected in occasional human cases. In the case of multiple pathogens that coexist within a rodent reservoir involved in overlapping transmission cycles (as is the case for B. burgdorferi, B. microti, the HGA agent, and perhaps other organisms), it is reasonable to hypothesize that immune responses to one organism may have an impact on concurrent infections, especially if the underlying infection is associated with immune suppression. Infections by both Babesia and Anaplasma species are associated with substantial immunosuppressive or immunomodulatory effects (reviewed in Persing, 1997). Coinfection by the agent of HGA and B. burgdorferi or by B. microti and B. burgdorferi could have substantial theoretical effects on the immune response, but the practical questions are these: Are disease outcomes altered, and are immunologic effects severe enough to alter immune responses so that they can no longer be used as reliable indicators of infection?

Animal models are helpful in answering these questions. Consistent with the above predictions, experimental coinfection of a mouse model with B. burgdorferi and A. phagocytophilum increased the number of CD4+ cells and drove the cytokine responses toward a Th1 lymphocyte response (Zeidner et al., 2000). In another animal model, coinfection with B. burgdorferi and A. phagocytophilum led to increased pathogen burden in blood and tissue, and to more severe Borrelia-induced arthritis than single infection with B. burgdorferi alone (Thomas et al., 2001). However, during coinfection, levels of IL-12, gamma interferon, and tumor necrosis factor in serum were paradoxically decreased whereas levels of IL-6 were elevated. A similar study of coinfection in C3H/HeN mice evaluated the tissue distribution of tick-transmitted B. burgdorferi and A. phagocytophilum infection by quantitative PCR (Holden et al., 2005). Coinfected animals had increased spirochetal burdens in multiple tissues but Anaplasma numbers (found primarily in blood) remained constant. Although antibody responses were diminished somewhat for A. phagocytophilum, levels of antibody that developed against B. burgdorferi were not affected.

Although coinfection with B. burgdorferi and B. microti was found to be associated with increased disease severity and greater likelihood of spirochetemia in human subjects enrolled in a blinded clinical evaluation, experimental evidence of increased severity in animal models has been mixed. Initial studies showed immunologic effects of coinfection in some mouse strains but not others. C3H mice showed no evidence of increased severity, but normally Lyme disease-resistant Balb/c mice showed an increase in arthritis severity

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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at day 30, along with reductions in levels of immunosuppressive cytokines IL-10 and IL-13 (Moro et al., 2006). Another mouse model showed that dual infection with B. burgdorferi and B. microti appeared to follow independent courses, with no apparent increase in Lyme disease severity (Coleman et al., 2005), although mouse strains used and inoculation times differed between the two studies. In both studies, serological responses to both agents appeared to be largely unaffected by coinfection.

Taken together, the data from animal models and human clinical studies suggest that coinfection with A. phagocytophilum and/or B. microti may have immunological effects during the course of B. burgdorferi infection, but these effects are not in themselves sufficient to completely abrogate cellular or humoral immune responses to the point of complicating the serodiagnosis of Lyme disease. Likewise, the presence of concomitant infection with B. burgdorferi does not appear to suppress immune responses to either the HGA agent or B. microti to the point that infection cannot be detected in diagnostic assays. A. phagocytophilum infection may be associated with false positive serologic responses to B. burgdorferi, (Hofmeister et al., 1996; Wormser et al., 1996), but not false negative responses.

Clinical and Initial Laboratory Evaluation of Tick-Borne Diseases

For patients exposed to ticks in areas where multiple tick-borne pathogens are endemic, it seems reasonable for clinicians to be aware of clinical signs that may be consistent with each infection alone or in combination, especially when patients with Lyme disease fail to respond promptly to antibiotic therapy. Patients with uncomplicated erythema migrans, without systemic symptoms, may require no further laboratory-based evaluation and can be treated presumptively for Lyme disease in many cases. More severe presentations may merit closer scrutiny. Symptoms including nausea and/or vomiting, fever, chills, sweats, severe malaise, and a delayed clinical response to antibiotic therapy for presumptive Lyme disease were characteristic of Babesia-co infected patients (Krause et al., 1996d). Fever, chills, myalgias, and severe headache are characteristic of granulocytic anaplasmosis (Thomas et al., 2009). Carditis has been described as a complication of Lyme disease, but has also been described in patients with HGA without evidence of B. burgdorferi infection (Jahangir et al., 1998).

Initial laboratory evaluations to be considered include examination of blood smears for the presence of intraerythrocytic inclusions (merozoites) typical of babesial infection and granulocytic morulae typical of HGA. However, the sensitivity of blood smear evaluations for immunocompetent, normosplenic patients has not been firmly established and may be relatively low for both diseases (see below). The presence of elevated liver enzymes or hematologic abnormalities may be especially useful in identifying coinfected

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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patients, since both babesiosis and anaplasmosis have been associated with increases in the levels of alanine aminotransferase. Thromocytopenia may also be present in patients with either disease, but it is rarely a feature of uncomplicated Lyme disease. Thus, the presence of thromobocytopenia in patients presenting with early Lyme disease should trigger a suspicion of coinfection with one or the other agent.

Laboratory Diagnosis of Tick-Borne Zoonoses

In general terms, the available laboratory methods for the diagnosis of the tick-borne diseases described here fall into two categories: 1) Direct methods (microscopy, culture, or PCR, depending on the agent), and 2) indirect methods (detection of organism-specific immune responses). With some notable exceptions, direct methods are generally useful for characterization of acute or active infections, whereas detection of antibody responses is most useful for confirmation of clinical suspicion in post-acute and convalescent phases.

Irrespective of the diagnostic method used, an important consideration is the pre-test probability of infection. Since Lyme disease, HGA and human babesiosis are all characterized initially by seasonal occurrence of a nonspecific febrile illness, the likelihood of tick-bite or tick exposure, guided by prevalence information for each of the infectious agents, should be a critical gating item for physician test ordering. Unfortunately, I. scapularis tick exposure is fairly common, and all three agents have been described in most of the areas endemic for Lyme disease, so laboratory testing plays an unusually prominent role in the diagnosis. However, since all of the laboratory methods currently in use have been shown to give rise to false-positive results, the positive predictive values of each of these methods may reach unacceptable levels, particularly when a multiplicity of tests is ordered. According to a recent treatment guideline from the American College of Physicians and the IDSA, patients with vague subjective complaints (headache, fatigue, and myalgia in the absence of respiratory symptoms) apart from other risk factors are at low risk for Lyme disease. They recommend against routine testing of such patients because the odds of a false positive result are greater than for obtaining a true positive result (Tugwell et al., 1997; Wormser et al., 2000b). Likewise, for patients with nonspecific persistent fatigue without a history of Lyme disease, even if living in or near endemic areas, seroprevalence rates for HGA and B. microti are low and these organisms are unlikely to be implicated (Macdonald et al., 1996).

Hematologic Evaluation

The complete blood count (CBC) with a manual differential (direct blood smear evaluation by a medical technologist) can be an extremely

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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useful tool in the initial evaluation of patients with nonspecific presentations. blood counts and peripheral blood smears along with tests of liver function. Leukopenia, lymphopenia, granulocytopenia, and especially thrombocytopenia are found in HGA. Granulocytopenia is less commonly associated with uncomplicated Lyme disease but has been described in some cases. Anemia and hemolysis are more common in babesiosis, and especially thrombocytopenia is frequently evident in babesiosis and HGA infections.

Babesiosis and HGA can diagnosed directly by observing organisms on Giemsa-stained smears of peripheral blood. For patients with intact spleens, erythrocytes may show B. microti ring forms on thin blood smears; this proportion may be as high as 80% for asplenic patients (Homer et al., 2000a; Meldrum et al., 1992; Vannier and Krause, 2009). In one study (Krause et al., 1996b), most patients coinfected with Borrelia and Babesia species were smear negative for babesiosis at the time of presentation and at all time points thereafter.

Blood smear evaluation has been advocated for the diagnosis of HGA when the index of suspicion is high (Bakken and Dumler, 2006; Dumler et al., 2007; Thomas et al., 2009), but detection by this route is unlikely unless the examining technologist is alerted to the possibility of HGA. Moreover, visual inspection of blood smears for the length of time required to find a single morula may be impractical. In one study, a small subset of HGA patients with mild infection had intragranulocytic morulae detected on smears (Belongia et al., 2001), in contrast with symptomatic, untreated patients whose smear results were evaluated after several days of fever (Bakken et al., 1994). The blood smear evaluation for HGA should be carried out within a week of disease onset, as sensitivity is highest at this time (Bakken and Dumler, 2006). Blood samples should be collected prior to administering doxycycline therapy since morulae are eliminated from the blood within 24–72 h after the start of therapy (Thomas et al., 2009). However, the since the sensitivity for detecting A. phagocytophilum is only 25–75%, blood smear evaluation is useful if the results are positive but not particularly helpful if the results are negative.

False-positive results are possible; artifacts such as platelets superimposed on red cells or Howell-Jolly bodies can appear like Babesia (Matthews et al., 2003); and to an untrained eye, a well-separated nuclear segment within a neutrophil may give the appearance of a morula. Acridine orange stain, which intercalates into double stranded DNA, can help enhance detection of B. microti inclusions in red cells and avoid detection of platelet artifacts.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Direct Detection Methods
Direct Detection of
B. burgdorferi

For direct detection of B. burgdorferi, a variety of approaches have been used in the clinical or research laboratories, including microscopic evaluation of tissues, detection of B. burgdorferi-specific proteins (by EIA or by immunohistochemistry) or nucleic acids (by PCR), and in vitro cultivation. Direct microscopic detection of B. burgdorferi has limited usefulness because of low throughput, low organism abundance in tissues (such as skin biopsies) that are confirmed positive by other methods, and the requirement for silver staining and a skilled operator. Antigen detection assays for detection of B. burdorferi have suffered similar limitations; although B. burgdorferi antigens can be detected by immunohistochemistry in tissues and by EIA within specimens from confined anatomical sites such as cerebrospinal fluid (CSF) and synovial fluid, where clearance of antigens is limited. Their presence in other samples such as urine has been more controversial (Dorward et al., 1991) (Hyde et al., 1989) (Klempner et al., 2001b) and has not stood up well to additional scrutiny. In contrast, culture and PCR techniques do appear to be diagnostically useful in certain circumstances, and we will limit the remainder of this section to these methods.

Culture-based methods for detection of B. burgdorferi were used for the initial establishment of the etiologic basis of Lyme disease, and have been used on and off for decades in the evaluation of various clinical samples for research protocols. However, their use for clinical diagnosis has been hampered by long incubation times, poor sensitivity (with the possible exception of skin biopsies from EM), and limited availability of the specialized growth medium for routine use.

The liquid media currently used for recovery of B. burgdorferi are modified versions of the original Kelly medium (Kelly, 1971) through various modifications made over time (Barbour, 1984) (Stoenner et al., 1982) (Barbour, 1986). The most commonly used medium (Barbour-Stoenner-Kelly II) is commercially available and is used for direct recovery of spirochetes from clinical specimens including plasma, CSF, whole blood and skin biopsies. Since serum supplementation is required for this medium, one source of variability in the efficiency of spirochete recovery has been the presence of anti-spirochetal antibodies in the serum (Pollack et al., 1993). Cultures are visually inspected by darkfield microscopy or after staining with specific antibodies or intercalating dyes. With newer modified media protocols, spirochetes can be detected within 5-7 days, but they may require incubation for up to three months at 30-34°C.

Recent studies of high-volume inoculation of whole blood or plasma have been surprisingly successful at recovering circulating spirochetes. For many years, rates of recovery of B. burgdorferi from blood samples collected

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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from untreated patients with EM had been less than 5-10% (Wallach et al., 1993) (Steere et al., 1983). However, the inoculum volumes in these studies were generally small. Based on previous studies which showed that circulating bacteria in patients with sepsis are often rare, and that the volume of cultured blood is directly related to culture yield, a team of investigators at New York Medical College investigated the use of high volume inocula of blood or blood fractions. They showed the following: 1) recovery of B. burgdorferi was superior from serum or plasma compared to the same volume of whole blood (Wormser et al., 1998) and 2) the culture yields from plasma were significantly greater than that from serum (Wormser et al., 2000a). Recovery of B. burgdorferi from high-volume cultures (9 or more ml of plasma) inoculated into a modified BSK II medium was above 40%. However, increasing the volume of plasma from 9 ml to 18 ml for adult patients with EM met with diminishing returns; a mere 10% increase in culture yield was observed after doubling the inoculum volume (Wormser et al., 2000a).

PCR protocols for detection of B. burgdorferi have been in use since a few years after the description of PCR itself. PCR was initially promising as a study tool in studies of the retrospective epidemiology of B. burgdorferi, including detection of the organism in suitable tick vectors 30 years prior to the formal recognition of Lyme disease in the U.S. (Persing et al., 1990a) and in suitable animal reservoirs nearly a century earlier (Marshall et al., 1994b). However, its track record for dramatically improving the general lot of Lyme disease diagnostics has been more spotty, and in general disappointing (reviewed in Dumler, 2001), (Schmidt, 1997), (Aguero-Rosenfeld, 2003, 2008). A variety of chromosomal and/or plasmid targets have been used in the various PCR protocols with varying levels of sensitivity (Dumler, 2001), (Schmidt, 1997), (Aguero-Rosenfeld, 2003, 2008).

A number of studies have compared PCR to culture for detection of spirochetes in skin biopsies. Culture has proven to be roughly equivalent to PCR in several studies with a few exceptions (Moter et al., 1994) (Nowakowski et al., 2001) (Steere et al., 1998) as reviewed in (AgueroRosenfeld et al., 2005). Widely disparate results are likely to be attributable to differences in the various studies in the PCR protocols employed, including type of PCR and/or primer and target selection and/or method of tissue preservation, as well as differences in culture techniques, including size of the skin biopsy sample cultured and/or choice of culture medium. In one study of skin biopsy samples of 47 untreated patients with EM lesions, culture sensitivity was 51%, compared 81% by using a Taqman-based realtime PCR (Nowakowski et al., 2001).

In contrast to the experience with skin samples, the sensitivity of PCR for detection of B. burgdorferi in blood samples has been much lower in patients with EM (Goodman et al., 1995) (Oksi et al., 2001). In a prospective

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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study of U.S. patients with EM, B. burgdorferi sensu stricto DNA was detected by PCR in only 14 of 76 (18.4%) plasma samples (Goodman et al., 1995). Detection of the spirochete in blood by PCR in blood samples for patients with disseminated disease has also been disappointing (Demaerschalck et al., 1995) (Liebling et al., 1993). This is likely due to the same issue that hampered early studies of culture in blood samples of Lyme disease patients, specifically the relative paucity of circulating spirochetes in the small volumes of blood that are typically extracted in a PCR procedure. Most PCR protocols test only 100 to 200 microliter samples, and these may simply be inadequate to capture enough circulating spirochetal DNA for detection, even by as sensitive a method as PCR. So it is no surprise that, given the relative lack of sensitivity of PCR in blood for detection of early, even disseminated disease, it would fare even more poorly in patients with later disease manifestations, despite positive serological findings in many of these patients (Klempner et al., 2001a).

Within anatomically confined compartments, PCR detection methods generally fare better. In a study of 60 U.S. patients with neuroborreliosis (16 with early and 44 with late neuroborreliosis), the sensitivity of PCR in CSF was 38% in early and 25% in late neuroborreliosis, and an inverse correlation was found between duration of antimicrobial treatment and PCR results (Nocton et al., 1996). In this study, four different PCR primer or probe sets were used, three targeting OspA genes and one targeting OspB genes, and concordance between the different assays was relatively poor which suggested low target number within the samples. Other studies from Europe have generated similar findings (Ornstein et al., 2002) (Lebech et al., 2000). Studies of synovial fluid, have provided the greatest clinical utility of PCR testing for the diagnosis of active Lyme arthritis and for monitoring the course of therapy (Aguero-Rosenfeld, 2008; Aguero-Rosenfeld et al., 2005; Bradley et al., 1994; Dumler, 2001; Eiffert et al., 1998; Jaulhac et al., 1996; Malawista et al., 1992; Nocton et al., 1994; Persing et al., 1994a). In a landmark study of 88 patients, B. burgdorferi DNA was detected in synovial fluid of 75 (85%) patients with Lyme arthritis (Nocton et al., 1994). Not surprisingly, the PCR detection rate was lower in patients who had received what should have been effective antibiotic therapy compared to untreated or undertreated patients. Of 73 patients who were untreated or treated with only short courses of oral antibiotics 70 (96%) had DNA detected by PCR in synovial fluid samples. In contrast, 7 of 19 (37%) patients who received either parenteral antibiotics or oral antibiotics for more than 1 month were still PCR positive (Nocton et al., 1994). The observation of higher sensitivity of PCR detection of plasmid-encoded OspA compared to multiple chromosomal loci (the 16S rRNA gene and flagellin) in synovial fluid specimens (Persing et al., 1994b; Nocton et al., 1994; Persing et al., 1994a) was referred to as “target imbalance.” It has been speculated that

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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B. burgdorferi sensu stricto present in the synovium may selectively shed OspA DNA segments into the synovial fluid (Persing et al., 1994a). With the same or similar reagents, this phenomenon did not appear to occur in CSF specimens (Lebech et al., 1998).

A subsequent meta-analysis has largely confirmed the above assessment; it showed that PCR is a sensitive diagnostic tool for detection of B. burgdorferi DNA in skin biopsy and synovial fluid specimens whereas detection of the organism in blood or blood fractions and in CSF specimens is relatively low (Dumler, 2001). Given the paucity of supporting data for use of PCR as a diagnostic technique in samples other than skin and synovial fluid, extreme caution must be exercised in interpreting PCR test results from samples such as whole blood, urine, and cerebrospinal fluid. Even the best PCR laboratories have had problems with PCR amplicon contamination which, if sporadic, can give rise to undetected rates of false positive results which have been reported in a number of PCR assays, including those for B. burgdorferi. Because of the high credibility assigned to PCR by most clinicians, false positive PCR results can lead to inappropriate treatment and mismanagement, sometimes with fatal results (Molloy et al., 2001; Patel et al., 2000). Laboratories performing PCR should follow Good Laboratory Practices for controlling amplicon contamination, including strict separation of amplified material from areas where clinical samples are being prepared and inclusion of appropriate positive and negative controls in each run.

Direct Detection of Babesia microti

Babesia microti has not been successfully grown in culture, despite multiple attempts, and animal inoculation of whole blood via the intraperitoneal route has been the mainstay of organism propagation for many years. This method is used primarily for organism isolation from patients with obvious parasitemia as demonstrated on Wright-Giemsa stained blood films, and it is limited for practical reasons to research laboratories. Hamster blood, which supports replication of B. microti, begins to show parasitemia at around day 7 after inoculation, and typically reaches peak levels at 2-3 weeks although samples with low numbers of parasites may take longer.

PCR has gained popularity as a diagnostic method, mainly for two reasons: 1) it provides good sensitivity levels and a broad dynamic range, making it suitable for parasitemic patients who are smear negative as well as smear positive, and 2) its turnaround time and general availability as a diagnostic procedure are far superior to comparable methods based on animal inoculation. Initial descriptions of PCR for detection of B. microti were based on conserved elements of the 18 S ribosomal gene, and showed that all strains of B. microti tested were reactive whereas DNA

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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from Plasmodium and other related parasites were negative (Persing et al., 1992). The 3 hour method was much faster and easily 10- to 100-fold more sensitive than hamster inoculation when tested against a limiting dilution of parasites in whole blood (Persing et al., 1992). The same PCR assay was then used in several studies of babesial infection and co-infection with B. burgdorferi to demonstrate that it was more sensitive than blood smear evaluation for the diagnosis of babesial infection (Krause et al., 1996c) and that it could be used to detect B. microti infection in symptomatic and asymptomatic individuals including blood donors (Krause et al., 1998; Krause et al., 1996c; Krause et al., 1994; Krause et al., 1996b).

The utility of PCR for detection of B. microti was demonstrated in several prospective studies of exposed populations living in Block Island, RI, and Eastern Connecticut. Krause et al showed that patients with convincing evidence of simultaneous infection with B. burgdorferi and B. microti often had more severe disease and a higher likelihood of persistent post-infectious fatigue (Krause et al., 1996b). Coinfected patients also appeared to be more likely to be spirochetemic as determined by detection of B. burgdorferi DNA in their blood. In another landmark study (Krause et al., 1998), Krause et al showed 1) that patients with babesial infection often had prolonged and sometimes persistent parasitemia, as demonstrated by PCR, after primary infection, and 2) that many patients with primary infection with B. microti had infections that were subclinical and/or asymptomatic, and which, even if suspected, would not have been detected by blood smear evaluation (Krause et al., 1998). However, for practical purposes it has been found that virtually all patients who are symptomatic and PCR positive for B. microti are already also seropositive (Homer et al., 2000a; Krause et al., 1994), so the use of serologic methods, even in the initial diagnosis of babesial infection or coinfection with other tick borne organisms, is not unreasonable (see below).

These studies paved the way for a better understanding of the incidence of chronic, subclinical infection and the potential risk to the blood supply of blood donors who may unwittingly donate parasitemic blood to increasingly compromised populations including transplant patients, cancer patients, and other vulnerable recipients. Several studies have been done using serologic testing followed by PCR testing to identify asymptomatic carriers of B. microti in the blood donor population (Leiby et al., 2002; Leiby et al., 2005). In almost all cases, persons identified as asymptomatic carriers are blood smear negative and thus would have escaped detection upon routine examination, yet some of them are positive by hamster inoculation and all are considered potential persistent carriers of B. microti. In part due to the recent rise in the number of transfusion related deaths associated with B. microti infection, several new initiatives by the FDA and CDC are underway to institute screening measures by both serologic methods and PCR

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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to detect asymptomatic donors in order to exclude infected units of blood from entering the U.S. blood supply (Leiby et al., 2002; Leiby et al., 2005). Because PCR may be able to detect parasitemia before serocoversion, it may play a pivotal role in such screening efforts.

Direct Detection of Anaplasma phagocytophila

Direct cultivation of Anaplasma phagocytophilum was first accomplished by Goodman and colleagues (Goodman et al., 1996) in the few years after the first recognition the disease, by culture of whole blood in the promyelocytic leukemic cell line HL-60. Recovery of A. phagocytophilum from peripheral blood in cell culture can be used to definitively diagnose infection (Horowitz et al., 1998; Thomas et al., 2009). The bacteria develop within vacuoles to form morulae in the cytoplasm of infected cells, which can be detected using Wright or Giemsa staining. Intracellular organisms can be visualized as soon as 5 days postinoculation or can remain undetectable for more than 2 weeks. Culture of A. phagocytophilum in HL-60 cells is arguably the most sensitive method for the direct diagnosis of human anaplasmosis (HA), owing again to the relatively large volume of blood that can be analyzed compared to PCR methods (Aguero-Rosenfeld et al., 2000; Horowitz et al., 1998; Ravyn et al., 2001) However, as a routine diagnostic method, cell culture is rarely or ever used, and detection methods offered by most medical centers rely on demonstration of characteristic inclusion bodies on peripheral smears, immunoserologic methods, and PCR.

PCR is also a sensitive tool for detecting A. phagocytophilum. PCR was used early on to demonstrate the presence of the organism in blood samples and in initial studies that led to the identification of the deer tick as a vector (Pancholi et al., 1995). Several studies and reviews of the diagnostic performance of PCR for the diagnosis of HGA have been published (Aguero-Rosenfeld, 2003; Alberti and Sparagano, 2006; Comer et al., 1999; Krause et al., 2002; Walls et al., 2000). Sensitivity is approximately 67–90% for detecting A. phagocytophilum DNA (Horowitz et al., 1998), but just as for direct smear evaluation, the PCR sensitivity will likely be affected by the phase of infection and antibiotic therapy. After the first week, the bacteremic phase of infection rapidly wanes, thereby limiting the effectiveness of PCR as a diagnostic technique (Bakken and Dumler, 2006). In general, PCR positivity correlates with the concurrent presence of IgM antibodies and eventual IgG seroconversion.

Immunodiagnostic Methods

For all of the tick-borne infections described here, the mainstay of the laboratory diagnosis is the detection of antibody responses in serum of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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affected individuals. Initial detection of organism-specific IgM antibodies during acute illness is accompanied by conversion to IgG during the convalescent phase, usually 10 to 14 days later. Serologic testing is more available than direct detection methods based on culture or PCR, and usually less expensive. Given the relative lack of sensitivity of direct detection methods, serologic testing is also usually more sensitive, especially for detection of B. burgdorferi infection. Multiple testing formats are available from commercial sources, including ELISA, IFA, and immunoblotting. This section will provide a summary of immunodiagnostic approaches for each of the three agents addressed by this review.

B. burgdorferi

The regional antigenic variability and complexity of the antigenic components of B. burgdorferi have posed challenges for the serodiagnosis of LB. In Europe, Lyme borreliosis is caused primarily by the three species: Borrelia burgdorferi sensu stricto, B. afzelii and B. garinii. In the U.S., substantial genetic heterogeneity of B. burgdorferi sensu stricto exists, as assessed by pulsed-field gel electrophoresis (PFGE) typing, but the vast majority of human clinical isolates fall into a few closely related PFGE clusters of strains that have similar antigenic composition (Mathiesen et al., 1997). B. burgdorferi strains used in the U.S. for immunodiagnosis generally are drawn from these groups, so it is likely that sufficient serologic cross reactivity exists among these strains to allow for detection of antibody responses irrespective of the geographic location of the infection (Mathiesen et al., 1997). However, to complicate things, some immunodominant antigens or epitopes are expressed exclusively in vivo but not in cultures of organisms that are used to prepare antigens for diagnostic testing (Das et al., 1997) (Fikrig et al., 1997). This has led to the use of serological expression cloning to detect antigens that are expressed in vivo, which in some cases have led to the identification of diagnostically useful reagents.

Several initial studies of the immune response to B. burgdorferi recognized the flagellin protein as an immunodominant antigen that was recognized by IgG and IgM antibody subclasses within a few days of infection (Coleman and Benach, 1987; Craft et al., 1986). Unfortunately, the flagellin gene is conserved among multiple species of bacteria, so crossreactivity and nonspecific immune responses are quite common, especially on immunoblots where the protein is denatured (Fawcett et al., 1992) (Luft et al., 1993). Another immunodominant antigen recognized early during infection with B. burgdorferi sensu lato is the OspC protein which is encoded on a plasmid (Engstrom et al., 1995). OspC is upregulated by the spirochete while is still in the tick midgut and when it begins to migrate to the tick mouthparts prior to transmission. Some strains of B. burgdorferi cultured

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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in vitro express little or no OspC; indeed, this antigen was unrecognized in early studies that used high-passage strains as the source of antigen. OspC is genetically and antigenically very heterogeneous (Theisen et al., 1993). Recently, conserved epitopes within the OspC protein have been identified comprising the C-terminal 10 amino acids of OspC (pepC10) (Mathiesen et al., 1998). Inclusion of this peptide in immunoassays may be an important step toward developing improved immunodiagnostic assays for Lyme disease (see below).

The so-called Vmp-like sequence expressed (VlsE) protein, a hypervariable immunodominant surface lipoprotein encoded by a linear plasmid, was described in conjunction with expression cloning experiments (Zhang et al., 1997a; Zhang and Norris, 1998a, 1998b). Although subject to extensive antigenic variation, presumably because of immunological pressure, within the variable regions a constant domain was identified called IR6 (or C6). Peptide mapping of this region showed that it is highly immunogenic (Lawrenz et al., 1999). Broad conservation of this region across multiple species of B. burgdorferi sensu lato have suggested that it would make a good immunodiagnostic reagent, and several studies have now been published that support its use alone or in combination with other immunodominant peptides. Several other antigens have been identified for potential immunodiagnostic use, including decorin binding protein (DBP1) (Heikkila et al., 2002) and a fibronectin binding protein (BBK32) (Fikrig et al., 2000).

Testing Formats

Over the years, many commercial immunoassays to detect B. burgdorferi antibodies have been cleared for use in the United States by the Food and Drug Administration (FDA). Most of these assays use the B31 type strain of B. burgdorferi as the source of antigen, but several newer assays have employed recombinant antigens and/or peptides. In general, performance of these tests on blinded proficiency surveys of laboratories across the U.S. has been good, but a significant degree of performance variation still exists between test manufacturers and test methods (unpublished observation from 2009 CAP surveys). One potential source of variability is the method used for antigen preparation. For immunoassays using whole cell preparations, a surprising amount of antigenic variability will be encountered depending on growth conditions, medium used, incubation temperatures, growth phase of the organisms, and methods used to extract antigens, concentrate them and link them to specific substrates for test preparation. Lot-to-lot reproducibility and quality control are major concerns for methods based on whole cell lysates. In contrast, methods based on recombinant proteins or peptides are better defined and may lead to more lot consistency, but the presence of one or a few

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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epitopes poses a different kind of limitation: the intrinsic variability of the human immune response. Thus, justification of the use of a variety of assay formats continues for a variety of reasons ranging from test performance to cost per test. In general, however, efforts to encourage better standardization should lead to better defined immunologic substrates, and challenging proficiency testing programs are one of the best ways to identify the strengths and weaknesses of individual tests and approaches, whether they are user-developed or commercial methods.

Indirect fluorescent antibody tests look for immunoadsorption of patient antibodies to cultured spirochetes attached to glass slides. A dilution series of patient serum is placed in adjacent wells, incubated on the substrate for a short time, and then detected by fluorescent microscopy after staining with fluorophore-congugated-human IgG or IgM antibody. Antibody titers of 1:64 or above are generally considered positive, though there may be considerable day-to-day and technologist-to-technologist variation in the determination of values because of the subjective nature of the procedure. Automated fluorescence readers have the potential to improve upon this, but variations in the procedural steps such as preparing the dilution series and washing stringency will continue to contribute to variability.

Enzyme immunoassay (EIA) is the most commonly used method for detection of immune responses to B. burgdorferi. Typically, antigen preparations comprising whole-cell sonicates of B. burgdorferi are bound to plastic EIA plates for detection of total Ig response or individual antibody subclasses. With EIAs using well prepared whole cell antigen preparations, about half of patients presenting within a week of the development of erythema migrans (EM) will register positive results. In untreated patients after one week, and in patients with multiple EM lesions or signs of systemic involvement, sensitivities of EIA approach 90% (Dressler et al., 1993). EIA is nearly uniformly positive in sera of patients with late manifestations of disease (Dressler et al., 1993).

False positive EIA reactions can and do occur in some patients with bacterial infections due to other organisms; this is thought to be due to cross reactivity with common bacterial antigens such as heat shock proteins, flagellin, and other conserved bacterial proteins (Fawcett et al., 1992) (Luft et al., 1993). Because all commercially available assays using whole cell sonicates contain the OspA protein, individuals who in the past have received the OspA vaccination will often generate false positive results (Aguero-Rosenfeld et al., 1999) (Molloy et al., 2000). EIAs based on strains that are negative for OspA (by virtue of losing the linear plasmid encoding the protein) or recombinant protein or peptide EIAs devoid of OspA epitopes will be non-reactive in these individuals (Zhang et al., 1997b). Because of the lack of specificity of EIA procedures, and because the pretest probability of having Lyme disease is often lower than the false

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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positive rate (especially in non-endemic areas), EIA reactive sera should be confirmed by Western immunoblotting according to so-called two-tier testing guidelines.

Western immunoblotting is performed by carrying out electrophoretic separation of spirochetal antigens from whole cell sonicates, followed by transfer to nylon filters and detection of patient antibody reactivity to the denatured proteins on the blot by using labeled anti-IgG or IgM antibodies. Several commercial kits for WIB are available which employ a variety of B. burgdorferi strains. Choice of the strain and the growth conditions used will likely affect expression levels of many immundominant proteins, so significant variation has been seen in WIB performance between laboratories, as determined in proficiency testing surveys (Robertson et al., 2000). Rates of detection of IgM antibodies in patients with EM early in the course of disease have ranged from as low as 3% to as high as 84% (Engstrom et al., 1995; Dressler et al., 1993); some commercially available WIB kits failed to detect IgM responses even after several weeks of infection (Aguero-Rosenfeld et al., 1996; Aguero-Rosenfeld et al., 1993). For detection of IgG antibodies, performance has generally been better, especially for convalescent sera (Aguero-Rosenfeld, 2008; Dressler et al., 1993). Early IgG responses are dominated by antibody to OspC (assuming the strain used makes sufficient levels of OspC) and flagellin. As mentioned, flagellin responses are the least specific of all the IgG responses for reasons cited above. Later in the convalescent phase, additional reactivities are observed against a range of proteins including BmpA (39 kDa) and B31 proteins of 93-, 66-, 45-, 35-, 30-, and 18-kDa.

Interpretive criteria for IgG and IgM WIB have been established for U.S. patients (Recommendations for test performance and interpretation from the second national conference on serologic diagnosis of lyme disease, 1995). The IgM criteria of Engstrom et al. (1995) were adopted based on a study of early Lyme disease patients; they were established for use only within the first 4 weeks of illness. A positive IgM blot was defined by the presence of two of three reactive protein species in strain 297 (OspC, 41 or 39 kDa). The IgG criteria were based on work from Dr. Alan Steere’s group (Dressler et al., 1993); these were intended for use at any time during the course of illness, although they were expected to be more informative and applicable to patients later in their disease course. IgG reactivity against at five of 10 protein species (93, 66, 58, 45, 41, 39, 30, 28, 21, or 18 kDa) in strain 39/40 was considered the minimum number to be considered positive. WIB may be more sensitive than EIA for detection of early Lyme disease, but the two methods are similar in sensitivity for convalescent and late-stage infection. In a study of 46 culture-confirmed patients with EM, IgM WIB was considered reactive in 43% of patients, compared with 33% by EIA (Aguero-Rosenfeld et al., 1996).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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This is curiously the opposite of two-tier strategies used for viral serological testing, in which the first test is more sensitive, the second more specific. Operational aspects preclude the use of WIB as a screening test, however, and other factors may influence the performance of the WIB as a screening test. For example, many of the commercial WIB kits use strain B31, which was included in none of the studies that led to the standard interpretive criteria. Although each kit is supposed to have custom criteria that match the standard criteria, this is subject to interpretive error. Subtle differences in molecular weight of antigens, along with antigen degradation can lead to confusing results, even in experienced laboratories. In addition, as with EIA methods, false positives can occur from previous vaccination with the OspA-containing vaccine (Aguero-Rosenfeld et al., 1999; Molloy et al., 2000).

Despite this apparent role reversal of screening and confirmatory testing, the recommended use of two-tier testing has helped to resolve much diagnostic uncertainty in the diagnosis of Lyme disease in the U.S., largely because it improves overall specificity. In most studies of the two-tiered strategy, specificity levels have been 97 to 99%. The low false positive rate has been welcomed, especially in areas where the pre-test probability of infection is low, and among patients presenting with non-specific symptoms in endemic areas. The reduction of sensitivity for detection of early disease was an unfortunate compromise, since non-specific febrile illness can be presenting features of HGA, Lyme disease, and human babesiosis, where diagnostic differentiation is most critical. In 280 patients with various manifestations of Lyme disease, 38% of patients with EM during the acute phase were seroreactive; 67% were positive after antimicrobial treatment. (Bacon et al., 2003). The sensitivity increased in patients with evidence of more invasive disease; 87% of patients with early neuroborreliosis and to 97% of those with Lyme arthritis were seroreactive. Similar results were obtained in another study of 47 patients with clinically defined EM, for whom the sensitivities of the two-tier test were 40.4% in acute-phase sera and 66% during the convalescent phase after treatment (Nowakowski et al., 2001).

Newer antibody tests based on recombinant proteins or immunodominant peptides have the potential of maintaining current levels of specificity without sacrificing sensitivity, especially for detection of early disease. Many studies have been done on recombinant proteins, many of which have been mentioned above, with sensitivities ranging from 30% to nearly 100% depending on the antigen used and the stage of disease being tested reviewed recently in (Aguero-Rosenfeld, 2008). Specificity levels have been somewhat lower than expected (as low as 91%), perhaps because of the presence of small amounts of contaminating protein from the strains of bacteria or yeast used for protein expression. In general, however, no single

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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recombinant protein has served as the universal solution for immunologic detection of both early and late disease (Aguero-Rosenfeld, 2008). Considerably more promise has been shown in combining immunodominant epitopes, especially those that derive from antigens that are recognized early in the course of disease.

In a different study of the same set of 839 serum samples (including those from 280 Lyme disease patients) cited above, antibody responses to recombinant VlsE1, the C6 peptide, and the conserved C terminal peptide from OspC (pepC10) were evaluated by kinetic enzyme-linked immunoassay (Bacon et al., 2003). At 99% specificity, the overall sensitivities for detecting IgG antibody to rVlsE1 or C6 in samples from patients with diverse manifestations of Lyme disease were equivalent to that of two-tiered testing. When data were considered in parallel, two combinations (IgG responses to either rVlsE1 or C6 in parallel with IgM responses to pepC10) maintained high specificity (98%) and were significantly more sensitive than two-tiered analysis in detecting antibodies to B. burgdorferi in patients with acute erythema migrans. In later stages of Lyme disease, the sensitivities of the in-parallel tests and two-tiered testing were high and statistically equivalent. In established cases of Lyme disease, the C6 ELISA may also be useful for tracking therapeutic responses (Marques et al., 2002; Philipp et al., 2003; Philipp et al., 2005; Wormser et al., 2008a; Wormser et al., 2008b). Although similar observations were made in other studies, some studies have not confirmed these findings (Peltomaa et al., 2003). Operational differences in the ways the assays were performed may account for this. Taken together, these data are supportive of the goal of potentially replacing two-tiered testing while improving the diagnosis for early Lyme disease patients.

Serodiagnosis of Babesiosis

The serological testing methods for B. microti are not as developed as those for Lyme disease, mainly because the organism has not been propagated in vitro. The mainstay of the laboratory diagnosis is the IFA test, in which a standard 1:16 or 1:32 dilution of serum is dispensed onto wells of a microscope slide that has been previously coated with infected red blood cells, usually of hamster origin After a wash step, addition of fluorescent anti-human IgG or IgM, and an additional wash, the microscope wells are examined under a fluorescent microscope for staining of intraerythrocytic merozoite forms of the organism. If the screening serologic testing is positive, further 1:4 serial dilutions are performed to determine the serum titer. Determination of titer end point is somewhat subjective; it is usually associated with a significant, abrupt drop in the level of observed fluorescence. In most laboratories, a 1:64 cutoff titer has been established and is considered to be consistent with exposure to B. microti.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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In animal models of infection, IgM antibodies precede IgG responses by 7 to 10 days, but in humans, by the time patients present (usually with nonspecific “flu-like” symptoms) they are already IgG positive (Benach et al., 1985; Homer et al., 2000a; Krause et al., 1996a; Krause et al., 1994). During the acute phase of infection in which patients are PCR positive, antibody titers typically reach 1: 512, 1:1024 or higher and then decline in the weeks and months after therapy. Even with therapy, however, antibody levels typically persist at 1:64 or above for years after the initial infection. Thus, the finding of an antibody titer at 1:64 during acute presentation should not be assumed to be due to active infection; it may simply reflect past exposure, especially if the patient is from an endemic area. PCR testing may be helpful in resolving this issue. On the other hand, titers of greater than 1:512 have been found to be consistently associated with acute infection and correlate with PCR positivity (Krause et al., 1996a; Krause et al., 1998; Krause et al., 1996e).

Enzyme immunoassays based on antigen preparations from infected hamster erythrocytes have been developed, but have been generally hampered by the presence of anti-rodent antibodies in serum of a few percent of patients. These confounding antibodies can to some extent be pre-adsorbed prior to testing to reduce this problem. Immunoblots made from partially purified antigens have also been developed (Houghton et al., 2002).

More recently, recombinant expression cloning efforts, using B. microti expression libraries screened with human serum, led to the discovery of several recombinant proteins that show promise as immunodiagnostic reagents (Homer et al., 2000b; Houghton et al., 2002). From two serocomplementary B. microti-specific antigens, peptide mapping was done to identify immunodominant epitopes that could be combined in a peptide EIA. The prototype peptide EIA was used to detect B. microti-specific antibodies in 15 sera taken before infection and 107 taken after infection from 59 individuals with known tick-borne infections previously confirmed by other methods. The combination peptide detected 98 out of 107 sera taken after infection that were immumnoblot positive; this included 12/12 samples that were PCR positive and six sera from smear-negative patients that were confirmed positive by PCR, immunoblot, or IFA.

In another interesting study, proteins of B. microti that are potentially secreted or surface exposed were identified by serologic expression cloning (Homer et al., 2003). This report described the identification and initial characterization of 27 clones representing seven genes or gene families that were isolated through serological expression cloning by using a technique that was specifically designed to screen for shed antigens. In this screen, sera from B. microti-infected SCID mice, putatively containing secreted or shed antigens from the parasites, were harvested and used to immunize syngeneic immunocompetent mice (BALB/c). After boosting, the sera from

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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the BALB/c mice, containing antibodies against the immunodominant secreted antigens, were used to screen a B. microti genomic expression library. Analyses of the putative peptides encoded by the novel DNA sequences revealed characteristics indicating that these peptides might be secreted. Initial serological data obtained with recombinant proteins and a patient serum panel demonstrated that several of the proteins could be useful in developing diagnostic tests for detection of B. microti antibodies and antigens in serum. Unfortunately, however, to date none of these recombinant peptides or proteins has been converted into an immunodiagnostic test that is widely available.

Unlike for Lyme disease serology, no proficiency testing programs yet exist for serodiagnosis of B. microti infection, mainly because of lack of demand for such a service. However, this leaves open the possibility that among laboratories performing serodiagnostic methods for this organism, significant inconsistencies may exist between laboratories and within laboratories from run-to-run.

Serodiagnosis of HGA

Like for B. microti, detection of antibody responses in patient serum by the indirect immunofluorescence (IFAT) assay is the most frequently used test for clinical purposes (Walls et al., 1999). However, unlike for B. microti infections, the onset of symptoms after tick bite is fairly abrupt, and symptomatic patients are frequently seronegative. IFA assays typically use HL-60 cells infected with A. phagocytophilum as a substrate, and screening and dilution series are typically performed as described above for B. microti. Sensitivity is high 2–4 weeks following disease onset compared with a few days after onset for PCR, blood smear microscopy and cell culture. A diagnosis of A. phagocytophilum is confirmed by a fourfold increase in antibody titer between acute and convalescent sera or a seroconversion to a titer of 128 or higher (Walls et al., 1999) (Thomas et al., 2009). Like for B. microti, seropositivity for A. phagocytophilum often lasts for months and sometimes years after initial exposure (Aguero-Rosenfeld et al., 2000). Thus, like for B. microti and B. burgdorferi, an HGA antibody titer must be considered in light of other clinical evidence of infection and should not be used as the only criterion for diagnosis. False-positive or cross reactive serologic test results can be seen in cases of Rocky Mountain spotted fever, typhus, Q fever, brucellosis, Lyme disease, Epstein–Barr infection and any variety of autoimmune disorders associated with production of auto antibodies (Dumler et al., 2007). Aguero-Rosenfeld et al evaluated the antibody responses by IFA in the sera of 24 patients with culture-confirmed HGA (Aguero-Rosenfeld et al., 2000). Patients were followed for up to 14 months. Seroconversion was observed in 21 of 23 patients (91.3%)

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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from whom convalescent-phase sera were obtained. Antibodies were first detected at an average of 11.5 days after onset of symptoms. Peak titers (>/=2,560 for 71.4% of patients and >/=640 for 95.2% of patients) were obtained an average of 14.7 days after onset of symptoms. Most patients were still considered seropositive after 6 months, and half of the patients were still seropositive after 11 months.

Some progress has been made toward development of recombinant serological reagents for the diagnosis of HGA, which might be more amenable to automated testing and or rapid immunodiagnostic assay formats (Lodes et al., 2001). Lodes et al described a panel of seven recombinant antigens, derived from the HGA agent, which were evaluated by class-specific ELISAs for utility in the diagnosis of the infection. Fourteen genomic fragments, obtained by serologic expression screening, contained open reading frames encoding 16 immunodominant antigens. Eleven of these antigens were members of the major surface protein (MSP) multigene family. In addition to two MSP recombinant antigens (rHGE-1 and -3) and a fusion protein of one of these antigens (rErf-1), five further recombinants were evaluated by ELISA. Two of these antigens (rHGE-14 and -15) were novel, while a third (rHGE-2), with no known function, had already been described. The final two recombinant antigens (rHGE-9 and -17) represented overlapping segments of the ankyrin gene. When serologic data for all recombinants were combined, 96.2% (26 of 27) of convalescent-phase patient serum samples and 85.2% (23 of 27) of acute-phase patient serum samples were detected, indicating the potential of these antigens for use in the development of a rapid serologic assay for the diagnoses of HGA.

Conclusions

The three identified infections transmissible by the bite of a deer tick in the United States—Lyme disease, HGA and human babesiosis—have distinct and overlapping clinical features that, in the case of infection by more than one organism, may confound each other. Each may require different treatment approaches, although one can argue that tetracycline derivatives, with activity against B. burgdorferi and HGA, should become the drug of choice for patients with confusing clinical pictures or features of more than one infection. Much of the management of patients with nonspecific presentations will depend on specific diagnostic test results. Fortunately, although babesiosis and HGA have immunosuppressive effects, these effects are not sufficient to confound the specific serologic responses to the cognate infectious agents. In the case of HGA and babesiosis, direct detection by blood smear, culture or PCR (HGA) or smear and PCR (babesiosis) are diagnostic options, but none of the direct detection approaches are very useful for the diagnosis of early Lyme disease. The diagnosis of all of these conditions

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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may be improved by the use of next generation serologic testing and molecular diagnostic approaches, both of which are likely to make their way into increasing numbers of laboratories over the next decade.

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Walls, J. J., P. Caturegli, J. S. Bakken, K. M. Asanovich, and J. S. Dumler. 2000. Improved sensitivity of pcr for diagnosis of human granulocytic ehrlichiosis using epank1 genes of ehrlichia phagocytophila-group ehrlichiae. J Clin Microbiol 38(1):354-356.

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A5
EHRLICHIOSES, RICKETTSIOSES, AND ANAPLASMOSIS IN THE UNITED STATES: CURRENT STATUS AND OPPORTUNITIES FOR NEW VACCINES

Jere W. McBride,5 Xue-jie Yu,5 and Kelly Brayton6

Ehrlichioses

Introduction

Ehrlichia are obligately intracellular gram-negative bacteria that are associated with emerging, tick-transmitted, life-threatening zoonoses in humans. Human monocytotropic ehrlichiosis (HME) and human ehrlichosis ewingii (HEE) are now well established zoonoses in the United States caused by E. chaffeensis and E. ewingii, respectively. The first recognized case of human ehrlichiosis occurred in 1986 in a patient that acquired the infection in Arkansas (Maeda et al., 1987), and a previously unknown pathogen, E. chaffeensis, was later identified as the etiologic agent (Anderson et al., 1991). As epidemiologic and ecologic understanding of E. chaffeensis biology has developed, it is now considered a prototypical emerging pathogen (Paddock and Childs, 2003). Shortly after the emergence of E. chaffeensis, the canine pathogen, E. ewingii, associated with granulocytic ehrlichiosis in dogs, was molecularly identified in four patients from Missouri presenting with fever, headache and thrombocytopenia (Buller et al., 1999). The emergence of human ehrlichioses has been attributed to changes in biological, demographic and environmental factors, and these factors in addition to increased surveillance and diagnostic capability are likely to result in increasing recognized incidence of human ehrlichiosis in the future (Paddock and Childs, 2003). Thus, there is an immediate need for effective vaccines now for human ehrlichiosis and into the foreseeable future. In this review, we summarize the current status of vaccines and examine the status of new prospects for vaccine development for human ehrlichiosis.

5

Department of Pathology, Center for Biodefense and Emerging Infectious Diseases, Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas.

6

Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, School for Global Animal Health, Washington State University, Pullman, Washington.

Commissioned by the Institute of Medicine of the National Academies Committee on Lyme Disease and Other Tick-Borne Diseases: The State of the Science September 2010.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Etiologic agents of the human ehrlichioses

Ehrlichia species are in the subdivision of Proteobacteria and members of the family Anaplasmataceae, which also includes the genera Anaplasma, Wolbachia, and Neorickettsia. Organisms in the genus Ehrlichia include E. chaffeensis, E. ewingii, E. canis, E. ruminantium, and E. muris. Ehrlichia replicate in a membrane-bound cytoplasmic vacuole forming a microcolony called morula. Multiple morulae (1.0 to 6.0 μm) are often present in an infected cell, and by light microscopy they appear as dark blue-to-purple intracytoplasmic inclusions demonstrated by Romanovsky-type stains (Rikihisa, 1991). Morphologically individual ehrlichiae are coccoid and coccobacillary and exhibit two ultrastructural cell types, a larger reticulate cell (RC) (0.4 to 0.6 μm by 0.7 to 1.9 μm) and a smaller dense-cored cell (DC) (0.4 to 0.6 μm in diameter). Both forms have a gram-negative cell wall, characterized by a cytoplasmic membrane and rippled outer membrane separated by a periplasmic space. Reticulate cells are pleomorphic and have uniformly dispersed nucleoid filaments and ribosomes, and DC ehrlichiae are typically coccoid and have centrally condensed nucleoid filaments and ribosomes (Popov et al., 1995; Popov et al., 1998). Small and large morulae containing both RC and DC or exclusively containing DC or RC ehrlichiae usually in loosely packed clusters can be observed within a single infected cell (Popov et al., 1995; Popov et al., 1998). The intramorular space in some morulae contains a fibrillar matrix of ehrlichial origin (Popov et al., 1995). The DC ehrlichiae are infectious and attach to the host cell surface where they are rapidly internalized and transition into a replicating RC forms. RC replicate, doubling every 8 hrs, and then mature to DC within 72 hr after initial cell contact (Zhang et al., 2007).

The intracellular niche occupied by Ehrlichia has resulted in reductive evolutionary processes and corresponding severe loss of genes associated with metabolic processes provided by the host cell. Hence the genome sizes (~1-1.5 Mb) of Ehrlichia are relatively small compared to extracellular bacteria. The genomes of three Ehrlichia species have been sequenced (Collins et al., 2005; Dunning Hotopp et al., 2006; Mavromatis et al., 2006) and exhibit a high degree of genomic synteny, low G+C content (~30%) and one of the smallest genome coding ratios that is attributed to long non-coding regions and numerous long tandemly repeated sequences (TRs) (Frutos et al., 2006). These long non-coding regions and low G+C content in other related Rickettsiales members are speculated to represent degraded genes in the final stages of elimination and excess GC-to-AT mutations (Andersson and Andersson, 1999). Another feature of Ehrlichia genomes is the presence of a large number of long period TRs that appear to have evolved after divergence of the species (Frutos et al., 2007).

The identified agents of human ehrlichosis in the United States include

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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E. chaffeensis and E. ewingii. E. chaffeensis exhibits tropism for mononuclear phagocytes and causes mild to life-threatening disease in humans and mild to severe disease in dogs (Breitschwerdt et al., 1998b; Dawson and Ewing, 1992). E. chaffeensis is maintained in nature in a zoonotic cycle potentially involving many vertebrate species, and is transmitted primarily by the lone star tick, Amblyomma americanum (Paddock and Childs, 2003).

E. ewingii is an established canine pathogen first described in 1971 (Ewing et al., 1971). E. ewingii exhibits host cell tropism for granulocytes (neutrophils), and is also transmitted by the lone star tick, A. americanum (Anziani et al., 1990). Dogs are a reservoir for E. ewingii, and many individuals with documented infections reported contact with dogs before onset of symptoms (Buller et al., 1999). Most cases of HEE are manifested in immunocompromised patients, and thus, E. ewingii appears to be an opportunistic pathogen (Buller et al., 1999; Paddock et al., 2001).

E. canis is the type strain for the genus Ehrlichia and is the primary etiologic agent of canine monocytic ehrlichosis (CME), a serious and sometimes fatal, globally distributed disease of dogs (Keefe et al., 1982). E. canis is transmitted by the brown dog tick, Rhipicephalus sanguineus (Groves et al., 1975), and infects monocytes/macrophages in dogs. E. canis was initially described in dogs in the United States in 1963 (Ewing, 1963), but received more attention after its identification as the agent responsible for outbreaks of a cryptogenic hemorrhagic disease called tropical canine pancytopenia in American and British military dog units on duty in southeast Asia (Huxsoll et al., 1969; Seamer and Snape, 1970; Wilkins et al., 1967). Human infections with E. canis have been reported in Venuzuela (Perez et al., 1996; Perez et al., 2006). The clinical manifestations of acute infection with E. canis are similar to those observed in humans infected with E. chaffeensis.

Epidemiology and public health importance

Approximately 2,500 cases (passive surveillance) of HME have been formally reported to the Centers for Disease Control from 1999 to 2006, and HME and HEE are Nationally Notifiable Diseases on the public health information network. However, the incidence is likely underestimated since active surveillance studies performed in HME-endemic areas in Missouri, Tennessee and Georgia have revealed an incidence that is 10-100 times higher than reported by passive surveillance (Olano et al., 2003b). HME is a seasonal disease with most reported cases occurring in the spring and summer coinciding with higher tick activity, although cases can occur in the fall in more southern latitudes. The geographic distribution of HME follows the distribution of its vector A. americanum (lone star tick), that

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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begins in west central Texas and extends east along the Gulf Coast, north through Oklahoma and Missouri, eastward to the Atlantic Coast and proceeds northeast through New Jersey, encompassing all the south central, southeastern and mid-Atlantic states. The main zoonotic reservoir is the white-tailed deer (Odocoileus virginianus), but other potentially important reservoirs are naturally infected with E. chaffeensis including goats, domestic dogs, and coyotes (Breitschwerdt et al., 1998b; Dugan et al., 2000; Kocan et al., 2000). The states with highest incidence include Arkansas, North Carolina, Missouri, Oklahoma, and New Jersey (McQuiston et al., 1999). Outside the USA, HME has been described in Cameroon where confirmation of the diagnosis was based on PCR detection of E. chaffeensis DNA from ill patients and dogs (Ndip et al., 2009a; Ndip et al., 2009b). E. chaffeensis has been found in 5 to 15% of A. americanum ticks collected from at least 15 states in endemic areas in the eastern US (Ijdo et al., 2000; Stromdahl et al., 2001;Whitlock et al., 2000). Human infections with E. chaffeensis or antigenically related ehrlichiae have been reported in Europe (Nuti et al., 1998), Asia (Heppner et al., 1997), South America (Ripoll et al., 1999), and Africa (Uhaa et al., 1992). Most reports of HME from other countries are based on serological studies, and therefore cannot be confirmed as E. chaffeensis infections.

The epidemiology of HEE remains poorly defined due to the lack of a specific serologic assay for this organism and absence of a dedicated reporting system for this disease. Laboratory diagnosis relies on nucleic acid amplification, but new serologic assays to detect E. ewingii antibodies have been recently developed (Zhang et al., 2008). Most cases of HEE have been reported in Tennessee, Missouri, and Oklahoma. However, E. ewingii infection in deer, dogs and ticks have been described throughout the range of the lone star tick, suggesting that human infection with this pathogen might be more widespread than is currently documented. All cases involving tick transmission have been described in immunocompromised patients (Buller et al., 1999; Paddock et al., 2001).

Clinical spectrum and treatment

HME and HEE manifest as undifferentiated febrile illnesses 1 to 3 weeks after the bite of an infected tick. For HME, the most frequent clinical findings reported anytime during the acute illness are fever, malaise, headache, dizziness, chills, and myalgias (Eng et al., 1990; Everett et al., 1994; Fishbein et al., 1989; Fishbein et al., 1994; Olano et al., 2003a; Olano et al., 2003b; Schutze and Jacobs, 1997). HME is more common in male (>2:1) patients >40 years of age; the majority (>80%) report a tick bite (Fishbein et al., 1994; Olano et al., 2003b). Many HME cases are associated with recreational or occupational activities that increase exposure of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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humans to tick infested environments (Petersen et al., 1989; Standaert et al., 1995). HME presents as a more severe disease in patients >60 years of age and in immunocompromised patients including persons with HIV/AIDS in whom severe complications can arise such as adult respiratory distress syndrome, acute renal failure, shock and CNS involvement (Paddock et al., 2001). Patients with HEE present with a milder disease with few complications suggesting that E. ewingii is less pathogenic (Buller et al., 1999). Hematologic and biochemical abnormalities usually include leukopenia, thrombocytopenia, anemia, mildly elevated serum hepatic transaminase activities, and hyponatremia (Fishbein et al., 1994; Olano et al., 2003b; Paddock et al., 2001). A high proportion of immunocompetent (41 to 62%) and immunocompromised patients (86%) require hospitalization (Fishbein et al., 1994; Olano et al., 2003b; Paddock et al., 2001) and delays in antibiotic treatment are associated with more pulmonary complications, increased transfer to intensive care, and longer duration of illness (Hamburg et al., 2008). Immunocompromised patients (human immunodeficiency virus-infected persons, transplant recipients, corticosteroid-treated patients) have a high risk of fatal infection associated with overwhelming infection not typically observed in immunocompetent patients (Paddock et al., 2001). No deaths have been reported as a result of infection with E. ewingii (Buller et al., 1999; Paddock et al., 2001).

In vitro susceptibility testing has shown that E. chaffeensis is resistant to representatives of most classes of antibiotics including aminoglycosides (gentamicin), fluoroquinolones (ciprofloxacin), -lactams (penicillin), macrolides and ketolides (erythromycin and telithromycin), and sulfa-containing drugs (co-trimoxazole) (Brouqui and Raoult, 1992). Patients with HME or HEE respond well to tetracyclines, which have bacteriostatic activities against Ehrlichia spp. and other rickettsial agents (Brouqui and Raoult, 1992; Horowitz et al., 2001). Doxycycline is preferred over tetracycline because of its pharmacokinetics and negligible staining of immature teeth. After the first trimester of pregnancy, doxycycline is contraindicated, and successful treatment with rifampin has been reported as an effective alternative (Buitrago et al., 1998).

Overview of Protective Immune Mechanisms

Numerous studies with multiple Ehrlichia spp. indicate that IFN-γ is an essential mediator of protection (Mahan et al., 1994b; Mahan et al., 1996; Mutunga et al., 1998; Totte et al., 1993; Totte et al., 1996). Moreover, CD4+ and CD8+ T cells both contribute to IFN- production (Bitsaktsis et al., 2004; Esteves et al., 2004a; Esteves et al., 2004b; Ismail et al., 2004). Notably, similar conclusions regarding the importance of MHC class I, CD4+ and CD8+ T cells, and the synergistic roles of IFN- and TNF- have

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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been reported in mice infected with E. muris (Feng and Walker, 2004). An important role for CD4+ T cells in immunity to E. ruminantium and IOE has been suggested (Bitsaktsis et al., 2004; Byrom et al., 2000; Totte et al., 1997). Similarly, mice lacking functional MHC class II genes are unable to clear E. chaffeensis infection, suggesting that CD4+ T cells are essential for ehrlichial clearance (Ganta et al., 2002). The intradermal environment (natural route of inoculation) appears to promote the induction of protective type-1 responses characterized by increased CD4+ and CD8+ T cells and IFN- producing CD4+ T cells (Stevenson et al., 2006).

Antibody mediated immunity appears to play a significant role in protection against E. chaffeensis infection. Infection of SCID mice (B and T cell deficient) with E. chaffeensis results in an overwhelming infection (Li et al., 2001; Li et al., 2002; Winslow et al., 2000). Furthermore, mice lacking B cells or FcRI are unable to resolve an ordinarily sublethal infection by IOE, and passive transfer of antibodies in these mice results in significant reduction in bacterial load (Yager et al., 2005). Similarly, passive transfer of antibodies, but not Fab fragments, also protects mice against lethal infection (Feng and Walker, 2004). The specific anti-ehrlichial antibody-mediated mechanism is not fully understood, but appears to involve binding of antibody to the Fc receptor (Lee and Rikihisa, 1997; Yager et al., 2005) and subsequent generation of a proinflammatory cytokine response (Lee and Rikihisa, 1997) and generation of oxidative defenses (Yager et al., 2005).

Vaccines: Current status and feasibility

Although Ehrlichia are responsible for serious diseases of livestock, companion animals and humans, there are no vaccines available for human ehrlichioses and only one infection-treatment immunization regimen is available for the veterinary ehrlichial disease heartwater, caused by E. ruminantium. Ehrlichia are maintained in nature through subclinical infections of vertebrate hosts (carriers) as well as ticks and have evolved mechanisms to persistently infect mammalian hosts by subverting the innate and adaptive immune responses (Harrus et al., 1998). Effective immune responses leading to the elimination of infections without treatment have been described in E. canis-infected dogs (Breitschwerdt et al., 1998a; Harrus et al., 1998), and infection and treatment strategies in Africa for E. ruminantium have been used for decades to provide protection against challenge (van der Merwe, 1987). Furthermore, experimental E. ruminantium vaccines (inactivated, live attenuated and recombinant) have demonstrated protection against homologous challenge, although less protection has been achieved against natural field challenge (Allsopp, 2009). Cell mediated immune responses and IFN- production correlate with protection against Ehrlichia spp. (Bitsaktsis et al., 2004; Totte et al., 1997), and antibodies also play an

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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important role in immunity (Feng and Walker, 2004; Winslow et al., 2000; Yager et al., 2005). Thus, vaccines that stimulate humoral and cell mediated immune responses, prevent disease or minimize clinical signs, shorten duration of illness and/or prevent progression to a chronic infection appear to be feasible.

Experimental vaccines

The emergence of human ehrlichioses in the last decade and the risk to public health has elicited interest in the development of vaccines for HME. The use of vaccines to prevent HME may be especially useful for persons who are active outdoors and are at an increased risk level for acquiring the disease. Ehrlichioses, such as heartwater and CME, are important veterinary diseases. Thus, considerable effort has been made to develop vaccines for E. ruminantium, which causes large economic losses to the livestock industry in sub-Saharan Africa, and creates limitations on livestock production and export. Consequently, much of the knowledge base for ehrlichial disease vaccine development has involved E. ruminantium, where experimental vaccine compositions have been tested, including live, attenuated, nucleic acid and recombinant subunit candidates.

A small group of major immunoreactive proteins of E. chaffeensis and E. canis has been identified on the basis of immunoblot reactivity, and most of these proteins contain tandem repeats or ankyrin repeats, and most have been molecularly defined (Doyle et al., 2006; Luo et al., 2008; McBride et al., 2003; McBride et al., 2006; Yu et al., 1996). Moreover, many of these proteins are secreted effector proteins that have major species-specific antibody epitopes (Doyle et al., 2006; Luo et al., 2008; Luo et al., 2009; Luo et al., 2010; McBride et al., 2006; Nethery et al., 2007). However, there is relatively little information regarding the protective efficacy of specific immunoreactive proteins. Major immunoreactive E. chaffeensis proteins are 200-, 120-, 88-, 55-, 47-, 40-, 28- and 23-kDa (Chen et al., 1994; Rikihisa et al., 1994); E. canis, 200-, 140-, 95-, 75-, 47-, 36-, 28-, and 19-kDa (McBride et al., 2003); and E. ruminantium, 160-, 85-, 58-, 46-, 40-, 32-and 21-kDa (Mahan et al., 1994a). E. chaffeensis immunoreactive proteins (Ank200, TRP120, TRP47, TRP32 [VLPT], OMP-1 family [22 genes], and MAP2) have been molecularly characterized as well as the corresponding orthologs in E. canis (Ank200, TRP140, TRP36, TRP19 [VLPT], OMP-1 family [25 genes] and MAP2, respectively). Some of these immunoreactive orthologs have been molecularly identified and characterized in E. ruminantium including (MAP1 family [16 genes], MAP2, and mucin-like protein [clone hw26; TRP36/47 ortholog]) (Jongejan and Thielemans, 1989; Mahan et al., 1994a; Sulsona et al., 1999).

Major immunoreactive proteins identified in Ehrlichia spp. that have

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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been the primary targets for experimental subunit vaccines include the major outer membrane proteins. Recombinant subunit and nucleic acid vaccines that contain a major surface protein ortholog of Ehrlichia spp. (designated MAP1 in E. ruminantium; p28 in E. chaffeensis and p28/p30 in E. canis), which is a member of a paralogous nonidentical multigene family of outer membrane protein genes (16 to 25 genes) in each respective Ehrlichia species. Partial protection using a recombinant version of the E. chaffeensis P28 protein has been demonstrated in mice after homologous challenge (Ohashi et al., 1998). Moreover, significant protection against homologous challenge using E. ruminantium MAP1 DNA vaccination and recombinant protein boost was demonstrated in a mouse model (Nyika et al., 2002). There is substantial divergence in map1/p28 genes among different isolates of E. ruminantium and E. chaffeensis, and therefore this diversity may complicate development and implementation of vaccines utilizing this protein. Conversely, the p28/p30 genes of E. canis appear to be highly conserved among geographically dispersed strains, and thus may facilitate more rapid development of effective vaccines utilizing this antigen. Most recently, several new vaccine candidates have been identified and molecularly characterized in E. chaffeensis that have major species specific epitopes within tandem repeat regions. These tandem repeat proteins (TRP120, TRP47 and TRP32) from E. chaffeensis are consistently recognized by antibodies in convalescent antisera. The ability of these proteins to protect against homologous challenge is currently under active investigation.

Future prospects

The emergence of human ehrlichioses in the late 20th century has focused new resources and efforts to improve diagnosis and treatment, and to understand pathogenic and protective immune mechanisms that will facilitate vaccine development. The completion of several Ehrlichia genome sequences has provided insight into their evolution, virulence mechanisms, clues to the unique strategies that they utilize to survive in both invertebrate and vertebrate hosts, and their interaction with and dependence on the host cell for survival. Molecular identification and characterization of the majority of the major immunoreactive proteins has been accomplished. These new vaccine prospects, coupled with a more complete understanding of ehrlichial pathobiology and interaction with the innate and adaptive host immune responses, and useful animal models, will undoubtedly stimulate the development of new and more effective nucleic acid or subunit vaccines for human and veterinary use in the future. New technologies including next-generation sequencing will provide researchers with the capability to rapidly and fully explore pathogen gene expression in order to define the dynamics of pathogen phenotype in invertebrate and vertebrate hosts, and

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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new vaccine strategies will be identified through this exploration. New insights into immunoprotective mechanisms and molecular pathogen-host interactions have marked new areas of progress that have addressed key gaps in our knowledge that are required to make effective vaccines.

Key Points
  • Vaccination is the most cost-effective long-term means of controlling human ehrlichioses, and commercial interest and progress in vaccine development for heartwater and canine ehrlichiosis will enhance prospects for a human ehrlichiosis vaccine.

  • Immunologically well characterized murine models are available for determining vaccine candidate efficacy and defining protective and pathologic immune mechanisms.

  • Defining Ehrlichia proteins that elicit protective humoral and cell mediated immune responses is needed and is an area of active investigation.

  • Understanding innate and adaptive immune evasion strategies of Ehrlichia will improve prospects of effective vaccine development.

  • Effective vaccine development will depend on understanding eh­rlichial biology and phenotype in mammalian and arthropod host environments.

  • Major immunoreactive tandem and ankyrin repeat proteins of Eh­rlichia have been recently molecularly characterized that contain major continuous species-specific antibody epitopes. Some of these proteins are known to be involved in complex molecular host in­teractions that may contribute to pathogen survival and may be blocked by the host immune response.

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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Rikihisa, Y., Ewing, S. A., and Fox, J. C. (1994) Western immunoblot analysis of Ehrlichia chaffeensis, E. canis, or E. ewingii infections in dogs and humans. J Clin Microbiol 32: 2107-2112.

Ripoll, C. M., Remondegui, C. E., Ordonez, G., Arazamendi, R., Fusaro, H., Hyman, M. J. et al. (1999) Evidence of rickettsial spotted fever and ehrlichial infections in a subtropical territory of Jujuy, Argentina. Am J Trop Med Hyg 61: 350-354.

Schutze, G. E. and Jacobs, R. F. (1997) Human monocytic ehrlichiosis in children. Pediatrics 100: E10.

Seamer, J. and Snape, T. (1970) Tropical canine pancytopaenia and Ehrlichia canis infection. Vet Rec 86: 375.

Standaert, S. M., Dawson, J. E., Schaffner, W., Childs, J. E., Biggie, K. L., Singleton, J. J. et al. (1995) Ehrlichiosis in a golf-oriented retirement community. N Eng J Med 333: 420-425.

Stevenson, H. L., Jordan, J. M., Peerwani, Z., Wang, H. Q., Walker, D. H., and Ismail, N. (2006) An intradermal environment promotes a protective type-1 response against lethal systemic monocytotropic ehrlichial infection. Infect Immun 74: 4856-4864.

Stromdahl, E. Y., Evans, S. R., O’Brien, J. J., and Gutierrez, A. G. (2001) Prevalence of infection in ticks submitted to the human tick test kit program of the U.S. Army Center for Health Promotion and Preventive Medicine. J Med Entomol 38: 67-74.

Sulsona, C. R., Mahan, S. M., and Barbet, A. F. (1999) The map1 gene of Cowdria ruminantium is a member of a multigene family containing both conserved and variable genes. Biochem Biophys Res Commun 257: 300-305.

Totte, P., Blankaert, D., Zilimwabagabo, P., and Werenne, J. (1993) Inhibition of Cowdria ruminantium infectious yield by interferons alpha and gamma in endothelial cells. Rev Elev Med Vet Pays Trop 46: 189-194.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Totte, P., McKeever, D., Martinez, D., and Bensaid, A. (1997) Analysis of T-cell responses in cattle immunized against heartwater by vaccination with killed elementary bodies of Cowdria ruminantium. Infect Immun 65: 236-241.

Totte, P., Vachiery, N., Martinez, D., Trap, I., Ballingall, K. T., MacHugh, N. D. et al. (1996) Recombinant bovine interferon gamma inhibits the growth of Cowdria ruminantium but fails to induce major histocompatibility complex class II following infection of endothelial cells. Vet Immunol Immunopathol 53: 61-71.

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van der Merwe, L. (1987) The infection and treatment method of vaccination against heart-water. Onderstepoort J Vet Res 54: 489-491.

Whitlock, J. E., Fang, Q. Q., Durden, L. A., and Oliver, J. H., Jr. (2000) Prevalence of Ehrlichia chaffeensis (Rickettsiales: Rickettsiaceae) in Amblyomma americanum (Acari: Ixodidae) from the Georgia coast and barrier islands. J Med Entomol 37: 276-280.

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Zhang, C., Xiong, Q., Kikuchi, T., and Rikihisa, Y. (2008) Identification of 19 polymorphic major outer membrane protein genes and their immunogenic peptides in Ehrlichia ewingii for use in a serodiagnostic assay. Clin Vaccine Immunol 15: 402-411.

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Rickettsiosis

Introduction

Rickettsia are arthropod-borne, gram-negative, obligately intracellular bacteria that reside in the cytosol of host cells. Tick-borne Rickettsia include the most deadly bacterial organism, R. rickettsii, low pathogenic organisms such as R. parkeri and R. sibirica, and nonpathogenic organisms such as R. peacockii, R. bellii, and R. montanensis. Lethality of Rocky Mountain spotted fever (RMSF) caused by R. rickettsii in the pre-antibiotic era was as high as 80%. Even with the availability of effective rickettsiostatic antibiotic treatment, the mortality rate is around 3-5% for RMSF because of late diagnosis and delay in starting appropriate therapy (Paddock et al., 2002; Raoult et al., 2004). R. rickettsii not only causes severe disease naturally, it is also a potential terrorism agent because it is highly infectious at a very low dose (Wike et al., 1972).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Etiologic agents

Rickettsia are small gram negative bacteria (0.3 – 0.5 × 0.8 – 1.0 μm). Rickettsial diseases are transmitted by arthropods including ticks, mites, lice, and fleas. Based on LPS antigens rickettsiae are classified into typhus group (TG) and spotted fever group (SFG). TG rickettsiae are transmitted by lice and fleas. SFG rickettsiae include more than 20 species and most of them are tick-borne except for mite-borne R. akari and flea-borne R. felis. The nontick-borne Rickettsia will not be discussed further. All Rickettsia multiply in the cytoplasm of host cells, but SFG rickettsiae can also multiply in the nuclei of host cells. Rickettsia organisms have undergone genome reduction resulting in a smaller genome (approximately 1Mb), and have lost genes encoding enzymes for sugar metabolism, lipid biosynthesis, nucleotide synthesis and amino acid synthesis (Andersson et al., 1998). SFG rickettsiae spread from cell to cell via actin-based mobility (Teysseire et al., 1992).

Epidemiology/Public health importance

The distribution of tick-borne SFG rickettsioses is restricted to areas where their tick reservoirs are present such as Rocky Mountain spotted fever in the Americas, Mediterranean spotted fever in Europe, Africa and Asia, and Japanese spotted fever in Japan and Korea (Table A5-1).

Tick-borne rickettsiae are maintained in nature largely via transovarian transmission in ticks. Nonvirulent and low virulent tick-borne Rickettsia do not cause adverse effects on their tick vector, but virulent Rickettsia such as R. rickettsii and R. conorii are pathogenic for Dermacentor and Rhipicephalus ticks, respectively (Niebylski et al., 1999; Santos et al., 2002). Thus, virulent rickettsiae such as R. rickettsii need an animal host to amplify the organisms to establish new lines of transovarian rickettsial maintenance (e.g., D. variabilis ticks acquire R. rickettsii while feeding on rickettsemic cotton rats) (Niebylski et al., 1999). The vectors of Rocky Mountain spotted fever are D. variabilis (American dog tick) in the eastern two-thirds of the US and regions of the Pacific coast states, D. andersoni (wood tick) in the Rocky Mountain states, Rhipicephalus sanguineus (brown dog tick) in the southwestern US and northern Mexico, and Amblyomma cajennense and A. aureolatum in South America.

The seasonal and geographic distribution of each rickettsiosis reflects the months of activity of the vector and its contact with humans. Over 90% of cases of Rocky Mountain spotted fever occur during April through September. Approximately 250-1200 cases of Rocky Mountain spotted fever have been reported annually in the past (http://www.cdc.gov/ncidod/dvrd/rmsf/epidemiology.htm), and currently more than 2000 cases are reported each year.

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TABLE A5-1 Distribution of Tick-Borne Rickettsioses

Disease

Rickettsia agent

Geographic Distribution

African tick-bite fever

Rickettsia africae

Sub-Saharan Africa, Caribbean islands

Far eastern spotted fever

Rickettsia heilongjiangensis

Far East of Russia and China

Flinders Island spotted fever

Rickettsia honei

Australia and southeastern Asia

Mediterranean spotted fever

Rickettsia conorii

Southern Europe, southern and western Asia, and Africa

North Asian tick typhus Lymphangitis-associated Rickettsiosis

Rickettisa sibirica

Rickettsia sibirica mongolotimonae

Asia, Europe, and Africa

Oriental spotted fever

Rickettsia japonica

Japan and Korea

Queensland tick typhus

Rickettsia australis

Australia

Rocky Mountain spotted fever

Rickettsia rickettsii

North, Central and South America

Tick-borne lymphadenopathy

Rickettsia slovaca

Europe

Unnamed

Rickettsia parkeri

North and South America

Unnamed

Rickettsia massiliae

Europe and North and South America

Unnamed

Rickettsia aeschlimannii

Europe and Africa

Unnamed

Rickettsia monacensis

Europe

Unknown

Rickettsia helvetica

Europe and Asia

Clinical spectrum and treatment

Rickettsial diseases are characterized at onset by fever, severe headache, and muscle aches. In Rocky Mountain spotted fever, the characteristic maculopapular rash typically appears 3 to 5 days later. In severe disease, petechiae may appear in the center of the maculopapules. However, up to 10% to 15% of people with RMSF never develop a rash, a condition often referred to as “Rocky Mountain spotless fever” (Sexton and Corey, 1992). Rashes are less frequent in less severe rickettsioses such as African tick bite fever and R. parkeri infection. Focal skin necrosis with a dark scab (an eschar) at the site of tick feeding is a common feature of boutonneuse fever, African tick bite fever, North Asian tick typhus, Queensland tick typhus, Japanese spotted fever, Flinders Island spotted fever, tick-borne lymphadenopathy, and the recently described infections in the US caused by R. parkeri and a novel strain 364 D, but is rare in Rocky Mountain spotted fever.

Tetracyclines are first-line treatment, and doxycycline may be used to avoid tooth staining in children. Tetracyclines are rickettsiostatic, not rickettsicidal. Ciprofloxacin and other fluoroquinolones are effective against certain rickettsiae. Because diagnostic tests can take time and may be

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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insensitive, antibiotics are usually begun presumptively to prevent significant deterioration, death, and prolonged recovery.

Overview of protective immune mechanisms

Most of our understanding of the immune response against Rickettsia is derived from in vitro studies as well as the murine models of rickettsioses. Proinflammatory cytokines such as IFN- and TNF- are essential for primary defense against rickettsial infection. These cytokines act in concert to activate endothelial cells, the major target cells of rickettsial infections, as well as other minor target cells to kill intracellular organisms via a nitric oxide synthesis-dependent mechanism. The sources of these protective cytokines are hypothesized to be the T lymphocytes and macrophages that infiltrate the perivascular space surrounding the vessels with infected endothelium.

Cell mediated immunity plays a critical role in host defenses against rickettsial infections(Walker et al., 2001). There are two important effector components of acquired immune response against Rickettsia, namely IFN-production by CD4+ and CD8+ type-1 cells, which activates intracellular bactericidal mechanisms of endothelial cells and macrophages, and the generation of Rickettsia-specific cytotoxic CD8+ T cells that lyse infected target cells via pathways involving perforin and/or granzymes. CD8+ T cells are more important in clearance of rickettsial infection against rickettsiae than CD4+ T cells (Walker et al., 2001). Although adoptive transfer of either CD4 or CD8 immune T lymphocytes control the infection and lead to survival, only depletion of CD8 T lymphocytes altered the outcome of infection, and depletion of CD4 cells had no observed effect on the course or outcome of infection (Walker et al., 2001).

Humoral response may play an important role in protection against infection and antibodies against surface protein antigens are very likely critical effectors of vaccines-induce protective immunity. In animal experiments, antibodies to Rickettsia or rickettsial outer membrane proteins can neutralize rickettsial infection (Anacker et al., 1987; Li et al., 1988). However, natural infection does not result in the production of protective antibodies prior to clearance of rickettsiae. Thus, humoral immunity may be more important in preventing reinfection as in vaccine-induced immunity than in clearance of primary infection.

Vaccine feasibility and current status

Currently no commercial vaccine is available for any rickettsial disease. Infection with R. rickettsii and R. conorii is thought to provide long lasting immunity against re-infection. Thus, it is feasible to develop a vaccine against rickettsial diseases. In theory, a subunit vaccine targeting a

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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conserved rickettsial protein such as OmpB may be developed to prevent all rickettsial diseases. The best rickettsial vaccine may be an attenuated organism that can multiply but does not cause disease in the host. Attenuated Rickettsia has been achieved with gene knockout technology, and more attenuated strains of Rickettsia will become available for vaccine evaluation.

Experimental vaccines and other potential vaccine prospects

Inactivated rickettsial vaccine. The history of development of vaccines against Rocky Mountain spotted fever contains numerous failures and limited success in preventing or ameliorating disease. The first rickettsial vaccine was a killed R. rickettsii preparation from infected ticks (Spencer and Parker, 1925). The method of propagating R. rickettsii in yolk sac of embryonated chicken eggs was adapted soon after the development of this method in 1938 (Cox, 1939). A third killed Rocky Mountain spotted fever vaccine was prepared from cell culture-propagated R. rickettsii by the US Army in the 1970s (Kenyon et al., 1972).

A challenge trial in human volunteers was conducted in 1973. Neither the yolk sac vaccine nor the tick vaccine prevented the illness, which, of course, was treated promptly to prevent severe illness or death. The yolk sac vaccine was withdrawn from the market in 1978. Subsequent challenge trial of the killed-R. rickettsii vaccine prepared from cell culture yielded protection of 25% of the volunteers who received it. Evaluation of the recipients’ immune responses revealed failure to stimulate sustained cellular immunity (Clements et al., 1983).

Subunit vaccine for Rickettsia. Two surface protein antigens of R. rickettsii, OmpA and OmpB, have been identified as major protective antigens and are candidates for use as subunit vaccines. The first evidence that OmpA and OmpB contain protective epitopes came from the studies of monoclonal antibodies to heat sensitive epitopes of OmpA and OmpB, which neutralized R. rickettsii toxicity in mice and infection in guinea pigs (Anacker et al., 1987; Li et al., 1988). Immunization with the E. coli-expressed OmpA N-terminal fragment partially protects guinea pigs against a lethal challenge dose of R. rickettsii (McDonald et al., 1988). A fragment from the N-terminus of R. conorii OmpA protects guinea pigs against experimental infection with R. conorii and partially protects guinea pigs from challenge with the heterologous R. rickettsii (Vishwanath et al., 1990). Fragments of the ompA and ompB genes have been tested as DNA vaccines. In a regime of DNA immunization followed by boosters of the corresponding peptide, mice immunized with one of several R. rickettsii ompA or ompB fragments are partially protected against a lethal challenge with heterologous R. conorii (Diaz-Montero et al., 2001). It is not known

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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whether the incomplete protection of OmpA and OmpB to the heterologous Rickettsia species challenge in these experiments is caused by the antigenic differences between the rickettsial species, the immunization regime, or the antigen composition.

Attenuation of Rickettsia by gene knockout. Because of the difficulty of transforming Rickettsia, scientists have been unable to knock out rickettsial genes to test their function and to create an attenuated rickettsial vaccine until recently. The phopholipase D (pld) was the first rickettsial gene that was genetically knocked out. The pld- knockout Evir strain is avirulent for guinea pigs at the doses for which the Evir strain is virulent (Driskell et al., 2009). A Sca2 knockout strain of R. rickettsii has lost actin based mobility in cell culture, and in a guinea pig model of infection, the Sca2 mutant did not elicit fever, suggesting that Sca2 is a virulence factor of spotted fever group rickettsiae (Kleba et al., 2010).

Future prospects

The protective immune response to rickettsial infection involves both innate and adaptive immune responses. A concerted action of CD8+ T cells, and CD4+ T cells producing IFN-, and antibodies is required to clear infection and to prevent reinfection. Live attenuated vaccine mimics the natural infection, thus Rickettsia that are genetically attenuated by gene knockout are the strongest future direction for developing a rickettsial vaccine.

Key issues

Rickettsia are obligately intracellular bacteria and are transmitted by arthropods, including ticks.

R. rickettsii cause fatal disease that can be prevented by avoiding tick bites and removing attached ticks promptly.

There is no vaccine for rickettsial diseases despite the fact rickettsial infection stimulates long term immunity. Vaccines are needed for Rocky Mountain spotted fever.

Because diagnostic tests can take time and may be insensitive, antibiotic treatment should be initiated based on clinical and epidemiological information.

References

Anacker,R.L., McDonald,G.A., List,R.H., and Mann,R.E. (1987) Neutralizing activity of monoclonal antibodies to heat-sensitive and heat-resistant epitopes of Rickettsia rickettsii surface proteins. Infect Immun 55: 825-827.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Andersson,S.G., Zomorodipour,A., Andersson,J.O., Sicheritz-Ponten,T., Alsmark,U.C., Podowski,R.M. et al. (1998) The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature 396: 133-140.

Clements,M.L., Wisseman,C.L., Jr., Woodward,T.E., Fiset,P., Dumler,J.S., McNamee,W. et al. (1983) Reactogenicity, immunogenicity, and efficacy of a chick embryo cell-derived vaccine for Rocky Mountain spotted fever. J Infect Dis 148: 922-930.

Cox,H.R. (1939) Rocky Mountain spotted fever. Protective value for guinea pigs of vaccine prepared from rickettsiae cultivated in embryonic chick tissues. Public Health Rep 54: 1070-1077.

Diaz-Montero,C.M., Feng,H.-M., Crocquet-Valdes,P.A., and Walker,D.H. (2001) Identification of protective components of two major outer membrane proteins of spotted fever group rickettsiae. Am J Trop Med Hyg 65: 371-378.

Driskell,L.O., Yu,X.J., Zhang,L., Liu,Y., Popov,V.L., Walker,D.H. et al. (2009) Directed mutagenesis of the Rickettsia prowazekii pld gene encoding phospholipase D. Infect Immun 77: 3244-3248.

Kenyon,R.H., Acree,W.M., Wright,G.G., and Melchior,F.W., Jr. (1972) Preparation of vaccines for Rocky Mountain spotted fever from rickettsiae propagated in cell culture. J Infect Dis 125: 146-152.

Kleba,B., Clark,T.R., Lutter,E.I., Ellison,D.W., and Hackstadt,T. (2010) Disruption of the Rickettsia rickettsii Sca2 autotransporter inhibits actin-based motility. Infect Immun 78: 2240-2247.

Li,H., Lenz,B., and Walker,D.H. (1988) Protective monoclonal antibodies recognize heatlabile epitopes on surface proteins of spotted fever group rickettsiae. Infect Immun 56: 2587-2593.

McDonald,G.A., Anacker,R.L., Mann,R.E., and Milch,L.J. (1988) Protection of guinea pigs from experimental Rocky Mountain spotted fever with a cloned antigen of Rickettsia rickettsii. J Infect Dis 158: 228-231.

Niebylski,M.L., Peacock,M.G., and Schwan,T.G. (1999) Lethal effect of Rickettsia rickettsii on its tick vector (Dermacentor andersoni). Appl Environ Microbiol 65: 773-778.

Paddock,C.D., Holman,R.C., Krebs,J.W., and Childs,J.E. (2002) Assessing the magnitude of fatal Rocky Mountain spotted fever in the United States: comparison of two national data sources. Am J Trop Med Hyg 67: 349-354.

Raoult,D., Woodward,T., and Dumler,J.S. (2004) The history of epidemic typhus. Infect Dis Clin North Am 18: 127-140.

Santos,A.S., Bacellar,F., Santos-Silva,M., Formosinho,P., Gracio,A.J., and Franca,S. (2002) Ultrastructural study of the infection process of Rickettsia conorii in the salivary glands of the vector tick Rhipicephalus sanguineus. Vector Borne Zoonotic Dis 2: 165-177.

Sexton,D.J., and Corey,G.R. (1992) Rocky Mountain “spotless” and “almost spotless” fever: a wolf in sheep’s clothing. Clin Infect Dis 15: 439-448.

Spencer,R.R., and Parker,R.R. (1925) Rocky Mountain spotted fever: vaccination of monkeys and man. Public Health Rep 40: 2159-2167.

Teysseire,N., Chiche-Portiche,C., and Raoult,D. (1992) Intracellular movements of Rickettsia conorii and R. typhi based on actin polymerization. Res Microbiol 143: 821-829.

Vishwanath,S., McDonald,G.A., and Watkins,N.G. (1990) A recombinant Rickettsia conorii vaccine protects guinea pigs from experimental boutonneuse fever and Rocky Mountain spotted fever. Infect Immun 58: 646-653.

Walker, D.H., Olano,J.P., and Feng,H.M. (2001) Critical role of cytotoxic T lymphocytes in immune clearance of rickettsial infection. Infect Immun 69: 1841-1846.

Wike, D.A., Tallent,G., Peacock,M.G., and Ormsbee,R.A. (1972) Studies of the rickettsial plaque assay technique. Infect Immun 5: 715-722.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Anaplasmosis

Introduction

Anaplasma are gram-negative -Proteobacteria belonging to the order Rickettsiales, and family Anaplasmataceae (Figure A5-1) (Dumler et al., 2001). Like most Rickettsiales, organisms in the genus Anaplasma are small, ranging from 0.2-0.9 μm. Of the four genera in the family Anaplasmataceae, Anaplasma is most similar in lifestyle and evolutionary history to the closely related Ehrlichia spp. The genus Anaplasma contains five recognized species: A. bovis, A. ovis, A. platys, A. marginale and

FIGURE A5-1 Phylogenetic tree of order Rickettsiales. [Genera in the families Anaplasmataceae (on yellow background) and Rickettsiaceae (on blue background) are shown. Species of interest are circled or boxed. The Rickettsia are subgrouped according to ancestral group (AG), transitional group (TrG), Typhus group (TG) and spotted fever group (SFG). The tree is based on a clustalW alignment of 16S ribosomal RNA gene sequences using POWER (http://power.nhri.org.tw/power/home.htm).]

FIGURE A5-1 Phylogenetic tree of order Rickettsiales. [Genera in the families Anaplasmataceae (on yellow background) and Rickettsiaceae (on blue background) are shown. Species of interest are circled or boxed. The Rickettsia are subgrouped according to ancestral group (AG), transitional group (TrG), Typhus group (TG) and spotted fever group (SFG). The tree is based on a clustalW alignment of 16S ribosomal RNA gene sequences using POWER (http://power.nhri.org.tw/power/home.htm).]

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A. phagocytophilum, with the first four species infecting animals, and the last being a zoonotic agent. The type species for the genus is A. marginale, a cattle pathogen that was recognized in the early 1900s (Theiler, 1910). Of these species, by far the most research has been done on the latter two species, A. marginale which causes anaplasmosis, and the human pathogen A. phagocytophilum, which causes human granulocytic anaplasmosis. All Anaplasma species are obligate intracellular organisms infecting mature or immature hematopoietic cells where they replicate within membrane bound vacuoles (Dumler et al., 2001). Anaplasma spp. are therefore blood-borne pathogens and are transmitted from host to host by Ixodid ticks. This manuscript will focus on the human pathogen, A. phagocytophilum.

Etiologic agent

A. phagocytophilum was previously classified as an Ehrlichia (the agent of human granulocytic ehrlichiosis). Accumulating genetic information on a number of pathogens originally named as Ehrlichia species drove the reorganization of the families Rickettsiaceae and Anaplasmataceae in 2001 wherein Ehrlichia equi, and Ehrlichia phagocytophila were unified as a single species with the agent of human granulocytic ehrlichiosis, to create the new species Anaplasma phagocytophilum (Dumler et al., 2001). Because anaplasmosis is recognized as a cattle disease, A. phagocytophilum is said to cause human granulocytic anaplasmosis (HGA).

A. phagocytophilum infects polymorphonuclear leucocytes (neutrophils), where it replicates within a membrane bound vacuole forming a morula or microcolony (Chen et al., 1994; Rikihisa, 1991). A. phagocytophilum has a biphasic developmental cycle with two morphologically distinct forms referred to as dense cored cells (DC) and reticulate cells (RC) (Popov et al., 1998). DCs are small electron dense bodies that predominate in early infection, are thought to be metabolically inert and play a role in attachment and invasion of the host cell (Munderloh et al., 1999). RCs are electron lucent larger pleomorphic cells that undergo binary fission and are thought to be the metabolically active form of the organism (Ismail et al., 2010; Troese and Carlyon, 2009).

The Rickettsiales are the closest extant relatives of the bacterial lineage that led to the mitochondria, and have undergone extensive genome reduction with individual species displaying small genome sizes between 0.8 and 1.5 Mb (Sallstrom and Andersson, 2005; Andersson et al., 1998; Viale and Arakaki, 1994). The A. phagocytophilum genome, completed in 2006, is 1,471,282 bp and is reported to contain 1264 protein coding genes as well as 37 tRNA and 3 rRNA genes (Dunning Hotopp et al., 2006). While this number of protein coding genes is greater than many of the closely related organisms (range = 805-1264), this difference is largely due to differences

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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in annotation style (many small open reading frames were annotated) rather than a real difference in coding capacity (Brayton et al., 2008).

Epidemiology/Public health importance

HGA was first identified as a human pathogen in 1990 when a patient in Wisconsin died after a short acute febrile illness (Dumler et al., 2005). HGA is increasingly recognized as a frequent cause of fever after tick bite in the Upper Midwest, New England, parts of the mid-Atlantic states, northern California (Figure A5-2), many parts of Europe and Asia (Dumler et al., 2005). In the United States, cases of HGA have increased since the CDC started tracking cases in 1999 (Figure A5-3) with 1009 cases reported in 2008 (Hall-Baker et al., 2010).

A. phagocytophilum infects many species including dogs, cats, horses, deer, cattle, sheep, mice, wood rats, bank voles, squirrels, opossums, skunks and raccoons (Foley et al., 2008; Hackett et al., 2006; Lester et al., 2005; Levin et al., 2002; Stuen and Bergstrom, 2001; Stuen et al., 2001a; Stuen et

FIGURE A5-2 Average annual incidence of HGA by state as reported in 2001-2002. Data from CDC National Electronic Telecommunications System for Surveillance.

FIGURE A5-2 Average annual incidence of HGA by state as reported in 2001-2002. Data from CDC National Electronic Telecommunications System for Surveillance.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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FIGURE A5-3 Number of HGA cases reported by year from 1999-2002. Data from CDC National Electronic Telecommunications System for Surveillance.

FIGURE A5-3 Number of HGA cases reported by year from 1999-2002. Data from CDC National Electronic Telecommunications System for Surveillance.

al., 2001b; Stuen et al., 2001c; Pusterla et al., 1999). Humans are accidental, dead end hosts for A. phagocytophilum, typically becoming infected when humans encroach on small mammal-tick habitats (Dumler et al., 2005). The major mammalian reservoir is the white-footed mouse, which typically has a transient bacteremia (1-4 weeks). While white tailed deer can be persistently infected, they do not appear to harbor strains of A. phagocytophilum that cause HGA (Massung et al., 2005). Strain definition for A. phagocytophilum is not well defined; however, 1-2 nucleotide differences in the 16S ribosomal RNA gene and 1-3 bp differences in the GroESL gene have been used to identify strain variants (Stuen et al., 2003; Massung et al., 2002).

In the Midwestern and Eastern US Ixodes scapularis is the vector, while I. pacificus vectors A. phagocytophilum in the Western US. I. ricinus is the major vector in Europe, and I. persulcatus transmits disease in Asia. Tick infection is established after an infectious blood meal, and the bacterium is transstadially but not transovarially passed (Dumler et al., 2005). These ticks also transmit agents that cause Lyme disease, babesiosis and tick-borne meningoencephalitis, with about 10% of HGA patients showing serological evidence of co-infection with one of these agents (Ismail et al., 2010; Dumler et al., 2007; Dumler et al., 2005).

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Clinical spectrum/Treatment

HGA presents with fever, headache, leukopenia, thrombocytopenia, absence of a skin rash and elevated liver enzymes. Symptoms typically begin a median of 9 days following tick bite, with the majority of patients seeking medical attention within the first 4 days of illness (Ismail et al., 2010; Dumler et al., 2005). Some individuals infected with A. phagocytophilum do not become ill or experience only very mild symptoms and do not seek medical treatment; however, at the other end of the spectrum, the disease can prove fatal, particularly in immunocompromised or elderly individuals (Thomas et al., 2009; Dumler et al., 2005).

Accurate diagnosis of HGA is often difficult due to the non-specific nature of the symptoms. An initial diagnosis is based on the patient’s symptoms and a possible history of tick exposure. Diagnosis is confirmed by laboratory tests: 1) microscopic examination of Wright- or Giemsastained peripheral blood smears looking for dark staining morulae within neutrophils can be used early in infection, 2) a polymerase chain reaction (PCR) assay is the most sensitive test, provides rapid diagnostic evaluation and can discriminate between several tick-borne diseases that present with similar symptoms, 3) A. phagocytophilum can be cultivated within two weeks in the human promyelocytic leukemia cell line HL-60 by direct inoculation of cell cultures with peripheral blood from a potentially infected patient, and 4) serodiagnosis is most commonly used, but is not rapid, as it requires time for antibody to develop which typically takes longer than the onset of clinical symptoms; additionally, nonspecificity of this test may result from cross reactions with Ehrlichia chaffeensis (Ismail et al., 2010; Thomas et al., 2009).

The treatment of choice for both adults and children is a tetracycline antibiotic, usually doxycycline, which should be initiated promptly for improved outcomes and continued for 10-14 days (Hamburg et al., 2008; Chapman et al., 2006).

Overview of protective immune mechanisms

Relatively little is known about protective mechanisms of immunity to A. phagocytophilum infection except that protective immunity is mediated by cellular and humoral immune mechanisms. Development of high titer antibody responses is believed to be indicative of protective immunity (Ismail et al., 2010). Studies in sheep indicate that protection can last from a few months to > 1 year and that a measure of heterologous protection is afforded by some strains but not others (Stuen et al., 2003). Reinfection has been confirmed in some individuals which suggests that long-term immunity was not engendered; however, a lack of cross protection between different

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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strains of A. phagocytophilum must also be considered (Levin et al., 2004; Horowitz et al., 1998).

Similar to A. marginale, A. phagocytophilum effects immune evasion through antigenic variation of the Msp2/p44 immunodominant surface protein (Granquist et al., 2010; Barbet et al., 2003). There is at least one expression site for msp2/P44 and ~100 functional pseudogenes which can recombine into the expression site to generate variation (Dunning Hotopp et al., 2006; Barbet et al., 2003). The Msp2/P44 protein is characterized by conserved amino- and carboxy-termini flanking a central hypervariable region (Murphy et al., 1998). Msp2/P44 functional pseudogenes are typically truncated at the 5’ and 3’ ends, and recombine into the expression site through a RecF dependent gene conversion mechanism (Lin et al., 2006).

Current vaccine status, experimental vaccines, and potential vaccine prospects

Vaccination against the cattle pathogen A. marginale is effected by infection with an avirulent strain, providing a measure of crossprotection without sterile immunity. This blood-based vaccine is not used in the U.S. due to the threat of transmitting emerging pathogens. There are no vaccines currently available for HGA. The search for vaccine candidates has focused on surface proteins as these are the interface for interactions with the host cell; however, these studies are in their infancy. Little is known about the surface proteins of A. phagocytophilum, aside from Msp2/P44, which due to rapid antigenic variation does not constitute a good vaccine candidate (Ge and Rikihisa, 2007). The genome sequence provides a useful tool to facilitate research to identify vaccine candidates and was recently used in combination with a proteomic approach to identify surface exposed proteins. Two proteins were identified, Asp55 and Asp62, that were also recognized by immune serum from a patient with HGA. Peptide anti-sera for these two proteins were able to partially neutralize A. phagocytophilum infection in the human promyelocytic leukemia cell line, HL-60 cells (Ge and Rikihisa, 2007).

Preliminary studies aimed at understanding the pathogen-tick interface have the long-term goal of developing transmission blocking vaccines, although this research has focused more on interrupting the transmission of the cattle pathogen A. marginale (de la Fuente et al., 2010; Ramabu et al., 2010; Noh et al., 2008). Novel approaches that could reduce the level of human contact with disease agents include the development anti-tick vaccines. An anti-tick vaccine based on the Rhipicephalus microplus gut protein Bm86 has been successful in field trials in Cuba; however, implementation of a similar vaccine was not successful in Australia (de la Fuente et al., 2007; Rodriguez Valle et al., 2004). A successful anti-tick vaccine

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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would be introduced orally to the wildlife reservoirs in a similar fashion to rabies vaccine, and could eliminate the need for broad scale human vaccina­tion (Slate et al., 2009). This strategy would reduce, but not eliminate risk of transmission. As yet, there are no candidates ready for testing for either of these strategies for ticks that transmit HGA.

Theraupeutics and other biologics for prevention

Preventative antibiotic therapy is contraindicated for individuals who have had recent tick bites but are not ill. Prevention is effected by avoid­ance of tick bites through the following strategies: 1) avoidance of tick dense areas, 2) wearing of light colored protective clothing (i.e., long pants, closed-toed shoes, etc.), 3) frequent checks for crawling and at­tached ticks, and 4) application of a repellant such as DEET (N,N-diethyl-m-toluamide). Should a person find an attached tick prompt removal reduces the threat of transmission, as studies have shown that a period of 4 to 24 hours may be necessary before successful transmission from tick to host takes place (Ismail et al., 2010; Bakken and Dumler, 2008; Katavolos et al., 1998).

Key issues
  • Additional effort in identifying surface exposed targets that could illicit protective immune responses is needed. The genome is a key tool in this endeavor and the advent of affordable, widely available proteomic tools should facilitate these efforts. Understanding mecha­nisms of immune evasion will also help in assessment of vaccine candidates.

  • Understanding the strain composition that makes up the A. phago­cytophilum species will facilitate development of appropriate vac­cine candidates; i.e., variation in leading vaccine candidate antigens may not be relevant if the variant strain does not infect humans. Representative A. phagocytophilum genome sequences from an ar­ray of hosts could assist in exploring the strain composition but this organism does not lend itself to high throughput, next generation sequencing strategies due to the highly repetitive nature of the ge­nome sequence.

  • Understanding of the transmission biology of A. phagocytophilum would facilitate the development of transmission blocking vaccines and potentially help elucidate targets for anti-tick vaccines as well.

  • Understanding host differences in pathogenesis would aid in deter­mining if vaccines tested in sheep, for example, would be relevant for humans.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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A6
EMERGING AND RE-EMERGING TICK-BORNE DISEASES: NEW CHALLENGES AT THE INTERFACE OF HUMAN AND ANIMAL HEALTH

Ulrike G. Munderloh and Timothy J. Kurtti Department of Entomology, University of Minnesota St. Paul, MN 55108

Introduction: Accelerated Increase and Uneven Distribution of Emerging Diseases

This manuscript is meant to be a synthesis of current knowledge about the forces that drive emergence of tick-borne diseases during this era of global change. This is an enormously complex field the components of

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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which are in constant flux and change dynamically all the time. We therefore do not present here a comprehensive list of all tick-borne pathogens, but rather discuss those that have been researched in sufficient detail to allow assessment of their impact, how they have changed, and how they interact with their environment.

Globally, the great majority of emerging diseases are zoonoses that are predominantly vector-borne (Jones et al., 2008). In temperate climates, tick-borne pathogens are the leading cause of vector-borne diseases, whereas insects dominate the scene as vectors of pathogens in the tropics (Kalluri et al., 2007). The incidence of vector-borne diseases has increased disproportionately in relationship to other emerging diseases, and peaks at times of severe weather events and climate anomalies (Githeko et al., 2000; Gray et al., 2009), a reflection of the sensitivity to and reliance of arthropods on permissive conditions including rain. These effects may be seen relatively quickly, as for pathogens transmitted by mosquitoes, especially those maintained in the insect population transovarially, reducing the lag time before transmission can occur following acquisition. Development of mosquitoes from egg to adult can be completed in two weeks or less, during which larvae feed on microbes suspended in the water. Complete development takes months or years for ticks, but each life stage (except the males of certain species) may transmit pathogens during a blood meal. As for mosquitoes, dynamics of tick-borne disease activity are shaped by climate, though less by rapid weather changes. Availability of suitable larval habitat is of prime importance for maintenance and establishment of mosquito populations, whereas availability of hosts and host behavior are major determinants for ticks. Thus, human activities can shape expansion of different arthropod vectors in different ways, both by habitat modification as well as by altering host populations and their composition. In all, the relationships among factors governing the emergence and spread of vector-borne pathogens, including those that are tick-borne, are very complex. Seasonal and yearly variability determines how ecosystem components interact and contribute to provide habitat suitable for vector arthropods; arthropods, in turn, have evolved behaviors that allow them to take advantage of microclimate niches as needed to “weather” unpredictable conditions (Killilea et al., 2008). These complexities have not been sorted out to date at a global scale, and await a standardized approach to analysis before meaningful conclusions can be drawn.

Climate, weather and temperature directly influence poikilothermic arthropods by dictating periods when important activities, e.g., host seeking, mating, or egg development are possible. Thus climate restricts geographic range to regions with sufficient cumulative degree days to allow completion of these necessary activities and development to the next life stage. Unlike a hot, dry summer that affects ticks when they are normally active,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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cold winters are more readily tolerated by ticks that had time to prepare physiologically by seeking suitably protective habitat and accumulating protective anti-freeze compounds (Burks et al., 1996). A recent analysis of gene expression in black-legged ticks subjected to cold revealed that a glycoprotein with homology to a blood protein in cold water fish was more efficiently induced in ticks carrying the zoonotic bacterial pathogen Anaplasma phagocytophilum than in uninfected ones (Neelakanta et al., 2010), presumably providing a selective advantage to overwintering nymphs and adults. This would enhance northward dispersal of “anaplasma-winterized” ticks, and could introduce this pathogen to the mice, chipmunks, squirrels, raccoons and other reservoir hosts that live there (Levin et al., 2002). Davies et al., (2009) proposed that the range of mammals and their ability to expand into new habitats could be predicted by the variability of historic conditions in their range during the Quarternary period. Animals that have evolved to adapt to profound changes in the past are thought to more readily be able to exploit new opportunities. Although a comparable fossil record does not exist for arthropods, ectoparasites that remain on hosts for days at a time, as ticks do, are readily translocated during host movement (Bjöersdorff et al., 2001; McCoy et al., 2003; Ogden et al., 2008; Reed, 2003), thus historic tick host ranges could serve as a proxy for historic ranges of ticks, and their evolved potential to disperse could then be modeled similarly.

Impact of Climate and Global Change Providing New Opportunities

The human population explosion has resulted in dramatic changes of the distribution and composition of natural habitat and land modified to sustain human needs in terms of living space and food production, and this is an ongoing, highly dynamic process. Changes in land use patterns favor establishment and expansion of ticks at the urban/agricultural interface and provide new habitat for highly adaptable wild hosts, as well as new domestic animal hosts for ticks. Even so, advancement of human settlements into virgin land has resulted in a reduction in species diversity and subsequent increase in the risk of tick-borne diseases. Much of the natural vegetation that would presumably cover the earth in the absence of humans (“potential vegetation”), and provide wildlife habitat, has been displaced by cropland and pastures (Foley et al., 2005). These managed agricultural systems lack the rich diversity of plant and animal species characteristic of undisturbed areas, and are more prone to damage from diseases or either natural of human-made disasters such as floods, fires or pressure from invasive species. A rich assembly of plant and animal communities provides a buffer against such events, and enables affected regions to rebound in their wake. Moreover, reduced biodiversity has been linked to increased risk of vector-borne

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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disease by depletion of natural hosts for vector and pathogen, as well as by provision of new hosts. Domesticated animals living close to farmers and herders, or sharing their dwellings, can act as new reservoirs and bridge hosts in the transfer of emerging diseases to humans (Keesing et al., 2006; LoGiudice et al., 2008; Vora, 2008). A recent example is the discovery of an active transmission focus of Rocky Mountain spotted fever (RMSF) rickettsiae, Rickettsia rickettsii, in Arizona, involving an introduced tick vector, the brown dog tick, Rhipicephalus sanguineus, and domestic dogs acting as reservoirs for the rickettsiae and hosts for the ticks (Demma et al., 2005). Since then, brown dog ticks infected with R. rickettsii have also been detected in California (Wikswo et al., 2007). This tick colonized the Americas along with humans and their dogs arriving from the Old World during the early colonial immigrations (Burlini et al., 2010). It is surprising that spotted fever group rickettsiae endemic to the Mediterranean region, Rickettsia conorii (Mumcuoglu et al., 1993), that are naturally transmitted by brown dog ticks, have thus far not been identified in the New World. The adaptation of R. rickettsii to a new tick vector is a good example of the host switching that can result when human-aided movement of animals and their parasites are introduced into new areas where they intermingle with resident hosts, parasites and disease agents (Hoberg et al., 2008). Such new combinations are more likely to turn up in the multiple host life cycle of tick-borne pathogens, especially when the vectors are non-specialized feeders as is the case with the black-legged tick Ixodes scapularis. In this situation, host switching without the need for subsequent adaptive evolution can occur in pathogens that inherently are equipped to take advantage of new opportunities provided by hosts undergoing range expansion in a process of ecological fitting (Brooks and Ferrao, 2005; Foley et al., 2008).

Human encroachment on wildlife habitat enhances contact with ticks as modern society embraces the concept of living with nature by building homes in natural settings and through engagement in outdoor sports such as hiking or camping. Regional and historical preferences for how and where homes are constructed, and how and where animals are housed or pastured have modified the zoonotic interface between humans and domestic and wild animals in ways that where not anticipated, but were predictable in retrospect. The desire to preserve natural vegetation such as mature stands of trees for aesthetic or practical reasons (e.g., to provide shade) has had the effect to attract wildlife to close proximity of human dwellings, enhancing contact with ticks and other arthropods that may carry disease agents. The increase in Lyme disease cases in residents of affluent housing developments in or near desirable natural wooded areas is a good example of this trend (Barbour and Fish, 1993; Linard et al., 2007). Although much research has been devoted to trying to describe the ecologic/sociologic interface that favors the presence of pathogens, vectors and reservoirs, and has

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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resulted in large sets of data that do not easily coalesce into a single, well-fitting mosaic, few efforts have been made to systematically incorporate them into urban/suburban/agricultural planning (Ward and Brown, 2004). There is a clear need to apply what has been learned to new and existing urban and suburban as well as agricultural and recreational landscapes. Disease prevention through landscape management must, however, always be in balance with protection of natural habitat, and its meaningful incorporation into managed areas (Foley et al., 2005; Stafford III, 2007). Such decisions must be based on scientific knowledge, and biologists, medical scientists and public health researchers must be included in the planning processes alongside city planners and construction company employees.

Areas that are likely to experience increased or prolonged seasonal tick activity are most likely those located at the current extremes of the current range of distribution, areas where climate change will be felt most acutely. In the northern hemisphere, this will be at the northern edge, and in the southern hemisphere, tick distribution ranges will likely shift further south. A prerequisite is the presence of ecosystems with suitable land cover and hosts to receive the immigrants. Occupation of montane habitat by Ixodes ricinus in Europe has already shifted to greater altitudes (Materna et al., 2005), exposing alpine farming communities to new risk of infection. At these greater latitudes and altitudes, specialized plant communities are utilized by relatively few wild animals that can serve as tick hosts and impose constraints that may limit or curb further spread of the ticks. Domestic animals seasonally introduced into borderline habitat and the people tending them will experience a greater burden of tick bites.

The Domestic Animal/Wildlife Interface

Driving flocks and herds out to pasture on a daily or weekly basis, or even turning live stock out onto range land for entire seasons, has been a tradition for centuries, and animal husbandry is thought to have been a source of human exposure to zoonoses since ancient times (Greger, 2007). A new and worrisome trend is the increasing practice of exotic animal farming and trade in exotic species. Exotic game farms have become popular with hunters seeking the thrill of a chance to shoot an African antelope without having to leave the USA, and offer farmers income from land that may be poorly suitable for traditional farming. Although animals imported from foreign countries must undergo rigorous testing for diseases and quarantine, any as yet unknown pathogens they may harbor may not be detected using existing diagnostics. In addition, tick-borne pathogens, e.g., the bovine anaplasmosis agent, Anaplasma marginale, which is widely present throughout the world, can chronically infect animals at undetectable levels (Eriks et al., 1989; Herrero et al., 1998), and other pathogens may

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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do the same. There are numerous reports in recent history of accidental introduction of tick-borne animal pathogens or ticks into previously unaffected areas, with economically disastrous results. When imported ticks become established on wild animals, their eradication may be very difficult or impossible, as shown in New Caledonia (Barré et al., 2001) where cattle ticks and bovine babesiosis were accidentally imported. The cattle tick, Rhipicephalus (Boophilus) microplus, is the vector of bovine babesiosis, a disease with major consequences for cattle production wherever it is present. It has spread through most warm regions of the world from its origin in Asia by hitching a ride on imported cattle (Hoogstraal, 1956; Madder et al., 2010). This parasite has adapted well to wild ungulates in infested areas, providing alternate hosts when cattle are intensively treated with acaricides, unraveling control efforts (Cantu-C et al., 2009). After being nearly eradicated in the USA, this tick has recently expanded its range considerably in Texas, in part aided by development of acaricide resistance resulting from intense treatment regimes (George, 2008). There is no reason to believe that R. microplus would not adapt to exotic game on farms, as it has displaced other Rhipicephalus species in West Africa (Madder et al., 2010). Although the development of promising antigens raises the hope that a vaccine could protect cattle against this parasite (Canales et al., 2009), their effectiveness in essentially wild or feral exotic animal species remains unproven.

Much as exotic animals can be a source of exotic pathogens endangering resident fauna, pathogens endemic in areas into which non-endemic species are introduced may prove to be highly infectious for non-indigenous animals. Farming game, e.g., elk (or wapiti, Cervus elaphus canadensis), has been promoted as a sustainable alternative to raising cattle, because these animals are less demanding and are superior in their ability to utilize nutrients from natural pasture. They also produce lean meat that fetches premium prices on the market. In their natural range in the Rocky Mountains of the USA and Canada, elk do not encounter I. scapularis (black-legged ticks), but when raised in the Midwest or Northeast, they are exposed to a protozoan blood parasite, Babesia odocoilei, transmitted by ticks among white-tailed deer who do not show signs of infection (Waldrup et al., 1990). Elk and deer from outside the range of the vector tick may become severely ill, even suffer a fatal infection. Outbreaks of fatal illness have also been documented in a number of animals at zoos, e.g., reindeer (Rangifer tarandus tarandus) and caribou (Rangifer tarandus caribou), bovids such as musk oxen (Ovibos moschatus) and yak (Bos grunniens), as well as other ruminants, e.g., muntjac (Muntiacus reevesi) and markhor goat (Capra falconeri) (Schoelkopf et al., 2005; Bartlett et al., 2009). This list of susceptible species is not inclusive, but serves to demonstrate the enormous infection potential of tick-borne pathogens in animals that have not co-evolved with them. Importation of exotic species for uncontrolled release should be avoided for other reasons as well, because

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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their impact on natural habitat is not easily predictable, and great environmental harm can result. One need only consider the devastation wrought by domestic goats released by sailors on many islands as a fresh food supply, or the disastrous release of European wild rabbits in Australia (Campbell and Donlan, 2005; Fenner, 2010).

Changes in Climate Favor Establishment and Expansion of Ticks

The spread of human settlement is accompanied by changes in land use that have been linked with increasing risk of disease due to vector-borne pathogens (Hoogstraal, 1981; Harrus and Baneth, 2005). Global change is the sum of largely man-made ecologic disturbances resulting in rising temperatures and altered patterns of precipitation that promote the expansion of the geographic range where conditions are favorable for survival of vector arthropods. Changes in vector distribution and seasonal activity resulting in increased disease incidence are likely to be most pronounced at the geographic extremes of vector distribution (Ogden et al., 2005).

In temperate climates, pathogens transmitted by ticks are the causative agents of the most common vector-borne diseases, far outnumbering those carried by mosquitoes. The incidence of Lyme disease transmitted by Ixodes spp. in North America and Europe has been increasing steadily since the 1970s and 1980s (Gray et al., 2009). In the US Midwest, this steady pace accelerated at the beginning of the new century, with significant deviations from the average rate tied to unusually dry and hot weather, such as during the summer of 2003 that was followed by a rebound in 2004 (Minnesota Department of Health; http://www.health.state.mn.us/divs/idepc/diseases/anaplasmosis/casesyear.html). Human anaplasmosis caused by A. phagocytophilum is now the second most common tick-borne disease in the US, and is also transmitted by I. scapularis. Although still much less common than borreliosis, this disease has paralleled the upward trend of Lyme disease (http://www.cdc.gov/ticks/diseases/anaplasmosis/statistics.html), and may be subject to similar dynamics and constraints of climate and tick biology. Clearly, climate plays a prominent role in the shifting boundaries of tick populations, but it is certainly only one of multiple factors in the equation. Warmer winters with increased precipitation and thus deeper winter snow pack allow enhanced tick overwintering rates by providing critical protection from desiccation and chill injury (Burks et al., 1996), and result in expansion into formerly unsuitable regions—as seen in Canada with I. scapularis (Odgen et al., 2005, 2008). In currently endemic areas, greater humidity and higher temperatures earlier and later in the year extend periods of tick activity into a longer tick season while creating inviting conditions for human outdoor activity. This effectively prolongs risk of exposure and infection.

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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Planning Ahead: Can Climate Models Predict Public Health Risk?

A number of research teams have attempted to model risk of infection with tick-borne pathogens. Intuitively, one should expect this to be possible in developed countries where there is a wealth of data on human disease cases, distribution of ticks and hosts, and climatologic data collected over decades. Areas that are currently considered to present high risk of encountering ticks can be identified at a regional level, and provide valuable guidance for the management of tick-borne disease risk through rational design of land use, and management of tick hosts and pathogen reservoirs (Ward and Brown, 2004; Stafford III, 2007). Risk assessments indicate that fragmented, patchy forest with a large proportion of edge habitat, support tick and mouse populations well (Allan et al., 2003; Brownstein et al., 2005; Foley et al., 2009; Eisen et al., 2010; Raizman et al., 2010). This agrees with the observation that disturbed ecosystems support larger numbers of ticks than intact ones, and reflects a variety of underlying reasons based in the biology of ecosystem participants. Deer, especially white-tailed deer, are important reproductive hosts for Ixodes ticks, and thrive in second growth forest that characterizes prime tick habitat (Foley et al., 2009). By contrast, intact old growth forests have much lower association with tick-bite risk, probably because they retain higher vertebrate species diversity that dilutes infection risk by interspecies competition and predation on reservoirs. This seeming discrepancy in the association of forests with tick bite risk is an example of the difficulties that analysts face when trying to make sense of the collective data set. The many abiotic and biotic factors that combine to shape the ecology of vector-borne diseases are highly complex, and published studies lack a standardized approach that would make them comparable (Kililea et al., 2008). Models that attempt to span expansive regions or to extend forecasts far ahead are often based on the assumption that current trends will remain continuous over long distances and into the future (Diuk-Wasser et al., 2006; Odgen et al., 2006). These assumptions remain to be validated, but nevertheless present plausible scenarios that have stimulated the debate about interventions and countermeasures. Long-term predictive models could be made more useful if they were continuously updated with new information to reflect the influence of changing populations and land use.

Tick Species with the Greatest Potential for Expansion

Lessons learned from the two globally most widely distributed tick species, the cattle fever tick (pantropical blue tick), Rhipicephalus (Boophilus) microplus (Madder et al., 2010), and the brown dog tick, Rhipicephalus sanguineus (Burlini et al., 2010), indicate that human-facilitated dispersal

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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of ectoparasites via movement on domestic hosts is by far the most effective mechanism. For ticks, this presents an ideal scenario that ensures a suitable or even preferred host is available at the new location. In the case of R. (Bo.) microplus this success was further enhanced by the fact that this is a one-host tick for which the eggs are the only off-host stage. Notwithstanding the great economic importance of R. (Bo.) microplus as a vector of livestock diseases agents, it does not parasitize humans, and therefore is of no relevance in tick-borne zoonoses.

The brown dog tick has likewise colonized the globe as a parasite of dogs accompanying humans (Burlini et al., 2010). It is found wherever dogs are kept in regions between the latitudes of 50° North and 30° South. It commonly infests kennels and even homes, seeking shelter in cracks, under window sills, and behind furniture. This tick preferentially parasitizes dogs, but may bite humans if dogs are not available, and does so apparently more readily in Europe where it has long been known to transmit Rickettsia conorii, the agent of boutonneuse fever, to people (Péter et al., 1984; Dantas-Torres, 2010). The recent identification of a North American focus of Rocky Mountain spotted fever with transmission of the agent among dogs and children (Demma et al., 2005) reinforces the zoonotic potential of this tick. Notably, brown dog ticks attack alternate hosts including humans more readily when ambient temperatures are high, can complete up to four generations a year, and may become more important vectors of human disease as climate warms in its current range (Dantas-Torres, 2010).

By contrast, tick dispersal on wild hosts is much less efficient, although it can account for increase of tick mobility to hundreds or thousands of miles on hosts such as deer or migratory birds (Klich et al., 1996; Bjöersdorff et al., 2001; Madhav et al., 2004; Odgen et al., 2008). Off host, I. scapularis ticks move at most a distance of a few meters (Carroll and Schmidtmann, 1996). Even though ticks can be carried great distances in these ways, there is no guarantee that their drop-off locations will present them with suitable habitat or hosts for subsequent life stages, but this will change as plant and animal communities respond to a warming climate.

The Interface Between Ticks and Emerging Disease Agents

Tick-borne pathogens of humans causing emerging diseases are primarily reported in temperate climates, but this trend may be a distortion of the true picture, as public health systems and disease reporting are much less accurate and often inconsistent in less developed and tropical countries. As a result, emerging diseases in these countries are under-reported by comparison to those in the Western world (Jones et al., 2008). In Brazil, increasing numbers of suspected tick-borne spotted fever cases previously thought to be of viral origin are being identified (Labruna, 2009), and

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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result in significant mortality. Brazilian spotted fever caused by a strain of Rickettsia rickettsii is now considered to cause the majority of such cases, but the true extent of its occurrence is not known (Rozental et al., 2006). Amblyomma spp. ticks have been implicated in transmitting the rickettsiae among rodents and opossums, although the presence of more abundant rickettsiae of undetermined pathogenicity has clouded the picture.

Ticks of greatest concern for human health are three-host generalist feeders, commonly utilizing small animals such as birds, rodents, squirrels and hedgehogs during the larval and nymphal stages, and feeding on larger hosts as nymphs and adults. They thus act as bridge vectors between animal reservoirs that are usually not affected by the pathogen, and humans who are dead-end hosts but suffer disease symptoms. A good example are ticks in the genus Ixodes, found around the globe in temperate and subtropical regions. In North America, the black-legged tick, I. scapularis, is probably the most notorious vector of zoonotic pathogens, capable of transmitting viruses (Powassan encephalitis virus; Pesko et al., 2010), bacteria (Borrelia burgdorferi, A. phagocytophilum, and possibly Bartonella spp. as well as a new Ehrlichia muris-like organism; Burgdorfer et al., 1982; Chen et al., 1994; Adelson et al., 2004; Pritt et al., 2009), and protozoa (Babesia microti; Piesman and Spielman, 1980). In Europe, the closely related tick species Ixodes ricinus is involved in a similarly broad spectrum of pathogen transmission, but has a much greater role in viral infections caused by tick-borne encephalitis viruses (Flaviviridae). Certainly, the many different types and species of vertebrates that are suitable hosts for I. scapularis and I. ricinus immature stages contribute significantly to their potential encounters with pathogens that are capable of colonizing and being transmitted by them. It is interesting to note that most zoonotic pathogens vectored by Ixodes species are maintained transstadially in ticks, even when infection rates in vertebrate reservoirs are low and of limited duration. This seems to be the case for A. phagocytophilum in white-footed mice that clear the infection within two weeks (Telford et al., 1996). Anaplasma phagocytophilum has been identified as an emerging human pathogen primarily in the US where it now is responsible for the second most common tick-borne illness (Chen et al., 1994). Serial re-infections of immune-intact laboratory mice (C57BL/6) by inoculation of culture-derived human-infectious A. phagocytophilum carrying different antibiotic and fluorescent marker genes suggests that mice do not develop a protective immune response to re-infection despite the fact that the bacteria are cleared after every inoculation (our unpublished results). If wild-type A. phagocytophilum behaves similarly in wild mice, sufficient levels of infected populations could thus be maintained, as per the susceptible-infected-susceptible model proposed by Kurtenbach et al. (2006).

Although transovarial transmission does occur in pathogens vectored by Ixodes ticks and contributes to viral maintenance in tick populations,

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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this mechanism appears to be less important than horizontal transmission among co-feeding ticks, at least in European tick-borne encephalitis virus where it has been examined in greatest detail (Labuda et al., 1993; LaSala and Holbrook, 2010). Whether this preference also holds true for Powassan virus (Costero and Grayson, 1996) remains to be determined.

One of the notorious tick-borne diseases in North America has long been Rocky Mountain spotted fever, and as its name implies, it was first described in the Rocky Mountain region in the latter part of the 19th century. There, the agent, R. rickettsii, circulates among small to medium mammals and the Rocky Mountain wood tick, Dermacentor andersoni, in which it is maintained transovarially (Niebylski et al., 1999). Both ticks and mammals can serve the role of reservoir. Over the decades, the greatest disease incidence has shifted south and east, and North Carolina and Oklahoma now account for the highest number of cases (http://www.cdc.gov/ticks/diseases/rocky_mountain_spotted_fever/statistics.html). In these states, the main vector is the American dog tick, Dermacentor variabilis. In both tick vectors, infections are very low at less than 1%, making it hard to predict risk by sampling tick populations. Likewise, this makes it difficult to track how this geographic shift has occurred, if it has occurred, or whether the apparent redistribution of cases is a reflection of better diagnostics and surveillance. Dermacentor and Amblyomma spp. ticks, both of which are present in these states, carry a variety of more abundant related microbes of undetermined or low pathogenicity, e.g., Rickettsia parkeri and Candidatus Rickettsia amblyommii (Paddock, 2009) that are suspected of contributing to Rocky Mountain spotted fever. While R. parkeri is a proven though mild infectious agent, the status of C. R. amblyommi remains undetermined, and it could just as well exclude R. rickettsii from ticks in a manner as Rickettsia peacockii does (Burgdorfer et al., 1981).

Pathogen Evolution Is a Dynamic, Ongoing Process

Anaplasma phagocytophilum, an obligate intracellular bacterium, has been known as a tick-borne pathogen of sheep, goats and cattle in Europe for decades where it was previously named Cytoecetes phagocytophila or Ehrlichia phagocytophila (Dumler et al., 2001; Woldehiwet, 2006). Ruminants remain persistently infected and experience cyclic bacteremia (Stuen, 2007). An organism named Ehrlichia equi was likewise known to infect Californian horses since the mid 1900s (Madigan and Gribble, 1987), but there, as in Europe, human cases are rare (Foley et al., 2009). Notably, A. phagocytophilum variants not found in human patients have been identified in deer in several locations of the US. One can imagine a scenario where European settlers unknowingly introduced infected livestock to North America, and American Ixodes ticks subsequently acquired and

Suggested Citation:"Appendix A: Commissioned Papers." Institute of Medicine. 2011. Critical Needs and Gaps in Understanding Prevention, Amelioration, and Resolution of Lyme and Other Tick-Borne Diseases: The Short-Term and Long-Term Outcomes: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/13134.
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spread the agent which thrived in deer. Whether this strain later developed the ability to infect mice and humans (as well as dogs and horses), or whether the human-infectious strains were introduced separately, or even were already present in North America awaits further phylogenetic analysis.

In Minnesota, I. scapularis may be infected with different variants of A. phagocytophilum (Michalski et al., 2006; Baldridge et al., 2009), not all of which cause human anaplasmosis (HA). We are currently testing the hypothesis that a whole genome comparison of A. phagocytophilum (Ap) isolates that infect humans (Ap-ha) versus those that are pervasively found in ticks and wild animals (Ap-variants) will reveal genetic differences that underlie Ap pathogenicity. Research has focused on Ap-ha and we know little about the biology of the more recently described Ap variants (Massung et al., 2005, 2007; Baldridge et al., 2009). Besides their potential ability to regulate the epidemiology of HA (Massung et al., 2002), the genome sequence of Ap-variants would be a valuable resource to identify mechanisms of host specificity, virulence and tick transmission in Ap-ha. We found that 64% of I. scapularis and 45% of Dermacentor albipictus (the winter or moose tick) collected from whitetail deer (WTD) in the army base at Camp Ripley, MN, carried Ap variants, including two with 16S rRNA gene sequences identical to Ap variants from Wisconsin deer. The D. albipictus variants were transovarially transmitted to F1 larvae at efficiencies of up to 40%, the first evidence for vertical transmission of Ap to tick progeny. These represent the highest Ap prevalence rates reported for any location, notably in the absence of increased numbers of human HA cases, supporting the notion that Camp Ripley Ap variants are truly distinct from Ap-ha. Unlike human-infectious strains, they do not infect mice, and can only be cultured in a cell line from the vector tick, suggesting they are biologically very different (Massung et al., 2005, 2007). Using tick cell line ISE6, we obtained 8 isolates of Ap variants from ticks feeding on WTD hunted in Camp Ripley. One of these, MN-61-2, was infectious for a goat but not mice, similar to Ap-variant 1 from Rhode Island, suggesting that the Northeast and Midwest variants are related (Massung et al., 2007). All our variant Ap isolates have the same 16S rRNA sequences but different ankA gene sequences. Now that Ap-variant isolates are available, their genomes can be sequenced to address the salient differences between Ap-ha and Ap variants: what genes/operons determine infectivity for humans versus ruminants, and what do the genomes reveal about the evolution of this emerging pathogen?

Research with other agents reinforces the notion that genetic population structure of tick-borne pathogens affects the interaction of human-infectious and animal-infectious isolates in endemic areas. There is evidence that multiple genotypes of B. burgdorferi have arisen from multiple, distinct foci (Hoen et al., 2009), and that human infectious borreliae may displace