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.



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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. 219

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221 APPENDIX A 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 Preven- tion, 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 Cen- tury, 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 Eu- rope, 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

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222 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES 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 mo- lecular 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 contem- porary diagnostic methods have cast suspicion on certain aspects of the 11 9 10 8 Lyme disease incidence per 100, 000 population 9 RMSF incidence per 1, 000, 000 population 7 8 6 7 5 6 5 4 4 3 3 2 2 1 1 FIGURE A1-1 Average annual incidence of Rocky Mountain spotted fever and Lyme disease in the United States, 1992-2008 (Bacon et al., 2008; Openshaw0 et 0 al., 2010).1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 1992 Lyme disease Rocky Mountain spotted fever Figure A1-1.eps

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223 APPENDIX A 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)

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224 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES 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 dis- eases (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 im- portant 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 contempo- rary synthesis of all observations may serve as a guide for subsequent epi- demiologic 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 in- cidence 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

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225 APPENDIX A over time, including ecologic, climatologic, or social variables, case defini- tions, 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 zoono- ses 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 inci- dence 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). Dur- ing 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, Okla- homa, 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 com- munities in Eastern Arizona that resulted in an average annual incidence of

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226 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES 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), Figure A1-2 in the United States (Bacon et al., 2008; Openshaw et al., 2010). R01965 bitmapped

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227 APPENDIX A 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 circum- stances, 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 in- terpretation. 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 R01965 bitmapped, box added

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228 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES 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). Dur- ing 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 R01965 bitmapped

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229 APPENDIX A 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 of reported spotted fever group rickettsioses were documented in several R01965 countries bordering the Mediterranean Sea, including Israel, Italy, and bitmapped 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 re- ported 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 infec- tions 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

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486 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES Response: One cannot reliably compare rates of reported Lyme disease between states unless one knows whether or not they are making the same level of surveillance effort and what the density and infection rates of tick vectors are. Further, most states with high levels of endemic Lyme disease have very different rates from one part of the state to another. Thus, even the overall state incidence of Lyme disease does not reflect the different risk in different parts of the state (see Figure A10-2). The same principles apply to comparison of rates of Lyme disease within a state over time (Ertel, 2006 and 2008). If surveillance methods are stable, then data should accurately reflect changes in Lyme disease risk over time. However, overall state num- bers and trends may not reflect risk and trends throughout the state. Some parts of the state may have plateaued and have some years when human disease incidence (and number of infected ticks) decrease while tick popula- tions in other parts of the state and human illness are increasing. Issue: A number of states and counties report cases of Lyme disease an- nually but are not known to have a competent tick vector or the presence of B. burgdorferi in tick populations. Do they really have Lyme disease? Are these really cases of Lyme disease? Response: For purposes of national public health surveillance, a labo- ratory confirmed case meeting the clinical case definition will be counted from any state that chooses to count it, even if infection cannot be readily attributed to exposure where B burgdorferi and competent tick vectors are known to be well established (i.e., travel to an endemic area, as defined in the case definition). However, such a “case” in a state or county with no known competent tick vector or infected ticks could be a false case. Other diseases can cause similar symptoms and even immunoblot tests are not perfect. When such disease is diagnosed, it is incumbent on the state or county to attempt to look for the tick vector and find infected ticks before announcing that this is a new endemic area and counting persons who only could have been exposed locally. Definitive human risk in any given area is dependent on there being competent tick vectors and infected ticks. Of particular interest in this regard is the recognition of a new disease char- acterized by EM, Southern Tick-Associated Rash Illness (STARI) following the bite of the lone star tick (not a competent Lyme disease vector) which may be a more common cause of EM in some southern states than Lyme disease (Georgia Department of Human Resources, 2001; CDC, 2010). STARI was recognized during efforts to validate human risk for Lyme dis- ease after EM was diagnosed in some southern states and counties without known B. burgdorferi infected Ixodes species. Public Health Surveillance for Other Tickborne Diseases in the U.S. There are at least 6 other recognized tickborne diseases in the United States: Rocky Mountain Spotted Fever, Ehrlichiosis/anaplasmosis, babesiois,

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487 APPENDIX A Powassan virus meningoencephalitis, tickborne relapsing fever and STARI. Of these, four, Rocky Mountain Spotted Fever, Ehrlichiosis/anaplasmosis, Powassan virus encephalitis and babesiosis are included in the National Notifiable Disease Surveillance System. A presentation of the public health surveillance objectives for each and their past and current case definitions and history of public health surveillance are discussed below. None has had the public interest that has been generated by Lyme disease nor as compli- cated a clinical picture with different stages of illness. Thus far, there has been less concern about what surveillance efforts and case definitions for these diseases can and cannot do. Rocky Mountain Spotted Fever Rocky Mountain Spotted Fever (RMSF) is an acute, severe and some- times fatal tickborne illness transmitted in most parts of the country by the bite of Dermacentor species but in Arizona by Rhiphicephalus sanguineus (the brown dog tick). It has been under public health surveillance since at least 1944 (CDC, 1994). The main objective of public health surveillance is to provide information on the temporal, geographic, and demographic occurrence of Rocky Mountain Spotted Fever (and other spotted fever rickettsioses) to facilitate its prevention and control (CSTE, 2009). Recom- mended surveillance methods are both provider and laboratory reporting. Although under national public health surveillance for a long time, the case definition for national surveillance was first published in 1990 (CDC, 1990). At that time, a case was defined as follows: “Clinical description—An illness most commonly characterized by acute onset and fever, usually accompanied by myalgia, headache, and petechial rash (on the palms and soles in two-thirds of the cases). To be counted as confirmed, a case needs to be laboratory confirmed. Four differ- ent laboratory criteria can independently be used to confirm a diagnosis: a) fourfold or greater rise in antibody titer to the spotted fever group antigen by immunofluorescent antibody (IFA), complement fixation (CF), latex ag- glutination (LA), microagglutination (MA), or indirect hemagglutination (IHA) test, or a single titer greater than or equal to 64 by IFA or greater than or equal to 16 by CF; or b) demonstration of positive immunofluo- rescence of skin lesion (biopsy) or organ tissue (autopsy); or c) Isolation of Rickettsia rickettsii from a clinical specimen. In addition to confirmed cases, a “probable” case is: “a clinically compatible case with supportive serology (fourfold rise in titer or a single titer greater than or equal to 320 by Proteus OX-19 or OX-2, or a single titer greater than or equal to 128 by LA, IHA, or MA test).” Since 1990, the case definition has been revised several times, each time to make modifications based on newer laboratory test methods. In 1996, the laboratory confirmation criteria changed to include having a positive

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488 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES polymerase chain reaction assay to R. rickettsii as another independent confirmation criterion (CDC, 1997). In 2003, the 4 main confirmatory laboratory test results were reframed in an effort to make them clearer (CSTE, 2003). In 2007, another revision was made to “clarify misleading or poorly defined laboratory statements, and to improve case classification for re- porting” including adding a “suspected” case category (CSTE, 2007). The clinical description of disease was simplified to “any reported fever and one or more of the following: rash, headache, myalgia, anemia, thromobocyto- penia, or any hepatic transaminase elevation,” and the description of con- firmatory laboratory tests was further clarified. A positive laboratory test became one of the following: a) serological evidence of a fourfold change in immunoglobulin G (IgG)-specific antibody titer reactive with Rickett- sia rickettsii antigen by indirect immunofluorescence assay (IFA) between paired serum specimens (one taken in the first week of illness and a second 2-4 weeks later); b) detection of R. rickettsii DNA in a clinical specimen via amplification of a specific target by PCR assay; c) demonstration of spotted fever group antigen in a biopsy/autopsy specimen by IHC; or d) isolation of R. rickettsii from a clinical specimen in cell culture. Laboratory supportive evidence was defined as: has serologic evidence of elevated IgG or IgM antibody reactive with R. rickettsii antigen by IFA, enzyme-linked immunosorbent assay (ELISA), dot-ELISA, or latex agglutination. A con- firmed case needed to have both clinical and laboratory confirmation, a probable case needed clinical confirmation in combination with laboratory supportive evidence, while a suspect case only needed laboratory evidence or recent or past infection (no clinical information needed). The various iterations of surveillance definitions have been used to de- scribe the geographic distribution within the U.S. and trends in occurrence over time. Most recently, without a substantial change in geographic dis- tribution (mostly southeastern and south central U.S. with scattered cases throughout the country), the number of reported cases has increased 300% in the past decade with a trend toward stabilization in the 4 years since 2005 (CDC, 2010). In 2008, a total of 190 confirmed and 2,367 probable cases were reported. Erhlichiosis/Anaplasmosis Human ehrlichiosis was recognized as a distinct acute disease entity caused by an intracellular parasitic organism in the Rickettsiae family in the late 1980s, when human monocytic ehrlichiosis (HME) was described (CDC, 1988). Since then, three different species with their own ecology have been identified as causing ehrlichiosis and one has been reclassified as Anaplasma. Despite there being at least three known causes of ehrlichiosis,

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489 APPENDIX A they have been grouped together for public health surveillance purposes. After recognition of a second type of ehrlichiosis that resulted in severe, acute disease with a predilection to affect granulocytes (human granulocytic ehrlichiosis, HGE) and which had an apparently different epidemiology than the previously described HME (Bakken et al., 1994; CDC, 1995), CSTE ap- proved a standard case definition for voluntary reporting to CDC, recogniz- ing that this was an emerging infection. However, it did not initially vote to include it in the Nationally Notifiable Disease Surveillance System, in part because it was reportable in only a minority of states (CSTE, 1996). At that time there were two known causes: E. chaffeensis causing HME, apparently transmitted by Lone Star (Amblyomma americanum) ticks, mainly affecting persons in the southeastern and south central U.S., and an E. equi-like agent causing HGE, suspected of being transmitted by Ixodes ticks and mainly affecting persons in the northeastern and north central states. The provisional case definition included a clinical description of illness and laboratory criteria for diagnosis, a confirmed case being a person with a clinically compatible illness who met the laboratory criteria (CSTE, 1996). The clinical description was “A febrile illness most commonly characterized by acute onset, accompanied by headache, myalgia, rigors and/or malaise; clinical laboratory findings may include: intracytoplasmic microcolonies (morulae) in leukocytes of peripheral smear, cerebrospinal fluid or bone marrow aspirate or biopsy, cytopenias (especially thrombocytopenia and leukopenia), and elevated liver enzymes (especially alanine aminotransfer- ase or aspartate aminotransferase).” Laboratory criteria included any of the following: “a) fourfold or greater change in antibody titer to Ehrlichia spp. antigen by immunofluorescence antibody (IFA) test in acute and convales- cent specimens ideally taken four weeks or more apart. HME diagnosis re- quires E. chaffeensis antigen and HGE diagnosis currently requires E. equi or HGE-agent antigen; b) positive polymerase chain reaction (PCR) assay. Distinct primers are used for the diagnosis of HGE and HME; or c) intra- cytoplasmic morulae identified in blood, bone marrow or CSF leukocytes and an IFA antibody titer >=1:64.” Probable cases were defined as persons with a compatible illness with a single IFA serologic titer >=1:64 or intra- cytoplasmic morulae identified in blood, bone marrow or CSF leukocytes. In 1998, CSTE voted to formally add ehrlichiosis to the NNDSS effec- tive January 1999 (CSTE, 1998). The purpose of public health surveillance was severalfold: 1) to define the epidemiology of ehrlichia infections in the United States; 2) to monitor incidence trends and changes in the geographic distribution of these infections over time; and 3) to identify risk factors for ehrlichia infections. The earlier recommended case definition was approved for national public health surveillance. In 2000, the case definition was re- vised to account for the recognition that E. phagocytophilum was the cause of HGE, to add a new human disease-causing species, E. ewingii, and to

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490 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES incorporate newer laboratory test methods (CSTE, 2000). In addition, the reporting classification was modified, “Three categories of confirmed or probable ehrlichiosis should be reported: 1) human ehrlichiosis caused by E. chaffeensis (HME), 2) human ehrlichiosis caused by E. phagocytophi- lum (HGE), and 3) human ehrlichiosis (other or unspecified agent), which includes cases that cannot be easily classified by available laboratory tech- niques, and cases caused by novel Ehrlichia species such as E. ewingii.” In addition, the laboratory criteria became ehrlichia category-specific. Additional changes to the case definition were made in 2007 in part to update taxonomic changes in the pathogens causing ehrlichiosis (CSTE, 2007). E. phagocytophilum was reclassified to Anaplasma phagocytophi- lum, the specific disease name changed from HGE to human granulocytic anaplasmosis (HGA) and the overall ehrlichiosis reporting classification was further expanded to 4 categories: 1) human ehrlichiosis caused by Ehrlichia chaffeensis, 2) human ehrlichiosis caused by E. ewingii, 3) hu- man anaplasmosis caused by Anaplasma phagocytophilum, and 4) hu- man ehrlichiosis/anaplasmosis—undetermined. Cases reported in the fourth sub-category can only be reported as “probable” because the cases are only weakly supported by ambiguous laboratory test results. Laboratory confirmatory and supportive (probable) criteria were modified to include E. ewingii and “undetermined” categories as follows: E. ewingii: “Because the organism has never been cultured, antigens are not available. Thus, Ehrlichia ewingii infections may only be diagnosed by molecular detection methods: E ewingii DNA detected in a clinical specimen via amplification of a specific target by polymerase chain reaction (PCR) assay.” “Undeter- mined” infections “can only be reported as ‘probable’ because the cases are only weakly supported by ambiguous laboratory test results.” In 2008, a total of 2107 confirmed cases of human ehrlichiosis were reported, with disease caused by A. phagocytophilum (1,009 cases) and by E. chaffeensis (957 cases) accounting for 93% of all cases (CDC, 2010). The incidence of both major forms of ehrlichiosis (HGA, HME) has been steadily increasing since 1999, with a 4-5-fold increase since 2001. Surveil- lance has also confirmed the early findings on geographic distribution of HME and HGA and demonstrated that ehrlichiosis caused by E. ewingii has a similar geographic distribution as HME. Powassan Virus Encephalitis/Meningitis Powassan virus encephalitis/meningitis results from central nervous sys- tem infection with Powassan virus, a tickborne virus that causes rare cases of arboviral encephalitis in the upper Midwest and northeastern U.S. It was placed under national public health surveillance in 2002 to be included at the same time West Nile virus was added to the list of other domestic

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491 APPENDIX A arboviral encephalitis viruses which had been under national public health surveillance since 1995, including California serogroup virus, equine en- cephalitis, St. Louis encephalitis, and western equine encephalitis (CSTE, 2001). At the time it was described as “an under-recognized tickborne disease.” It was noted that laboratory testing was not widely available, but that 2 cases were diagnosed in New England during evaluation for West Nile virus infection and that there was a case-fatality rate of approximately 10%. The goals of surveillance were multiple: 1) assess the national public health impact of Powassan viral and other arboviral diseases of the CNS and monitor national trends, 2) identify high-risk population groups or geographic areas to target interventions and guide analytic studies, and 3) develop hypotheses leading to analytic studies about risk factors for infec- tion and disease. The original case definition was the same for all the arboviruses causing central nervous system infection and recognized that infection may result in clinical disease of variable severity and variable CNS involvement. There was no specific definition for Powassan virus infection. However, cases could be classified as “neuroinvasive” or “nonneuroinvasive” depending on symptoms and demonstration of CNS involvement and required labora- tory confirmation in one of 4 ways: a) fourfold or greater change in virus- specific serum antibody titer; b) isolation of virus from or demonstration of specific viral antigen or genomic sequences in tissue, blood, cerebrospinal fluid (CSF), or other body fluid; c) virus-specific immunoglobulin M (IgM) antibodies demonstrated in CSF by antibody-capture enzyme immunoassay (EIA); or d) virus-specific IgM antibodies demonstrated in serum by anti- body-capture EIA and confirmed by demonstration of virus-specific serum immunoglobulin G (IgG) antibodies in the same or a later specimen by an- other serologic assay (e.g., neutralization or hemagglutination inhibition). From 2002-2008, a total of 13 cases of Powassan virus infection were reported with a peak of 7 cases in 2007. All were neuroinvasive, most from upstate New York with several from Maine, Minnesota and Wisconsin (CDC, 2010). In 2009, CSTE voted to continue surveillance for Powassan virus infection with the same objectives (CSTE, 2009). The one change to the case definition was to add a “probable” category. Confirmed cases con- tinue to need clinical criteria for neuroinvasive (any of a variety of central nervous system symptoms plus pleocytosis on lumbar puncture) or non- neuroinvasive (at least fever) and laboratory confirmation. Probable cases need to have a compatible clinical illness plus a lesser degree of laboratory confirmation, either a) stable (less than or equal to a two-fold change) but elevated titer of virus-specific serum antibodies, or b) virus-specific serum IgM antibodies detected by antibody-capture EIA but with no available results of a confirmatory test for virus-specific serum IgG antibodies in the same or a later specimen.

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492 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES Babesiosis Babesiosis is a tickborne disease caused by several different species of malaria-like red blood cell infecting parasites of the genus Babesia. B. microti is the most common cause of babesiosis in the U.S., particularly in New England, East coast and Midwestern states, with B. duncani caus- ing disease in California and Washington. Infection ranges from asymp- tomatic to a life-threatening illness resembling malaria, being most severe in immunosuppressed, asplenic and/or elderly persons. Prior to the 1980s, documented human illness was rare and largely acquired in islands off the coast of New England and New York. In addition to causing disease fol- lowing tick bites, Babesia can be transmitted by blood transfusion from asymptomatically infected persons, with transfusion-associated disease first described in the U.S. in 1979. During the 1980s, it was recognized that in some states, babesiosis was a growing problem. In some of those states, babesiosis was made report- able and increases in incidence and geographic range were documented. For example, New York made babesiosis reportable in 1986 following apparent increases in incidence on Long Island. In 1986, 18 cases were reported, all from Long Island. In 2008, 261 cases were reported: 96 from Long Island, 126 from 12 additional counties in New York state and 39 from New York City (New York State Department of Health, 1994 and 2008). In Con- necticut, a cluster of 6 cases occurred in 1989 in New London County, near where Lyme disease was first recognized (CDC, 1989). Babesiosis was made reportable in 1991. In 2007, 156 cases were reported from all 8 counties (Connecticut Department of Public Health, 2007). With the increasing incidence and spread of babesiois, the incidence of blood transfusion-associated disease increased (Stramer et al., 2009). Cor- respondingly, in 2010, CSTE voted to add babesiosis to the list of notifiable diseases under national public health surveillance (CSTE, 2010). The pur- pose of surveillance is to provide information on the temporal, geographic, and demographic occurrence of babesiosis, including transfusion-associated babesiosis, to facilitate its prevention and control. It is recommended that states conduct both healthcare provider and laboratory surveillance. The case definition has three categories of disease: confirmed, probable and suspect, with confirmed and probable being under national public health surveillance. The probable definition includes blood donors and recipients without symptoms associated with a transfusion case or a known infected donor, as long as the probable case has either supportive or confirmatory laboratory evidence of infection.

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493 APPENDIX A Other Tickborne Illnesses, Coinfection There are several other tickborne infections known to occur in the US that currently are not under national public health surveillance: STARI and tickborne relapsing fever. Neither disease is known to be common nor widespread enough for CSTE to seriously consider voting it to be part of the National Notifiable Disease Surveillance System. However, individual states in which they are present can choose to make them locally reportable. Given that Ixodes ticks, especially in the northeast and north-central states, are vectors for Lyme disease, ehrlichiosis/anaplasmosis and babesio- sis, it is possible for ticks to carry and transmit more than one agent. In fact, coinfections are not unusual and can result in more severe illness than infection with a single agent (Swanson et al., 2006). At present, there is no systematic effort at national surveillance for coinfection. However, the potential exists in any state to match persons reported with one infection to reports of those with either of the other infections. Thus far, no results of such matching to determine population levels of coinfection have been reported. References* * All with Internet URLs accessed September 1-10, 2010. Bakken J.S., J.S. Dumler, S.M. Chen, M.R. Eckman, L.L. Van Etta, and D.H. Walker. 1994. Human granulocytic ehrlichiosis in the upper midwest U.S. J Am Med Assoc 272:212–8. CDC. 1981. Lyme disease—United States. 1980. MMWR Morb Mortal Wkly Rep 30:489-92,497. CDC. 1982. Lyme disease. MMWR Morb Mortal Wkly Rep 31:367-368. Available at: http:// www.cdc.gov/mmwr/preview/mmwrhtml/00015561.htm. CDC. 1988. Epidemiologic notes and reports human ehrlichiosis – United States. MMWR Morb Mortal Wkly Rep 37:270,275-77. Available at http://www.cdc.gov/mmwr/preview/ mmwrhtml/00000020.htm. CDC. 1989. Epidemiologic notes and reports, babesiosis – Connecticut. MMWR Morb Mortal Wkly Rep 38:649-650. Available at http://www.cdc.gov/mmwr/preview/ mmwrhtml/00001468.htm. CDC. 1990. Case definitions for public health surveillance. MMWR Morb Mortal Wkly Rep 39(RR-13):1-43. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00025629. htm. CDC. 1994. Summary of notifiable diseases – United States, 1993. MMWR Morb Mortal Wkly Rep 42:1-91. Available at http://www.cdc.gov/mmwr/PDF/wk/mm4253.pdf. CDC. 1995. Human granulocytic ehrlichiosis – New York, 1995. MMWR Morb Mortal Wkly Rep 44:593-595. Available at http://www.cdc.gov/mmwr/PDF/wk/mm4432.pdf. CSTE. 1996. Position statement 1996-17. Ehrlichiosis. Available at http://www.cste.org/ ps/1996/1996-17.htm. CDC. 1997. Case definitions for infectious conditions under public health surveillance. MMWR Morb Mortal Wkly Rep 46(RR-10):1-55. Available at: http://www.cdc.gov/ mmwr/preview/mmwrhtml/00047449.htm.

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494 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES CDC. 1999. Recommendations for the use of Lyme disease vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). Appendix: methods used to cre- ate a national Lyme disease risk map. MMWR Morb Mortal Wkly Rep 48(RR-07):21-24. Available at: http://www.cdc.gov/mmwr/PDF/rr/rr4807.pdf. CDC. 2001. Updated guidelines for evaluating public health surveillance systems: recommen- dations of the guidelines working group. MMWR Morb Mortal Wkly Rep 50(RR-13):1- 36. Available at: http://www.cdc.gov/mmwr/PDF/rr/rr5013.pdf. CDC. 2004. Lyme Disease — United States, 2001—2002 MMWR Morb Mortal Wkly Rep 53:365-369. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5317a4. htm. CDC. 2007. Lyme Disease — United States, 2003—2005. MMWR Morb Mortal Wkly Rep 56:573-76. Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5623a1.htm. CDC. 2008. Surveillance for Lyme disease – United States, 1992-2006. MMWR Morb Mortal Wkly Rep 57(SS-10):1-9. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ ss5710a1.htm. CDC. 2010. Southern tick-associated rash illness. Available at http://www.cdc.gov/ncidod/ dvbid/stari/. CDC. 2010. Summary of notifiable diseases – United States, 2008. MMWR Morb Mortal Wkly Rep 54:1-94. Available at http://www.cdc.gov/mmwr/PDF/wk/mm5754.pdf. Connally N.P., A.J. Durante, K.M. Yousey-Hindes, J.I. Meek, R.S. Nelson and R. Heimer. 2009. Peridomestic Lyme disease prevention: results of a population-based case-control study. Am J PrevMed 37(3):201-6. Connecticut Department of Public Health. 2010. Reported cases of disease by county, 2007. Available at http://www.ct.gov/dph/lib/dph/infectious_diseases/pdf_forms_/ct_disease_ cases_by_county_2007_fnl.pdf. Coyle B.S., G.T. Strickland, Y.Y. Liang, C. Pena, R. McCarter, and E. Israel. 1996. The public health impact of Lyme disease in Maryland. J Infect Dis 173:1260-62. Cromley, E.K., M.L. Cartter, R.D. Mrozinski, and S.H. Ertel. 1998. Residential setting as a risk factor for Lyme disease in a hyperendemic region. Am J Epidemiol 147:472-77. CSTE. 1990. Position statement 1: National surveillance of Lyme disease and resources for Lyme disease and epidemiology. Available at: http://www.cste.org/ps/1990/1990-01.htm. CSTE. 1996. Position statement 96-18: Revised case definitions for public health surveillance: infectious disease. Available at: http://www.cste.org/dnn/AnnualConference/Position- Statements/tabid/191/Default.aspx. CSTE. 1998. Position statement 1998-ID-6. Adding Ehrlichiosis as a condition reportable to the National Public Health Surveillance System (NPHSS). Available at http://www.cste. org/ps/1998/1998-id-06.htm. CSTE. 2000. Position statement 2000-ID-3. Changes in the case definition for human ehrlichi- osis, and addition of a new ehrlichiosis category as a condition placed under surveillance according to the National Public Health Surveillance System (NPHSS). Available at http:// www.cste.org/ps/2000/2000-id-03.htm. CSTE. 2001. Position statement 2001-ID-06: Inclusion of West Nile encephalitis/meningitis and Powassan encephalitis/meningitis in the National Public Health Surveillance System (NPHSS), and revision of the national surveillance case definition of arboviral diseases of the central nervous system (CNS). Available at http://www.cste.org/ps/2001/2001- id-06.htm. CSTE. 2003. Position statement 03-ID-08: Rocky Mountain spotted fever. Available at http:// www.cste.org/PS/2003pdfs/2003finalpdf/03-ID-08Revised.pdf. CSTE. 2007. Position statement 07-ID-11: Revised national surveillance case definition for Lyme disease. Available at: http://www.cste.org/PS/2007ps/2007psfinal/ID/07-ID-11.pdf.

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495 APPENDIX A CSTE. 2007. Position statement 2007-ID-05: Revision of the surveillance case definitions for Rocky Mountain spotted fever. Available at http://www.cste.org/PS/2007ps/2007psfinal/ ID/07-ID-05.pdf. CSTE. 2007. Position statement 2007-ID-03. Revision of the National Surveillance Case Definition for Ehrlichiosis (Ehrlichiosis/Anaplasmosis). Available at http://www.cste.org/ PS/2007ps/2007psfinal/ID/07-ID-03.pdf. CSTE. 2009. Position statement 2009-ID-16: Public health reporting and national notification for spotted fever rickettsiosis (including Rocky Mountain spotted fever). Available at http://www.cste.org/ps2009/09-ID-16.pdf. CSTE. 2009. Position statement 09-ID-25: Public health reporting and national notification for Powassan virus disease. Available at http://www.cste.org/ps2009/09-ID-25.pdf. CSTE. 2010. Position statement 2010-ID-27. Public health reporting and national surveillance for babesiosis. Available at http://www.cste.org/ps2010/10-ID-27.pdf. Ertel S., B. Esponda, R. Nelson, and M.L. Cartter. 2006. Lyme disease- Connecticut, 2005. Connecticut Epidemiologist 26:13-14. Available at http://www.ct.gov/dph/lib/dph/infec- tious_diseases/pdf_forms_/vol26no4.pdf. Ertel S. P. Gacek, R. Nelson, and M.L. Cartter. 2008. Lyme disease – Connecticut, 2007. Connecticut Epidemiologist 28:5-6. Available at http://www.ct.gov/dph/lib/dph/infec- tious_diseases/ctepinews/vol28no2.pdf. Georgia Department of Human Resources, Division of Public Health, Epidemiology Branch. 2001. Tick bites and erythema migrans in Georgia: It Might NOT be Lyme disease! Georgia Epidemiology Report 17:1-3. Available at http://health.state.ga.us/pdfs/epi/gers/ ger0801.pdf. Gould H.L., R.S. Nelson, K.S. Griffith, E.B. Hayes, J. Piesman, P.S. Mead and M.L. Cartter. 2008. Knowledge, attitudes, and behaviors regarding Lyme disease prevention among Connecticut residents, 1999–2004. Vector-borne and Zoonotic Diseases 8:769-776. Hadler, J.L. and L.R. Petersen. 2007. Surveillance for vector-borne diseases. In Infectious Disease Surveillance, edited by N.M. M’ikanatha, R. Lynfield, C.A. Van Beneden and H. de Valk. Oxford: Blackwell Publishing. Pp. 107-123. Ley, C., E.M. Olshen, and A.L. Reingold. 1995. Case-control study of risk factors for incident Lyme disease in California. Am J Epidemiol 142:S39-S47. Mather T.N., M.C. Nicholson, E.F. Donnelly, and B.T. Matyas. 1996 Entomologic index for human risk of Lyme disease. Am J Epidemiol 144:1066--9. Meek J.I., C.L. Roberts, E.V. Smith, Jr, and M.L. Cartter. 1996. Underreporting of Lyme dis- ease by Connecticut physicians, 1992. J Public Health Manag Pract 2:61-65. Meriwether, R.A. 1996. Blueprint for a national public health surveillance system for the 21st century. J Public Health Manag Pract 2(4):16-23. Moulton, A.D., R.A. Goodman and W.E. Permet. 2007. Perspective: law and great pub- lic health achievements. In Law and Public Health Practice, 2nd ed, edited by R.A. Goodman, R.E. Hoffman, W. Lopez, G.W. Matthews, M. Rothstein, and K.L. Foster. New York: Oxford University Press. P 13. New York State Department of Health. 1994. Communicable disease in New York State, reported cases of selected diseases exclusive of New York City, 1984-1994. Available at http://www.nyhealth.gov/nysdoh/cdc/1994/sect5a.pdf New York State Department of Health. 2008. Reported cases by disease and county, AIDS- dengue fever. Available at http://www.nyhealth.gov/statistics/diseases/communica - ble/2008/cases/1.htm. Orloski, K., G. Campbell, C. Genese, J. Beckley, M. Schriefer, K. Spitalny, and D. Dennis. 1998. Emergence of Lyme disease in Hunterdon County, New Jersey, 1993: A case- control study of risk factors and evaluation of reporting patterns. Am J Epidemiol 147:391-7.

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496 CRITICAL RESEARCH NEEDS IN TICK-BORNE DISEASES Stafford K.C., III, M.L. Cartter, L.A. Magnarelli, S. Ertel, and P.A. Mshar. 1998. Temporal correlations between tick abundance and prevalence of ticks infected with Borrelia bur- dorferi and increasing incidence of Lyme disease. J Clin Microbiol 36:1240-4. Stramer S.L., F.B. Hollinger, L.M. Katz, S. Kleinman, P.S. Metzel, K.R. Gregory, and R.Y. Dodd. 2009. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion 49 Suppl 2:1S-29S. Swanson S.J., D. Neitzel, K.D. Reed, and E.A. Belongia. 2006. Coinfections acquired from Ixodes ticks. Clin Microbiol Rev 19:708-27. Vázquez M., C. Muehlenbein, M. Cartter, E.B. Hayes, S. Ertel and E.D. Shapiro. 2008. Ef- fectiveness of personal protective measures to prevent Lyme disease. Emerg Infect Dis 14:210-216. Available at: http://www.cdc.gov/eid/content/14/2/210.htm.