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What’s Eating You? Ixodes Tick and Related Diseases, Part 2: Diagnosis and Treatment of Regional Tick-borne Diseases
Author(s)
Kelsey D. Wilson, MD
Dirk M. Elston, MD

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.1 Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.2

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.8 Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Approximation of the geographic distribution of reportable tick-borne diseases transmitted by Ixodes species in the United States, including Lyme disease, Powassan virus, babesiosis, and human granulocytic anaplasmosis.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.9

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.11

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.12 Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.10

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.13 Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.14 Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.15 Tick attachment for at least 36 hours is required for transmission.13

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.16 Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.13 Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).17 Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.18 Indirect fluorescent antibody testing is species-specific but cannot verify active infection.10

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.10 Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.19

 

 

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.21 The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.22

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.27 Treatment is supportive. An inactivated vaccine is available for high-risk populations.28

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 20117 and was identified as a pathogen in both North America29 and Europe in 2013.30 Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.31,32 Meningoencephalitis may occur in immunocompromised patients.29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.31 If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.32

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.33 Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

References
  1. Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308:733-740.
  2. Dolan MC, Hojgaard A, Hoxmeier JC, et al. Vector competence of the blacklegged tick, Ixodes scapularis, for the recently recognized Lyme borreliosis spirochete Candidatus Borrelia mayonii. Ticks Tick Borne Dis. 2016;7:665-669.
  3. Rudzinska MA, Spielman A, Riek RF, et al. Intraerythrocytic ‘gametocytes’ of Babesia microti and their maturation in ticks. Can J Zool. 1979;57:424-434.
  4. Casals J, Olitsky PK. Enduring immunity following vaccination of mice with formalin-inactivated virus of Russian spring-summer (Far Eastern, tick-borne) encephalitis; correlation with serum-neutralizing and complement-fixing antibodies. J Exp Med. 1945;82:431-443.
  5. Magnarelli LA, Stafford KC III, Mather TN, et al. Hemocytic rickettsia-like organisms in ticks: serologic reactivity with antisera to Ehrlichiae and detection of DNA of agent of human granulocytic ehrlichiosis by PCR. J Clin Microbiol. 1995;33:2710-2714.
  6. McLean DM, Donohue WL. Powassan virus: isolation of virus from a fatal case of encephalitis. Can Med Assoc J. 1959;80:708-711.
  7. Platonov AE, Karan LS, Kolyasnikova NM, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816-1823.
  8. Diaz JH. A 60-year meta-analysis of tick paralysis in the United States: a predictable, preventable, and often misdiagnosed poisoning. J Med Toxicol. 2010;6:15-21.
  9. Bakken J, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015;29:341-355.
  10. Chapman AS, Bakken JS, Folk SM, et al; Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. 2006;55(RR-4):1-27.
  11. Dahlgren FS, Mandel EJ, Krebs JW, et al. Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000-2007. Am J Trop Med Hyg. 2011;85:124-130.
  12. Aguero-Rosenfeld ME. Diagnosis of human granulocytic ehrlichiosis: state of the art. Vector Borne Zoonotic Dis. 2002;2:233-239.
  13. Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015;29:357-370.
  14. Joseph JT, Roy SS, Shams N, et al. Babesiosis in Lower Hudson Valley, New York, USA. Emerg Infect Dis. 2011;17:843-847.
  15. McQuiston JH, Childs JE, Chamberland ME, et al. Transmission of tickborne agents by blood transfusions: a review of known and potential risks in the United States. Transfusion. 2000;40:274-284.
  16. Hatcher JC, Greenberg PD, Antique J, et al. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis. 2001;32:1117-1125.
  17. Healy GR, Ruebush TK. Morphology of Babesia microti in human blood smears. Am J Clin Pathol. 1980;73:107-109.
  18. Kowalski TJ, Jobe DA, Dolan EC, et al. The emergence of clinically relevant babesiosis in southwestern Wisconsin. WMJ. 2015;114:152-157.
  19. Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis. evidence for increased severity and duration of illness. JAMA. 1996;275:1657-1660.
  20. Centers for Disease Control and Prevention. Statistics & maps. http://www.cdc.gov/powassan/statistics.html. Updated February 14, 2017. Accessed December 11, 2017.
  21. Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging cases of Powassan virus encephalitis in New England: clinical presentation, imaging, and review of the literature. Clin Infect Dis. 2016;62:707-713.
  22. El Khoury MY, Camargo JF, White JL, et al. Potential role of deer tick virus in Powassan encephalitis cases in Lyme disease-endemic areas of New York, U.S.A. Emerg Infect Dis. 2013;19:1926-1933.
  23. World Health Organization (WHO). Vaccines against tick-borne encephalitis: WHO position paper. Wkly Epidemiol Rec. 2011;86:241-256.
  24. Centers for Disease Control and Prevention (CDC). Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000-2009. JAMA. 2010;303:2132-2135.
  25. Valarcher JF, Hägglund S, Juremalm M, et al. Tick-borne encephalitits. Rev Sci Tech. 2015;34:453-466.
  26. Schultze D, Dollenmaier G, Rohner A, et al. Benefit of detecting tick-borne encephalitis viremia in the first phase of illness. J Clin Virol. 2007;38:172-175.
  27. Holzmann H. Diagnosis of tick-borne encephalitis. Vaccine. 2003;21(suppl 1):S36-S40.
  28. Zavadska D, Anca I, André F, et al. Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group. Hum Vaccin Immunother. 2013;9:362-374.
  29. Gugliotta JL, Goethert HK, Berardi VP, et al. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240-245.
  30. Hovius JW, de Wever B, Sohne M, et al. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 2013;382:658.
  31. Molloy PJ, Telford SR III, Chowdri HR, et al. Borrelia miyamotoi disease in the northeastern United States: a case series. Ann Intern Med. 2015;163:91-98.
  32. Telford SR 3rd, Goethert HK, Molloy PJ, et al. Borrelia miyamotoi disease: neither Lyme disease nor relapsing fever. Clin Lab Med. 2015;35:867-882.
  33. Diaz JH. A comparative meta-analysis of tick paralysis in the United States and Australia. Clin Toxicol (Phila). 2015;53:874-883.
Article PDF
CT101004266.PDF
Author and Disclosure Information

From the Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina.

The authors report no conflict of interest.

This article is the second of a 3-part series. The first part appeared in the March 2018 issue. The last part will appear in the May 2018 issue.

The eTable is available in the PDF.

The images are in the public domain.

Correspondence: Dirk M. Elston, MD, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, 135 Rutledge Ave, MSC 578, Charleston, SC 29425 (elstond@musc.edu).

Issue
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MDedge Dermatology
Topics
Infectious Diseases
Page Number
266-268, 305
Sections
Environmental Dermatology
Author(s)
Kelsey D. Wilson, MD
Dirk M. Elston, MD
Author(s)
Kelsey D. Wilson, MD
Dirk M. Elston, MD
Author and Disclosure Information

From the Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina.

The authors report no conflict of interest.

This article is the second of a 3-part series. The first part appeared in the March 2018 issue. The last part will appear in the May 2018 issue.

The eTable is available in the PDF.

The images are in the public domain.

Correspondence: Dirk M. Elston, MD, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, 135 Rutledge Ave, MSC 578, Charleston, SC 29425 (elstond@musc.edu).

Author and Disclosure Information

From the Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, Charleston, South Carolina.

The authors report no conflict of interest.

This article is the second of a 3-part series. The first part appeared in the March 2018 issue. The last part will appear in the May 2018 issue.

The eTable is available in the PDF.

The images are in the public domain.

Correspondence: Dirk M. Elston, MD, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina, 135 Rutledge Ave, MSC 578, Charleston, SC 29425 (elstond@musc.edu).

Article PDF
CT101004266.PDF
Article PDF
CT101004266.PDF

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.1 Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.2

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.8 Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Approximation of the geographic distribution of reportable tick-borne diseases transmitted by Ixodes species in the United States, including Lyme disease, Powassan virus, babesiosis, and human granulocytic anaplasmosis.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.9

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.11

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.12 Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.10

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.13 Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.14 Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.15 Tick attachment for at least 36 hours is required for transmission.13

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.16 Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.13 Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).17 Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.18 Indirect fluorescent antibody testing is species-specific but cannot verify active infection.10

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.10 Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.19

 

 

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.21 The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.22

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.27 Treatment is supportive. An inactivated vaccine is available for high-risk populations.28

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 20117 and was identified as a pathogen in both North America29 and Europe in 2013.30 Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.31,32 Meningoencephalitis may occur in immunocompromised patients.29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.31 If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.32

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.33 Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

The Ixodes tick is prevalent in temperate climates worldwide. During a blood meal, pathogens may be transmitted from the tick to its host. Borrelia burgdorferi, a spirochete responsible for Lyme disease, is the most prevalent pathogen transmitted by Ixodes ticks.1 Borrelia mayonii recently was identified as an additional cause of Lyme disease in the United States.2

The Ixodes tick also is associated with several less common pathogens, including Babesia microti and the tick-borne encephalitis virus, which have been recognized as Ixodes-associated pathogens for many years.3,4 Other pathogens have been identified, including Anaplasma phagocytophilum, recognized in the 1990s as the cause of human granulocytic anaplasmosis, as well as the Powassan virus and Borrelia miyamotoi.5-7 Additionally, tick paralysis has been associated with toxins in the saliva of various species of several genera of ticks, including some Ixodes species.8 Due to an overlap in geographic distribution (Figure) and disease presentations (eTable), it is important that physicians be familiar with these regional pathogens transmitted by Ixodes ticks.

Approximation of the geographic distribution of reportable tick-borne diseases transmitted by Ixodes species in the United States, including Lyme disease, Powassan virus, babesiosis, and human granulocytic anaplasmosis.

Human Granulocytic Anaplasmosis

Formerly known as human granulocytic ehrlichiosis, human granulocytic anaplasmosis is caused by A phagocytophilum and is transmitted by Ixodes scapularis, Ixodes pacificus, and Ixodes persulcatus. The incidence of human granulocytic anaplasmosis in the United States increased 12-fold from 2001 to 2011.9

Presenting symptoms generally are nonspecific, including fever, night sweats, headache, myalgias, and arthralgias, often resulting in misdiagnosis as a viral infection. Laboratory abnormalities include mild transaminitis, leukopenia, and thrombocytopenia.9,10 Although most infections resolve spontaneously, 3% of patients develop serious complications. The mortality rate is 0.6%.11

A diagnosis of human granulocytic anaplasmosis should be suspected in patients with a viral-like illness and exposure to ticks in an endemic area. The diagnosis can be confirmed by polymerase chain reaction (PCR), acute- and convalescent-phase serologic testing, or direct fluorescent antibody screening. Characteristic morulae may be present in granulocytes.12 Treatment typically includes doxycycline, which also covers B burgdorferi coinfection. When a diagnosis of human granulocytic anaplasmosis is suspected, treatment should never be delayed to await laboratory confirmation. If no clinical improvement is seen within 48 hours, alternate diagnoses or coinfection with B microti should be considered.10

Babesiosis

The protozoan B microti causes babesiosis in the United States, with Babesia divergens being more common in Europe.13 Reported cases of babesiosis in New York increased as much as 20-fold from 2001 to 2008.14 Transmission primarily is from the Ixodes tick but rarely can occur from blood transfusion.15 Tick attachment for at least 36 hours is required for transmission.13

The clinical presentation of babesiosis ranges from asymptomatic to fatal. Symptoms generally are nonspecific, resembling a viral infection and including headache, nausea, diarrhea, arthralgia, and myalgia. Laboratory evaluation may reveal hemolytic anemia, thrombocytopenia, transaminitis, and elevated blood urea nitrogen and creatinine levels.16 Rash is not typical. Resolution of symptoms generally occurs within 2 weeks of presentation, although anemia may persist for months.13 Severe disease is more common among elderly and immunocompromised patients. Complications include respiratory failure, renal failure, congestive heart failure, and disseminated intravascular coagulation. The mortality rate in the United States is approximately 10%.10,16

A diagnosis of babesiosis is made based on the presence of flulike symptoms, laboratory results, and history of recent travel to an endemic area. A thin blood smear allows identification of the organism in erythrocytes as ring forms or tetrads (a “Maltese cross” appearance).17 Polymerase chain reaction is more sensitive than a blood smear, especially in early disease.18 Indirect fluorescent antibody testing is species-specific but cannot verify active infection.10

Treatment of babesiosis is indicated for symptomatic patients with active infection. Positive serology alone is not an indication for treatment. Asymptomatic patients with positive serology should have diagnostic testing repeated in 3 months with subsequent treatment if parasitemia persists. Mild disease is treated with atovaquone plus azithromycin or clindamycin plus quinine. Severe babesiosis is treated with quinine and intravenous clindamycin and may require exchange transfusion.10 Coinfection with B burgdorferi should be considered in patients with flulike symptoms and erythema migrans or treatment failure. Coinfection is diagnosed by Lyme serology plus PCR for B microti. This is an important consideration because treatment of babesiosis does not eradicate B burgdorferi infection.19

 

 

Powassan Virus

Powassan virus is a flavivirus that causes encephalitis. It is transmitted by Ixodes cookei (Powassan virus, lineage I) in the Great Lakes region and by I scapularis (Powassan virus, lineage II, or deer tick virus) in the northeastern United States. Transmission can occur within 15 minutes of tick attachment.6,20,21

Patients typically present with fever, headache, altered mental status, seizures, and focal neurologic deficits. Gastrointestinal symptoms and rash also have been reported.21 The diagnosis is made based on clinical presentation and laboratory testing with PCR or enzyme-linked immunosorbent assay (ELISA). Cross-reactivity on ELISA exists, necessitating confirmation with a neutralizing antibody or PCR. Treatment is supportive. Corticosteroids and intravenous immunoglobulin have been proposed as treatment modalities, but evidence of their efficacy is limited.22

Tick-borne Encephalitis

Tick-borne encephalitis is caused by the flavivirus tick-borne encephalitis virus in Europe and Asia. The tick-borne encephalitis virus is transmitted by Ixodes ricinus in Europe and by Ixodes persulcatus in eastern Russia, China, and Japan. It also has been associated with consumption of unpasteurized milk.23,24

Tick-borne encephalitis presents in a biphasic pattern. The initial viremic phase can persist for as long as 8 days with headache, nausea, myalgia, and fever. One-third of patients then enter an asymptomatic phase, followed by virus penetration into the central nervous system. The neurologic phase produces continued headache and fever with photophobia, focal neurologic deficits, seizures, respiratory depression, or coma. Neurologic sequelae persist in 10% to 20% of patients.25,26

In the viremic stage, diagnosis is made with PCR or culture. During the latent phase or neurologic phase, serologic testing for tick-borne encephalitis virus antibodies is indicated. Neutralizing antibody evaluation may be necessary due to cross-reactivity among flaviviruses.27 Treatment is supportive. An inactivated vaccine is available for high-risk populations.28

Borrelia miyamotoi Disease

Borrelia miyamotoi is a symbiont of the Ixodes tick formerly believed to have no pathogenic significance; however, B miyamotoi was isolated in febrile patients in Russia in 20117 and was identified as a pathogen in both North America29 and Europe in 2013.30 Disease presentation includes nonspecific symptoms of fever, fatigue, headache, arthralgia, myalgia, and nausea. Rash is uncommon. Laboratory abnormalities include leukopenia, thrombocytopenia, and transaminitis.31,32 Meningoencephalitis may occur in immunocompromised patients.29,30

The diagnosis of B miyamotoi disease is confirmed by PCR or serology. An ELISA that is positive for B burgdorferi IgM but negative with confirmatory immunoblot suggests B miyamotoi disease. Seroconversion using a glpQ protein ELISA also can be assessed.31 If ELISA is positive, Lyme disease can be excluded because B burgdorferi does not possess g1pQ. Treatment is with doxycycline.32

Tick Paralysis

Tick paralysis is an intoxication with holocyclotoxin from the saliva of gravid hard ticks. In the United States, intoxication is associated with ticks of various species of Amblyomma, Dermacentor, and Ixodes in the Northwest, Southeast, and Northeast. In Australia, intoxication is associated with Ixodes.33 Patients present with weakness and fatigue, progressing to ascending flaccid paralysis with sensory sparing. The treatment is tick removal.8,33

Conclusion

Arthropods carry many regional pathogens. Physicians outside of those regions should seek a travel history and be alert for imported disease.

References
  1. Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308:733-740.
  2. Dolan MC, Hojgaard A, Hoxmeier JC, et al. Vector competence of the blacklegged tick, Ixodes scapularis, for the recently recognized Lyme borreliosis spirochete Candidatus Borrelia mayonii. Ticks Tick Borne Dis. 2016;7:665-669.
  3. Rudzinska MA, Spielman A, Riek RF, et al. Intraerythrocytic ‘gametocytes’ of Babesia microti and their maturation in ticks. Can J Zool. 1979;57:424-434.
  4. Casals J, Olitsky PK. Enduring immunity following vaccination of mice with formalin-inactivated virus of Russian spring-summer (Far Eastern, tick-borne) encephalitis; correlation with serum-neutralizing and complement-fixing antibodies. J Exp Med. 1945;82:431-443.
  5. Magnarelli LA, Stafford KC III, Mather TN, et al. Hemocytic rickettsia-like organisms in ticks: serologic reactivity with antisera to Ehrlichiae and detection of DNA of agent of human granulocytic ehrlichiosis by PCR. J Clin Microbiol. 1995;33:2710-2714.
  6. McLean DM, Donohue WL. Powassan virus: isolation of virus from a fatal case of encephalitis. Can Med Assoc J. 1959;80:708-711.
  7. Platonov AE, Karan LS, Kolyasnikova NM, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816-1823.
  8. Diaz JH. A 60-year meta-analysis of tick paralysis in the United States: a predictable, preventable, and often misdiagnosed poisoning. J Med Toxicol. 2010;6:15-21.
  9. Bakken J, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015;29:341-355.
  10. Chapman AS, Bakken JS, Folk SM, et al; Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. 2006;55(RR-4):1-27.
  11. Dahlgren FS, Mandel EJ, Krebs JW, et al. Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000-2007. Am J Trop Med Hyg. 2011;85:124-130.
  12. Aguero-Rosenfeld ME. Diagnosis of human granulocytic ehrlichiosis: state of the art. Vector Borne Zoonotic Dis. 2002;2:233-239.
  13. Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015;29:357-370.
  14. Joseph JT, Roy SS, Shams N, et al. Babesiosis in Lower Hudson Valley, New York, USA. Emerg Infect Dis. 2011;17:843-847.
  15. McQuiston JH, Childs JE, Chamberland ME, et al. Transmission of tickborne agents by blood transfusions: a review of known and potential risks in the United States. Transfusion. 2000;40:274-284.
  16. Hatcher JC, Greenberg PD, Antique J, et al. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis. 2001;32:1117-1125.
  17. Healy GR, Ruebush TK. Morphology of Babesia microti in human blood smears. Am J Clin Pathol. 1980;73:107-109.
  18. Kowalski TJ, Jobe DA, Dolan EC, et al. The emergence of clinically relevant babesiosis in southwestern Wisconsin. WMJ. 2015;114:152-157.
  19. Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis. evidence for increased severity and duration of illness. JAMA. 1996;275:1657-1660.
  20. Centers for Disease Control and Prevention. Statistics & maps. http://www.cdc.gov/powassan/statistics.html. Updated February 14, 2017. Accessed December 11, 2017.
  21. Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging cases of Powassan virus encephalitis in New England: clinical presentation, imaging, and review of the literature. Clin Infect Dis. 2016;62:707-713.
  22. El Khoury MY, Camargo JF, White JL, et al. Potential role of deer tick virus in Powassan encephalitis cases in Lyme disease-endemic areas of New York, U.S.A. Emerg Infect Dis. 2013;19:1926-1933.
  23. World Health Organization (WHO). Vaccines against tick-borne encephalitis: WHO position paper. Wkly Epidemiol Rec. 2011;86:241-256.
  24. Centers for Disease Control and Prevention (CDC). Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000-2009. JAMA. 2010;303:2132-2135.
  25. Valarcher JF, Hägglund S, Juremalm M, et al. Tick-borne encephalitits. Rev Sci Tech. 2015;34:453-466.
  26. Schultze D, Dollenmaier G, Rohner A, et al. Benefit of detecting tick-borne encephalitis viremia in the first phase of illness. J Clin Virol. 2007;38:172-175.
  27. Holzmann H. Diagnosis of tick-borne encephalitis. Vaccine. 2003;21(suppl 1):S36-S40.
  28. Zavadska D, Anca I, André F, et al. Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group. Hum Vaccin Immunother. 2013;9:362-374.
  29. Gugliotta JL, Goethert HK, Berardi VP, et al. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240-245.
  30. Hovius JW, de Wever B, Sohne M, et al. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 2013;382:658.
  31. Molloy PJ, Telford SR III, Chowdri HR, et al. Borrelia miyamotoi disease in the northeastern United States: a case series. Ann Intern Med. 2015;163:91-98.
  32. Telford SR 3rd, Goethert HK, Molloy PJ, et al. Borrelia miyamotoi disease: neither Lyme disease nor relapsing fever. Clin Lab Med. 2015;35:867-882.
  33. Diaz JH. A comparative meta-analysis of tick paralysis in the United States and Australia. Clin Toxicol (Phila). 2015;53:874-883.
References
  1. Steere AC, Grodzicki RL, Kornblatt AN, et al. The spirochetal etiology of Lyme disease. N Engl J Med. 1983;308:733-740.
  2. Dolan MC, Hojgaard A, Hoxmeier JC, et al. Vector competence of the blacklegged tick, Ixodes scapularis, for the recently recognized Lyme borreliosis spirochete Candidatus Borrelia mayonii. Ticks Tick Borne Dis. 2016;7:665-669.
  3. Rudzinska MA, Spielman A, Riek RF, et al. Intraerythrocytic ‘gametocytes’ of Babesia microti and their maturation in ticks. Can J Zool. 1979;57:424-434.
  4. Casals J, Olitsky PK. Enduring immunity following vaccination of mice with formalin-inactivated virus of Russian spring-summer (Far Eastern, tick-borne) encephalitis; correlation with serum-neutralizing and complement-fixing antibodies. J Exp Med. 1945;82:431-443.
  5. Magnarelli LA, Stafford KC III, Mather TN, et al. Hemocytic rickettsia-like organisms in ticks: serologic reactivity with antisera to Ehrlichiae and detection of DNA of agent of human granulocytic ehrlichiosis by PCR. J Clin Microbiol. 1995;33:2710-2714.
  6. McLean DM, Donohue WL. Powassan virus: isolation of virus from a fatal case of encephalitis. Can Med Assoc J. 1959;80:708-711.
  7. Platonov AE, Karan LS, Kolyasnikova NM, et al. Humans infected with relapsing fever spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816-1823.
  8. Diaz JH. A 60-year meta-analysis of tick paralysis in the United States: a predictable, preventable, and often misdiagnosed poisoning. J Med Toxicol. 2010;6:15-21.
  9. Bakken J, Dumler JS. Human granulocytic anaplasmosis. Infect Dis Clin North Am. 2015;29:341-355.
  10. Chapman AS, Bakken JS, Folk SM, et al; Tickborne Rickettsial Diseases Working Group; CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. 2006;55(RR-4):1-27.
  11. Dahlgren FS, Mandel EJ, Krebs JW, et al. Increasing incidence of Ehrlichia chaffeensis and Anaplasma phagocytophilum in the United States, 2000-2007. Am J Trop Med Hyg. 2011;85:124-130.
  12. Aguero-Rosenfeld ME. Diagnosis of human granulocytic ehrlichiosis: state of the art. Vector Borne Zoonotic Dis. 2002;2:233-239.
  13. Vannier EG, Diuk-Wasser MA, Ben Mamoun C, et al. Babesiosis. Infect Dis Clin North Am. 2015;29:357-370.
  14. Joseph JT, Roy SS, Shams N, et al. Babesiosis in Lower Hudson Valley, New York, USA. Emerg Infect Dis. 2011;17:843-847.
  15. McQuiston JH, Childs JE, Chamberland ME, et al. Transmission of tickborne agents by blood transfusions: a review of known and potential risks in the United States. Transfusion. 2000;40:274-284.
  16. Hatcher JC, Greenberg PD, Antique J, et al. Severe babesiosis in Long Island: review of 34 cases and their complications. Clin Infect Dis. 2001;32:1117-1125.
  17. Healy GR, Ruebush TK. Morphology of Babesia microti in human blood smears. Am J Clin Pathol. 1980;73:107-109.
  18. Kowalski TJ, Jobe DA, Dolan EC, et al. The emergence of clinically relevant babesiosis in southwestern Wisconsin. WMJ. 2015;114:152-157.
  19. Krause PJ, Telford SR III, Spielman A, et al. Concurrent Lyme disease and babesiosis. evidence for increased severity and duration of illness. JAMA. 1996;275:1657-1660.
  20. Centers for Disease Control and Prevention. Statistics & maps. http://www.cdc.gov/powassan/statistics.html. Updated February 14, 2017. Accessed December 11, 2017.
  21. Piantadosi A, Rubin DB, McQuillen DP, et al. Emerging cases of Powassan virus encephalitis in New England: clinical presentation, imaging, and review of the literature. Clin Infect Dis. 2016;62:707-713.
  22. El Khoury MY, Camargo JF, White JL, et al. Potential role of deer tick virus in Powassan encephalitis cases in Lyme disease-endemic areas of New York, U.S.A. Emerg Infect Dis. 2013;19:1926-1933.
  23. World Health Organization (WHO). Vaccines against tick-borne encephalitis: WHO position paper. Wkly Epidemiol Rec. 2011;86:241-256.
  24. Centers for Disease Control and Prevention (CDC). Tick-borne encephalitis among U.S. travelers to Europe and Asia—2000-2009. JAMA. 2010;303:2132-2135.
  25. Valarcher JF, Hägglund S, Juremalm M, et al. Tick-borne encephalitits. Rev Sci Tech. 2015;34:453-466.
  26. Schultze D, Dollenmaier G, Rohner A, et al. Benefit of detecting tick-borne encephalitis viremia in the first phase of illness. J Clin Virol. 2007;38:172-175.
  27. Holzmann H. Diagnosis of tick-borne encephalitis. Vaccine. 2003;21(suppl 1):S36-S40.
  28. Zavadska D, Anca I, André F, et al. Recommendations for tick-borne encephalitis vaccination from the Central European Vaccination Awareness Group. Hum Vaccin Immunother. 2013;9:362-374.
  29. Gugliotta JL, Goethert HK, Berardi VP, et al. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240-245.
  30. Hovius JW, de Wever B, Sohne M, et al. A case of meningoencephalitis by the relapsing fever spirochaete Borrelia miyamotoi in Europe. Lancet. 2013;382:658.
  31. Molloy PJ, Telford SR III, Chowdri HR, et al. Borrelia miyamotoi disease in the northeastern United States: a case series. Ann Intern Med. 2015;163:91-98.
  32. Telford SR 3rd, Goethert HK, Molloy PJ, et al. Borrelia miyamotoi disease: neither Lyme disease nor relapsing fever. Clin Lab Med. 2015;35:867-882.
  33. Diaz JH. A comparative meta-analysis of tick paralysis in the United States and Australia. Clin Toxicol (Phila). 2015;53:874-883.
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What’s Eating You? Ixodes Tick and Related Diseases, Part 2: Diagnosis and Treatment of Regional Tick-borne Diseases
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What’s Eating You? Ixodes Tick and Related Diseases, Part 2: Diagnosis and Treatment of Regional Tick-borne Diseases
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Practice Points

  • Apart from the more familiar Borrelia burgdorferi, several less common pathogens associated with diseases transmitted by Ixodes ticks include Anaplasma phagocytophilum, Babesia microti, Borrelia miyamotoi, the Powassan virus, and the tick-borne encephalitis virus.
  • Overlap in both the geographic distribution and the clinical presentations of these uncommon pathogens underscores the importance of being familiar with their capacity for causing illness and effective treatment.
  • Intoxication with the saliva of some Ixodes species can cause an ascending flaccid tick paralysis.
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