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Home , Anaplasma, Anaplasmosis, Babesiosis, Ehrlichia, Ixodes, Ixodes scapularis

Anaplasmosis (Human Granulocytic )

1. Case Definition 1.2 Probable Case A clinically compatible case with non- 1.1 Confirmed Case confirmatory laboratory resultsIII (1) A clinically I compatible case that is laboratory confirmedII (1, 2, 3).

I Clinical evidence criteria include, plus one or more of the following: , , ,  All positive laboratory tests for , or any elevation of phagocytophilum (i.e. IFA , hepatic transaminase concentrations. detection by specific nucleic acid II Laboratory confirmation requires one of: amplification methods (NAAT), or 1) Serological evidence of a four-fold change in identification of the characteristic morulae IgG specific titre by indirect IFA on a blood smear) are reportable by assay between paired specimens (one laboratory. Operators of Manitoba taken during the first week of illness and a laboratories detecting evidence of second 2 – 4 weeks later), OR by specific Anaplasma in blood specimens must nucleic acid amplification test of blood forward residual blood specimen to specimen during acute phase of illness, OR Cadham Provincial Laboratory within 7 2) Detection of Anaplasma phagocytophilum days of report. DNA in a clinical specimen via amplification of a specific target by polymerase chain Health Professional: reaction (PCR) assay, OR  Clinical cases of Anaplasmosis are to be 3) Demonstration of anaplasmal antigen in a reported to Manitoba Health, Healthy / autopsy sample by Living and Seniors using the -Borne immunohistochemical methods, OR Diseases Clinical Case Report form 4) Isolation of A. phagocytophilum from a (www.gov.mb.ca/health/publichealth/cdc/protocol clinical specimen in cell culture. III /tickborneform.pdf) and submitted by fax to Non-confirmatory laboratory results include: the Communicable Disease Control Unit at 1) Identification of morulae in the cytoplasm of (204) 948-2190 (secure fax line). It is or eosinophils by microscopic important to supply a travel history or any examination, OR 2) Single A. phagocytophilum IgG antibody titre exposure to that is as complete and of 128 or greater plus A. phagocytophilum thorough as possible. Public Health IgM antibody titre of 20 or greater. practitioners may contact physicians/ clinicians for further information on reported cases as required. 2. Reporting and Other

Requirements In 2015 all cases became reportable to Manitoba Health, Healthy Living and Seniors Laboratory:

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Anaplasmosis (Human Granulocytic Anaplasmosis)

3. Clinical Presentation/ Natural with other tick-borne diseases such as and/ or should always be History considered when diagnosing and treating patients Clinical evidence of Anaplasmosis is characterized for Anaplasmosis (2, 9). Reported frequency of by an acute onset of fever with one or more of the co- among Anaplasmsosis patients with following non-specific symptoms or findings: , burgdorferi has been shown to range , headache, myalgia, , leukopenia, between 2.0 – 11.7% in regions (4). thrombocytopenia or elevated hepatic transaminases (1, 2, 4, 5). Less common non-specific symptoms may include: stiff neck, , cough, anaemia and 4. Etiology increased serum creatinine levels (4). It is important Anaplasmosis is a tick-borne infection caused by to obtain a thorough clinical history, including evidence of a tick bite, exposure to a Lyme disease the obligate, intracellular gram-negative , risk area or travel to an area with suitable tick Anaplasma phagocytophilum and transmitted in habitat within the previous 5 – 21 days prior to Manitoba by the blacklegged tick, symptom onset (1, 6, 7). It should be cautioned scapularis (3, 11). Anaplasmsma bacteria prefer that many patients have no recollection of a tick to infect leukocytes, in particular granulocytes bite, which corresponds to the relatively painless (9). There are biologically and ecologically bite and small size of nymphal ticks that play a distinct sub-populations of A. phagocytophilum key role in (6, 8). adapted to specific reservoir hosts and tick , which also exhibit varying pathogenicity. In most cases Anaplasmosis is a mild and self- Human anaplasmosis is associated with the Ap-ha limiting illness, and all clinical signs and variant. The distribution of this variant symptoms resolve in most patients within 30 corresponds closely with elevated incidence rates days, even in the absence of treatment (7, 12). (5). However, more severe presentations are common in older patients (> 60 years of age), those with co-morbidities (i.e. immune- 5. Epidemiology compromised) and in those where there has been 5.1 Vectors and Reservoir a delay in diagnosis and treatment (9, 10). Significant complications resulting in In North America vectors of Anaplasma hospitalization include: septic or toxic like shock phagocytophilum include , Ix. , respiratory insufficiency, invasive pacificus and Ix. spinipalpis, while in Europe and opportunistic (viral & fungal) , Asia the vectors are Ix. and Ix. perulcatus rhabdomyolysis, pancarditis, acute renal failure, respectively (13, 14). It should be noted however, hemorrhage, and neurological conditions such as that none of these hard bodied ticks are capable of brachial plexopathy, demyelinating persistently supporting A. phagocytophilum and acute transient sensori-neural infection and hence they are not reservoir hosts hearing loss (4, 9). The case fatality rate varies (14). The bacteria can be acquired while feeding between 0.2 and 1.2% (2, 3, 6, 9). on reservoir hosts by any of the three tick life stages (i.e. larvae, nymph or adult). However Consideration of the possibility of co-infection

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Anaplasmosis (Human Granulocytic Anaplasmosis)

once infected the pathogen can be transmitted to Rhode Island, and ) account each stage – known as trans-stadial transmission for 90% all reported cases (21). The distribution (9). The bacteria is maintained in the epizootic of Anaplasmosis cases in North America is cycle through a variety of reservoir hosts, which similar to that observed for Lyme disease given include white-footed and deer mice for juvenile the common , the blacklegged tick (8). In ticks (larvae & nymphs) and white tailed deer and Europe, where the incidence is significantly lower other large ruminants for adults (9). Studies have (fewer than 100 confirmed cases reported shown that the white-footed mouse is the continent-wide between 1997 and 2012) principal reservoir for the pathogenic variant, Ap- Anaplasmosis cases have been reported from a ha (14). number of countries including: Belgium, Bulgaria, Croatia, France, , Holland, 5.2 Transmission , Norway, Russia, , , Spain, Anaplasmosis is transmitted primarily when an Sweden, Switzerland and the U.K. (9, 13). The infected blacklegged tick takes a blood meal. distribution of cases in Europe corresponds to the studies have shown the typical range of the principal vector, Ix. ricinus which transmission window, the period between tick stretches from Scandinavia to the Mediterranean attachment and pathogen transmission, to be as and Russia to Portugal & Ireland (22). Elsewhere little as 24– 48 hours (6, 15, 16, 17). Further, Anaplasmosis has been described, again at lower small numbers of infected nymphs were able to incidence rates compared to North America, in transmit the pathogen in less than 24 hours (15, eastern Asian countries such as China, , 16). This narrow transmission window may and Siberian Russia (4, 23). reflect the shorter distance the bacteria have to travel, from the salivary glands, as opposed to the Canada: gut in the case of Lyme disease (15). This At present Anaplasmosis is reportable in abbreviated transmission window is also thought Manitoba, but not in any other jurisdictions in to be true in humans. Canada nor to the Public Health Agency of Canada. With the continued northward spread of Although the majority of transmission of A. Ix. scapularis populations, the risk of infection phagocytophilum occurs via tick vectors, other with tick-borne pathogens such as Anaplasmosis transmission modes have been documented. has increased. Recent studies have estimated the These other modes include transplacental rate of expansion to be from 33 to 55 km per year transmission, direct handling of infected (24). reservoirs (i.e. white-tailed deer), and blood and marrow transfusion (4, 9, 10, 18, 19, 20). Areas with evidence of established blacklegged tick populations and, hence, greater risk of tick- 5.3 Occurrence borne disease transmission, have been identified General: in Nova Scotia, New Brunswick, southern In North America the majority of Anaplasmosois Quebec, eastern, southwestern & northwestern cases are found in two endemic foci; the Ontario and southern Manitoba (24). Testing of northeastern US and the upper Midwest (3). Six ticks in these regions has shown evidence of A. states (New York, , ,

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phagocytophilum circulation within the border as far north as Norris Lake Provincial Park environment, with the highest prevalence rates (in the Interlake). For updated information seen in Manitoba, New Brunswick and Quebec regarding the distribution of Lyme disease risk (12). In addition, the rates of infection with the areas in Manitoba see pathogenic Ap-ha strain were highest in the http://www.gov.mb.ca/health/publichealth/cdc/tickborne/ prairie (Manitoba) and Atlantic (Nova Scotia & index.html New Brunswick) provinces. 5.4 Manitoba: The incubation period for Anaplasmosis ranges Since Anaplasmosis became provincially between 5 to 21 days following the bite of an reportable on January 1, 2015, positive laboratory infected tick (2, 5). Most symptomatic patients results have been reported in Manitoba. It should who recall a tick bite report exposure between 7 – be cautioned that the calculation of incidence 14 days prior to symptom onset (4). rates will require a minimum of 3 years of data. 5.5 Susceptibility and Resistance In Manitoba, blacklegged ticks are active from It is reasonable to assume that individuals who snow melt until the first permanent snow fall, or reside, work and/or engage in recreational o when air temperatures are consistently below 4 C activities within Lyme disease risk areas remain (typically April – November), and they are at risk for Anaplasmosis transmission. However, typically found: the frequency of re-infection has yet to be clarified. (4). It is also possible that patients who  Within and along the edges of wooded or develop elevated anti-body titres in response to A. forest habitat; and phagocytophilum infection may be protected  In areas with thick, woody shrubs and other against re-infection. Studies have shown vegetation that provide sufficient cover and persistent elevated anti-body titres for 12 – 36 typically high humidity. months post-infection (9).

Areas with established blacklegged tick 6. Laboratory Investigation populations, referred to as Lyme disease risk A fundamental understanding of the signs, areas, carry the highest Anaplasmosis risk. symptoms and epidemiology of Anplasmosis is However, because these ticks can attach to necessary to guide requests for tests and migrating birds and large ruminants (i.e. white- subsequent interpretation. Testing should be tailed deer), it is possible to find blacklegged limited to patients with clinical presentations ticks in other areas of the province. The risk of consistent with the illness. Anaplasmosis transmission outside of the endemic areas is relatively low. Laboratory confirmation requires one of: Regular surveillance activities have identified Serological evidence of a four-fold change in IgG Lyme disease risk areas throughout much of antibody titre to A. phagocytophilum antigen by southern Manitoba stretching from the Ontario indirect IFA in paired serum samples (one taken border as far west as Brandon and from the US

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Anaplasmosis (Human Granulocytic Anaplasmosis)

during the first week of illness and a second 2 – 4 948-2190 (secure fax line). It is important to weeks later). The titre in the convalescent sample complete the form as fully as possible, with should be 1:128 or higher (1, 6, 9, 13); emphasis on:

o IFA tests have been shown to have  detailed clinical history, including history poor sensitivity during the acute phase of transfusion, transplantation, or of illness (< 1 week following pregnancy; symptom onset) (25). However, the  actual and/ or potential tick exposure sensitivity increases significantly as activity within 21 days prior to symptom the illness progresses and if samples onset; are paired (6).  travel history (including local excursions)  Detection of A. phagocytophilum DNA in a within 21 days prior to symptom onset. clinical specimen via amplification of a specific target by PCR assay (1); Central Public health will consider travel history, o PCR tests are typically positive when exposure to potential tick habitat(s) and patient the patient is tested during the acute residence to determine potential exposure phase of illness, usually within the first location. week (25).  Demonstration of anaplasmal antigen in a It is also essential that residual blood specimens biopsy/ autopsy sample by immunehisto- be submitted to Cadham Provincial Laboratory chemical methods; within 7 days of reporting, to allow for  Isolation of A. phagocytophilum from a confirmation. clinical specimen in cell culture.

Bacteremia may persist for 28 days; there are no reports of active clinical (i.e. chronic) illness persisting beyond two month (9)

7. Key Investigations 8. Control & Prevention Positive laboratory and non-confirmatory serology results are referred to the health region 8.1 Management of Cases of residence for public health investigation. Appropriate antibiotic treatment should be Results of the investigation are to be reported to initiated immediately when a clinician suspects Manitoba Health, Healthy Living & Seniors using Anaplasmosis, based on clinical, laboratory or the Tick-Borne Diseases Clinical Case Report epidemiological findings, given the potential for Form serious and even fatal outcomes (2, 6, 9, 11, 13, (www.gov.mb.ca/health/publichealth/cdc/protocol/tickbo 23). As it is not possible to predict which patients rneform.pdf) and submitted by fax to the may have a self-limiting illness, all symptomatic Communicable Disease Control Unit at (204)

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patients should receive appropriate antibiotic infection with treatment. should also be treated with amoxicilllin or (5) Recommended treatment for Anaplasmosis includes: Fever typically subsides within 24 – 48 hours – after treatment. Adult patients have symptoms  For patients over 8 years of age the resolve following doxycycline or rifampin recommended dose is 100mg twice daily therapy with no subsequent relapse or chronic either intravenously or orally for 10 to 14 infection (5). The majority of symptoms typically days. If co-incubating infection with resolve within 30 days of onset, even in the Borrelia burgdorferi is suspected, a 14 day absence of antibiotic therapy (13). Severely ill treatment is recommended (4, 5, 9). patients may have a longer duration of symptoms  For patients less than 8 years of age the before clinical improvement is noted (6).Failure recommended dose is 2.2mg/kg (maximum to respond to antibiotic therapy after 48 – 72 of 100mg/dose) twice daily either hours may indicate infection with another tick- intravenously or orally for 4 – 5 days (2, 4). borne pathogen or a secondary opportunistic This normally corresponds to 3 days after infection not susceptible to (13). resolution of fever. Patients with co-infections (i.e. Borrelia o Where potential with burgdorferi and/ or microti) present with Borrelia burgdorferi is suspected, the more severe illness and effective treatment may remainder of the 14 day therapy should require multiple different therapies (7). be completed with an alternative agent (i.e. or ) Consultation with an infectious disease specialist (5, 23). is recommended for management of complex cases. –  For patients over 8 years of age the 8.2 Management of Contacts recommended dose is 500mg orally four Screening of blood donors for a history of tick times daily for 10 – 14 days (4). bite or exposure to a tick habitat is unlikely to be Rifampin – sensitive or specific, given that in endemic  Pediatric (< 18 years of age) 20mg/kg/day regions, such exposures are common and bites are (maximum 600 mg) in two divided doses often not recalled (19). Physicians are encouraged orally for 5 – 7 days (4) to consider Anaplasmosis in their differential  Adult (18 years or older) 300mg orally diagnosis in patients who develop post- twice daily for 5 – 7 days (4). transfusion acute thrombocytopenia or o Rifampin is recommended for pregnant leukopenia, especially when accompanied by patients and those with drug allergies fever (20). unable to take either doxycyline or Where Anaplasmosis is diagnosed during tetracycline (6, 9). pregnancy the newborn should be evaluated for o As rifampin is not an effective therapy for Lyme disease, patients with a co-

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presence of the bacteria, and treated with http://www.gov.mb.ca/health/publichealth/c appropriate if infection is identified dc/tickborne/index.html). (18). o Other methods such as using a match, petroleum jelly, soap, etc. are not 8.3 Preventative Measures recommended. Educate the public about Anaplasmosis o Cleanse the skin around the tick bite transmission and personal protection measures with soap and water or disinfectant. that should be adopted to minimize the risk of o Mark the date and location of the tick exposure to potentially infected ticks, including bite on a calendar for future reference. the following: o If symptoms develop, see your doctor.  After spending time outdoors, inspect In Lyme disease risk areas, a large number of yourself and your children for ticks and landscape management practices can be remove any ticks found as soon as possible. employed to help reduce the abundance of ticks, Bathing or showering within 2 hours of and thereby minimize the risk of exposure to coming indoors is a good way to find ticks. Anaplasmosis and other tick-borne diseases (26).  Apply an appropriate repellent (it should In general, tick numbers can be lowered through state ‘for use against ticks’ on the product activities such as keeping grass mowed short, label), as per instructions, on clothing and removing leaf litter and trimming other vegetation exposed skin. (shrubs and trees) to minimize shade cover in  Use trails, wherever possible, and stay to commonly used areas. Further, tick ‘unfriendly’ the center of trails or paths habitats can be created by using drier, less water  Wear light-colored clothing to make it demanding materials such as mulch, gravel, decks easier to see ticks crawling on your or cement in commonly used areas. More clothing. landscape management details can be found in the  Wear long pants and long sleeved shirt so Connecticut Agricultural Experimental Station’s that most exposed skin is covered. ‘Tick Management Handbook’ at  Tuck your shirt into your pants and your http://www.ct.gov/caes/lib/caes/documents/publications/ pants into your socks; this will make it bulletins/b1010.pdf. more difficult for the ticks to attach to your skin. References  Regularly inspect pets for ticks, as they can 1. U.S. Centres for Disease Control & bring ticks into the home. Prevention (Accessed October 2015)  If a tick is attached to the skin, remove it and Anaplasmosis 2008 Case with tweezers: Definition. National Notifiable Diseases o Grasp the tick close to the skin with Surveillance System. Available at tweezers and pull slowly upward with http://wwwn.cdc.gov/nndss/conditions/ehrlichiosis- steady pressure; avoid twisting or and-anaplasmosis/case-definition/2008/ crushing the tick (a video demonstration is available at

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2. Red Book: 2012 Report of the Committee on Anaplasmosis in the Upper Midwest. Infectious Diseases. 29th Edition. American Wisconsin Medical Journal 113 (3), 107-114. Academy of Pediatrics. L. K. Pickering, Ed. 8. Lovrich, S. D., Jobe, D. A., Kowalski, T. J., 3. Dumler, J. S. and Walker, D. H. (2015) Policepatil, S. M. and Callister, S. M. (2011) chaffeensis (Human Expansion of the Midwestern Focus for Monocytotropic Ehrlichiosis), Anaplasma Human Granulocytic Anaplasmosis into the phagocytophium (Human Granulocytic Region Surrounding La Cross, Wisconsin. Anaplasmosis), and Other . Journal of Clinical Microbiology 49(11), In Bennett, J. E., Dolin, R., Blaser, M. J. eds. 3855-3859. Mandell, Douglas and Bennett’s Principals 9. Bakken, J. S. and Dumler, S. (2008) Human and Practice of Infectious Diseases 8th ed. Granulocytic Anaplasmosis. Infectious Elsevier, Philadelphia Disease Clinics of North America 22, 433- 4. Bakken, J. S. and Dumler, S. (2015) Human 448. Granulocytic Anaplasmosis. Infectious 10. Dahlgren, F. S., Mandel, E. J., Krebs, J. W., Disease Clinics of North America 29, 341- Massung, R. F. and McQuinston, J. H. (2011) 355. Increasing Incidence of 5. Wormser, G. P., R. J. Dattwyler, E. D. and Anaplasma phagocytophilum in the Shapiro, J. J. Halperin, A. C. Steere, M. S. United States, 2000-2007. American Journal Klempner, P. J. Krause, J. S. Bakken, F. Strle, of Tropical Medicine and Hygiene, 85(1), G. Stanek, L. Bockenstedt, D. Fish, J. S. 124-131. Dumler and R. B. Nadelman (2006) The 11. Demma, L. J., Holman, R. C., McQuinston, J. Clinical Assessment, Treatment, and H., Krebs, J. W. and Swerdlow, D. L. (2005) Prevention of Lyme disease, Human Epidemiology of Human Ehrlichiosis and Granulocytic Anaplasmosis, and Babesiosis: Anaplasmosis in the United States, 2001 – Clinical Practice Guidelines by the Infectious 2002. American Journal of Tropical Medicine Diseases Society of America. Clinical and Hygiene 73 (2), 400-409. Infectious Diseases 43, 1089-1134. 12. Krakowetz, C. N., Dibernardo, A., Lindsay, 6. Chapman, A. S., Bakken, J. S., Folk, S. M., L. R. and Chilton, N. B. (2014) Two Paddock, C. D., Bloch, K. C., Krusell, D. J. Anaplasma phagocytophilum Strains in Sexton, S. C. Buckingham, G. S. Marshall, G. Ixodes scapularis Ticks, Canada. Emerging A. Storch, G. A. Dasch, J. H. McQuiston, D. Infectious Diseases 20 (12), 2064-2067. L. Swerdlow, J. S. Dumler, W. L. Nicholson, 13. Thomas, R. J., Dumler, J. S. and Carlyon, J. D. H. Walker, M. E. Eremeeva, and C. A. Ohl A. (2009) Current Management of Human (2006) Diagnosis and Management of Tick- Granulocytic Anaplasmosis, Human borne Rickettsial Diseases: Rocky Mountain Monocytic Ehrlichiosis and , Ehrlichiosis, and Anplasmosis ehrlichiosis. Expert Review of Anti-Infective – United States. Morbidity and Mortality Therapy 7 (6), 709-722. Weekly Review 55, 1 – 27. 14. Dugat, T., Lagree, A-C., Maillard, R., 7. Schotthoefer, A. M., Meece, J. K. and Boulouis, H-J. and Haddad, N. (2015) Fritsche, T. R. (2014) A Clinical, Diagnostic, Opening the black box of Anaplasma and Ecological Perspective on Human

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phagocytophilum diversity: current situation Srsen, S., Levicnik-Stezinar, S., Karner, P. and future perspectives. Frontiers in Cellular and Strle, F. (2012) Severe Human and Infection Microbiology 5, 1-18. Granulocytic Anaplasmosis Transmitted by 15. Des Vignes, R., Piesman, J., Heffernan, R., . Emerging Infectious Schulze, T. L., Stafford III, K. C. and Fish, D. Diseases 18(8), 1354-1357. (2001) Effect of Tick Removal on 21. US CDC Anaplasmosis Epidemiology & Transmission of Borrelia burgdorferi and Statistics page Ehrlichia phagocytophila by Ixodes http://www.cdc.gov/anaplasmosis/stats/ accessed scapularis Nymphs. The Journal of Infectious November 25, 2015. Diseases 183, 773-778. 22. European Centre for Disease Prevention and 16. Katavolos, P., Armstrong, P. M., Dawson, J. Control, Tick Maps page E. and Telford III, S. R. (1998) Duration of http://ecdc.europa.eu/en/healthtopics/vectors/vector- Tick Attachment Required for Transmission maps/Pages/VBORNET-maps-tick-species.aspx of Granulocytic Ehrlichiosis. The Journal of accessed November 30, 2015. Infectious Diseases 177, 1422-1425. 23. Ismail, N., Bloch, K. C. and McBride, J. W. 17. Hodzic, E., Fish, D., Maretzki, C. M., De (2010) Human Ehrlichiosis and Silva, A. M., Feng, S. and Barthold, S. W. Anaplasmosis. Clinics in Laboratory (1998) Acquisition and Transmission of the Medicine 30(1), 261-292. Agent of Human Granulocytic Ehrlichiosis by 24. Ogden, N. H., Koffi, J. K., Pelcat, Y. and Ixodes scapularis Ticks. Journal of Clinical Lindsay, L. R. (2014) Environmental Risk Microbiology 36 (12), 3574-3578. from Lyme disease in Central and Eastern 18. Dhand, A., Nadelman, R. B., Aguero- Canada: A Summary of Recent Surveillance Rosenfeld, M., Haddad, F. A., Stokes, D. P. Information. Canada Communicable Disease and Horowitz, H. W. (2007) Human Report 40 (5), 74-82. Granulocytic Anaplasmosis During 25. Schotthoefer, A. M., Meece, J. K., Ivacic, L. Pregnancy: Case Series and Literature C., Bertz, P. D., Zhang, K., Weiler, T., Review. Clinical Infectious Diseases 45, 589- Uphoff, T. S. and Fritsche, T. R. (2013) 593. Comparison of a Real-Time PCR Method 19. Kemperman, M., Netizel, D., Jensen, K., with Serology and Blood Smear Analysis for Gorlin, J., Perry, E., Myers, T., Miley, T., Diagnosis of Human Anaplasmosis: McQuinston, J., Eremeeva, M. E., Nicholson, Importance of Infection Time Course for W., Singleton, J. and Adjemian, J. (2008) Optimal Test Utilization. Journal of Clinical Anaplasma phagocytophilum Transmitted Microbiology 51(7), 2147-2153. Through Blood Transfusion – Minnesota, 26. Stafford III, K. C. (2007) Tick Management 2007. Morbidity and Mortality Weekly Handbook Revised Edition. The Connecticut Review 57(42), 1145-1148. Agricultural Experimental Station, New 20. Jereb, M., Pecaver, B., Tomazic, J., Haven. Muzlovic, I., Avsic-Zupanc, T., Premru-

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