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Ehrlichioses: Anaplasmosis and Human Ehrlichiosis
Ehrlichioses: Anaplasmosis and Human Ehrlichiosis Kristina St. Clair, DO, and Catherine F. Decker, MD, FACP, FIDSA Introduction Human ehrlichiosis and anaplasmosis are acute febrile tick-borne rickettsial diseases caused by organisms of the closely related genera Ehrlichia and Anaplasma. Over the past 20 years, Ehrlicha has become increasingly recognized as an emerging zoonotic infection since it was first found to cause human disease in 1986.1-4 The most common agents of human tick-borne ehrlichiosis include Anaplasma phagocytophlium, Ehrlichia chaffenenis, and Ehrlichia ewingii. The more commonly recognized infections include anaplasmosis (human granulocytic anaplasmosis [HGA]) and human ehrlichiosis (human monocytic ehrlichiosis [HME]).3-5 The causative agents of HME and HGA are small, Gramnegative, obligate intracellular bacteria that have tropism for specific leukocytes. HME has an affinity for monocytes and HGA preferentially infects granulocytes. Ehrlichieae replicate within vacuoles in these leukocytes forming microcolonies called morulae, derived from Latin word “Morus” for mulberry, which allows the organisms to avoid phagocytosis to facilitate their survival. Morulae can be visualized by light microscopy of Giemsa- or Wright-stained peripheral smears.3,4
Epidemiology HGA A. phagocytophilum (formerly Ehrlichia phagocytophilia) was first identified in humans in 1990 when a patient from Wisconsin died of an acute febrile illness 2 weeks after a tick bite. This organism was isolated in 1994 by polymerase chain reaction (PCR) and a taxonomic name Disclaimer. The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Navy, or the naval services at large. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army or the US Department of Defense. Dis Mon 2012;58:346-354 0011-5029/2012 $36.00 ⫹ 0 http://dx.doi.org/10.1016/j.disamonth.2012.03.006 346
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FIG 1. Reported cases of anaplasmosis by state, United States, 2008. (Reprinted with permission from Centers for Disease Control and Prevention. Annual reported incidence (per million population) for anaplasmosis in the United States for 2008. Available at: http:// www.cdc.gov/anaplasmosis/stats/. Accessed 2012) (Color version of figure is available online.).
changed occurred in 2001 to the current A. phagocytophilum (HGA).6 Anaplasmosis is most frequently reported in the upper midwestern and northeastern USA; 6 states account for 88% of all reported cases of anaplasmosis, including New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.7 More than 2900 cases of HGA have been reported to the Centers for Disease Control between 1994 and 2005, with the annual number of cases at an estimated incidence of 1.6 cases per million in the USA (Fig 1). During 2000-07, the reported incidence of A. phagocytophilum increased from 1.4 to 3.0 cases/million persons/year with a case-fatality rate of 0.6%, and a hospitalization rate of 36%.5 DM, June 2012
347
Serosurveillance studies suggest that asymptomatic disease is common with seroprevalence ranging between 9% and 35% in endemic regions.3-5 A seroprevalence of 15% was reported among healthy residents from northwestern Wisconsin who had no history of a recent tick bite.8A. phagocytophilum is transmitted by the Ixodes scapularis (black-legged tick) in the New England and North Central US. It is also the vector for Borrelia burgdorferi and Babesia microti and approximately 10% of patients with HGA have serologic evidence of coinfection with Lyme disease or babesiosis. It has been reported that approximately 10% to 50% of I. scapularis ticks are infected with A. phagocytophilum in endemic areas.3 The animal reservoirs for A. phagocytophilum are primarily small mammals with humans serving as dead end host. Cases do occur year-round, with a peak incidence during June and July.3,4 There are also case reports of transmission occurring perinatally and through blood transfusion.9,10
HME Ehrlichiosis was first characterized in humans in 1986 and there are 3 known species: Ehrlichia chaffeensis (HME), E. ewingii, and Ehrlichia muris-like (EML).3,4 E. chaffeensis and E. ewingii are transmitted by Amblyomma americanum (lone star tick) and E. muris-like (EML) has been identified in a small number of patients residing in or traveling to Minnesota and Wisconsin.11 A tick vector for EML has not yet been established. HME is the most frequently diagnosed tick-borne human illness in the southern US from the eastern seaboard extending westward to Texas.12,13 Three states (Oklahoma, Missouri, Arkansas) account for 35% of all reported E. chaffeensis infections.13 Animal reservoir for E. chaffeensis is the white-tailed deer, which can sustain infections for extended periods and infecting ticks without the development of illness.4 E. chaffeensis has been isolated from other ticks in North America, including the American dog tick (Dermacentor variabilis). The natural cycle of E. ewingii is not well defined but likely includes domestic dogs and deer.3,4 The ehrlichioses are nationally notifiable diseases.3 The incidence of human disease depends on the percentage of infected ticks. In a study in Tennessee, E. chaffeensis was detected in 2.6% and E. ewingii in 0.8% of lone star ticks.14 A higher prevalence was found in Missouri ticks and Oklahoma dogs.12 Approximately 3400 cases of HME were reported to the Centers for Disease Control from 2003 to 2008 (Fig 2). During 2000-07, the reported incidence rate of E. chaffeensis in348
DM, June 2012
FIG 2. Reported cases of ehrlichiosis by state, USA, 2008. (Reprinted with permission from Centers for Disease Control and Prevention. Annual reported incidence (per million population) for Ehrlichia in the USA for 2008. Available at: http://www.cdc.gov/ehrlichiosis/stats/ index.html. Accessed February 17, 2012.) (Color version of figure is available online.).
creased from 0.80 to 3.0 cases/million persons/year.13 This probably reflects better reporting. A seroprevalence study in Tennessee found a 12.5% seroprevalence of antibodies to E. chaffeensis in an asymptomatic population.15 Human transmission can occur anytime from spring to fall; however, infection is most common during the late summer and fall when the lone star ticks are most active. More infections occur in men, which may reflect greater recreational or occupational exposure.4,15 Generally, successful transmission happens in a dose-dependent fashion and an adequate inoculum may occur if the tick is attached and feeding for at least 24 hours. DM, June 2012
349
Clinical Presentation HME HME is a more severe disease than HGA with 40% of cases requiring hospitalization and a case fatality rate of 3%, with up to 17% of patients developing life-threatening complications, including acute renal failure, myocarditis, disseminated intravascular coagulopathy, and adult respiratory distress syndrome.3-5 HME and HGA may be more severe infections in patients who are immunocompromised, including those with advanced human immunodeficiency virus, malignancy, or advanced age, those who are asplenic, and those receiving immunosuppressive agents.3 HME can manifest as a multisystem disease resembling toxic shock or Rocky Mountain spotted fever, except for the infrequent occurrence of rash. Fever is an almost universal symptom followed by headache, myalgias, and arthralgias. A rash, which may be present in approximately 10% to up to 30% of cases, typically occurs 5 days after the onset of symptoms and can be maculopapular, petechial, or diffuse erythroderma, typically sparing the palms and soles. Gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are sometimes present.3,4 Neurologic symptoms, including meningitis and meningoencephalitis, have been reported in approximately 20% of patients with HME. In some cases, seizures and coma have been reported.16
HGA HGA generally tends to be a less severe illness than HME, although life-threatening complications can occur, including hemodynamic collapse and respiratory failure. The case-fatality rate has been reported to be about 0.6% with a hospitalization rate of 36%.3,5 HGA resembles HME with respect to the frequency of fever, headache, and myalgia; however, rash is uncommon, present in less than 10% of infected patients.3,4 Central nervous system involvement is also less common compared to HME with meningitis reported in approximately 1% of cases. In contrast, peripheral nerve involvement has been more frequently described, including brachial plexopathy, polyneuropathy, and cranial nerve palsies, including bilateral facial nerve palsy3,4,17 (Table 1).
Diagnosis HME and HGA Laboratory findings in HME and HGA are generally nonspecific, often characterized by leukopenia (50%), and thrombocytopenia (94%). Ele350
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TABLE 1. Comparison of clinical characteristics of HME and HGA Tick-Borne Illness Cell preferentially infected Presence of rash Morulae visible on peripheral blood smear Treatment Case fatality
Human Monocytic Ehrlichiosis
Human Granulocytic Anaplasmosis
Monocyte 60% children ⬍30% adults 20%
Granulocyte Generally not present 80%
Doxycycline
Doxycycline 0.6%
1.9%
vated liver-associated enzymes may be seen in over 90% of cases.3,4,12,17 In patients with HME who have neurologic symptoms and undergo lumbar puncture, a cerebrospinal fluid pleocytosis (cerebrospinal fluid ⬍100 cells/mm3) is identified in approximately 60% with a lymphocytic predominance in most instances, although a neutrophilic predominance may also be seen.16 Because of the limited availability of rapid diagnostic testing like PCR testing and the absence of antibodies at the time of presentation, diagnosis often rests on clinical signs, symptoms, and disease occurring in an endemic region with seasonality. Treatment should not be delayed while waiting for diagnostic test results.3,4 Confirmatory assays should be used retrospectively to validate the accuracy of diagnosis. A review of a Wright- or Giemsa-stained peripheral blood smear may provide early diagnosis. Although this method is rapid, it is relatively insensitive compared to other diagnostic tests and should be performed by an experienced microscopist. Its highest sensitivity is during the first week of illness when morulae may be seen in monocytes in 1% to 20% of patients with HME; however, it may be more useful in HGA where 20% to 80% of patients may have morulae detected in neutrophils3,18 (Figs 3 and 4). Serology has long been relied on for diagnosis. Indirect immunofluorescence antibody assay is used most but there is no standardized definition of positivity. Antibody levels only begin to rise after the clinical illness is established so serology may be negative during the first week of illness. Sensitivity of the immunofluorescence antibody is 94% to 100% 14 days after onset of illness. Testing of 2 sequential serum samples taken at least 2 to 3 weeks apart to examine for a 4-fold or greater rise in antibody titers is recommended.3,4,12,17,18 Diagnosis of ehrlichial infections by PCR, when available, is becoming the test of choice for confirming HME and HGA infection because of its specificity (60%-85%) and sensitivity (60%-85%) for E. chaffeenis and 67% to 90% for A. phagocytophilum. PCR is becoming more widely DM, June 2012
351
FIG 3. Morulae within a monocyte. (Reprinted with permission from Centers for Disease Control and Prevention. Morulae detected in a monocyte on a peripheral blood smear, associated with E. chaffeensis infection. Available at: http://www.cdc.gov/Ehrlichiosis/symptoms/index.html. Accessed February 17, 2012). (Color version of figure is available online.).
commercially available.3,4,19 It is particularly important for detection of infection at early stages when antibody levels are very low or undetectable. A negative PCR does not rule out the diagnosis. Treatment with antimicrobials will decrease sensitivity of PCR amplification. Isolation of these organisms through cell culture is labor-intensive, more timeconsuming than other diagnostic testing, and rarely used.3
Treatment The drug of choice for both HME and HGA in adults as well as in children is doxycycline.3 Therapy is most effective when started early in the disease course and should be initiated when diagnosis is suspected. Therapy should never be delayed while awaiting diagnostic workup. The adult dose of doxycycline is 100 mg orally every 12 hours and the dose for children under 45 kg is 2.2 mg/kg orally every 12 hours for 7-14 days and for 3 days after fever resolves. Some advocate treating longer if central nervous system involvement is present. In children, the usual dose and duration of doxycycline for treatment of HGA or HME does not cause tooth discoloration. Doxycycline is highly efficacious, and posttherapy relapse has not been reported. There is generally a rapid response to treatment with a marked clinical improvement within 24 to 48 hours. A lack of this response should prompt consideration for an alternative diagnosis. In those with HGA who do not respond to doxycycline, infection with Babesia should be considered.3 352
DM, June 2012
FIG 4. Morulae within a granulocyte. (Reprinted with permission from Centers for Disease Control and Prevention. Morulae detected in a granulocyte on a peripheral blood smear, associated with A. phagocytophilium infection. Available at: http://www.cdc.gov/anaplasmosis/symptoms/ index.html. Accessed February 20, 2012). (Color version of figure is available online.)
Guidelines do not exist for treatment of HGA or HME in pregnancy; however, if the disease is life-threatening, therapy with doxycycline may be warranted.3,9 A possible alternative for patients with a doxycycline allergy or with mild disease during pregnancy is rifampin.3,9 Other antibiotics, such as quinolones, cephalosporins, penicillins, and macrolides, are ineffective.3,12 There is some evidence that the use of sulfonamides may worsen the disease course.20 Prophylaxis is not recommended after a tick bite, even in endemic regions. Preventive measures include tick avoidance, early removal of attached ticks, and use of insecticides and are discussed in depth elsewhere in this monograph.3
REFERENCES 1. 2. 3.
Schneider JG. Human ehrlichiosis: a case study. Clin Lab Sci 2009;22(1):3-8. Fishbein DB, Sawyer LA, Holland CJ, et al. Unexplained febrile illnesses after exposure to ticks. Infection with an Ehrlichia? JAMA 1987;257(22):3100-4. Center for Disease Control. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States. MMWR Morb Mortal Wkly Rep 2006;55(RR04):1-27.
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4. 5.
6.
7. 8.
9.
10.
11. 12. 13. 14.
15. 16. 17. 18. 19. 20.
354
Ismail N, Bloch KC, McBride JW. Human ehrlichiosis and anaplasmosis. Clin Lab Med 2010;30(1):261-92. 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(1):124-31. Chen SM, Dumler JS, Bakken JS, et al. Identification of a granulocytotropic Ehrlichia species as the etiologic agent of human disease. J Clin Microbiol 1994;32(3):589-95. Available at: http://www.cdc.gov/anaplasmosis/stats/index.html. Accessed February 17, 2012. Bakken JS, Goellner P, Van Etten M, et al. Seroprevalence of human granulocytic ehrlichiosis among permanent residents of northwestern Wisconsin. Clin Infect Dis 1998;27:1491-6. Dhand A, Nadelman RB, Aguero-Rosenfeld M, et al. Human granulocytic anaplasmosis during pregnancy: case series and literature review. Clin Infect Dis 2007;45(5):589-93. Kemperman M, Neitzel D, Jensen K, et al. Anaplasma phagocytophilum transmitted through blood transfusion—Minnesota, 2007. MMWR Morb Mortal Wkly Rep 2008;57(42):1145-8. Pritt BS, Sloan LM, Johnson DK, et al. Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota. N Engl J Med 2011;365(5):422-9. Salinas LJ, Greenfield RA, Little SE, et al. Tickborne infections in the southern United States. Am J Med Sci 2010;340(3):194-201. Available at: http://www.cdc.gov/ehrlichiosis/stats/index.html. Accessed February 17, 2012. Cohen SB, Yabsley MJ, Garrison LE, et al. Rickettsia parkeri in Amblyomma americanum ticks, Tennessee and Georgia, USA. Emerging Infect Dis 2009;15: 1471-3. Standaert SM, Dawson JE, Schaffner W, et al. Ehrlichisosis in a golf-oriented retirement community. N Engl J Med 1995;333:420-5. Ratnasamy N, Everett ED, Roland WE, et al. Central nervous system manifestations of human ehrlichiosis. Clin Infect Dis 1996;23:314-19. Dumler JS, Madigan JE, Pusteria N, et al. Ehrlichiosis in humans: epidemiology, clinical presentation, diagnosis, and treatment. Clin Infect Dis 2007;4(1):S45-51. Bakken JS, Dumler JS. Human granulocytic ehrlichiosis. Clin Infect Dis 2000; 31(2):554-60. Anderson BE, Sumner JW, Dawson JE, et al. Detection of the etiologic agent of human ehrlichiosis by polymerase chain reaction. J Clin Microbiol 1992;30:775-80. Peters TR, Edwards KM, Standaert SM. Severe ehrlichiosis in an adolescent taking trimethoprim-sulfamethoxazole. Pediatr Infect Dis J 2000;19:170-71.
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Epidemiology HGA A. phagocytophilum (formerly Ehrlichia phagocytophilia) was first identified in humans in 1990 when a patient from Wisconsin died of an acute febrile illness 2 weeks after a tick bite. This organism was isolated in 1994 by polymerase chain reaction (PCR) and a taxonomic name Disclaimer. The opinions and assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of Defense, the Department of the Navy, or the naval services at large. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Department of the Army or the US Department of Defense. Dis Mon 2012;58:346-354 0011-5029/2012 $36.00 ⫹ 0 http://dx.doi.org/10.1016/j.disamonth.2012.03.006 346
DM, June 2012
FIG 1. Reported cases of anaplasmosis by state, United States, 2008. (Reprinted with permission from Centers for Disease Control and Prevention. Annual reported incidence (per million population) for anaplasmosis in the United States for 2008. Available at: http:// www.cdc.gov/anaplasmosis/stats/. Accessed 2012) (Color version of figure is available online.).
changed occurred in 2001 to the current A. phagocytophilum (HGA).6 Anaplasmosis is most frequently reported in the upper midwestern and northeastern USA; 6 states account for 88% of all reported cases of anaplasmosis, including New York, Connecticut, Massachusetts, Rhode Island, Minnesota, and Wisconsin.7 More than 2900 cases of HGA have been reported to the Centers for Disease Control between 1994 and 2005, with the annual number of cases at an estimated incidence of 1.6 cases per million in the USA (Fig 1). During 2000-07, the reported incidence of A. phagocytophilum increased from 1.4 to 3.0 cases/million persons/year with a case-fatality rate of 0.6%, and a hospitalization rate of 36%.5 DM, June 2012
347
Serosurveillance studies suggest that asymptomatic disease is common with seroprevalence ranging between 9% and 35% in endemic regions.3-5 A seroprevalence of 15% was reported among healthy residents from northwestern Wisconsin who had no history of a recent tick bite.8A. phagocytophilum is transmitted by the Ixodes scapularis (black-legged tick) in the New England and North Central US. It is also the vector for Borrelia burgdorferi and Babesia microti and approximately 10% of patients with HGA have serologic evidence of coinfection with Lyme disease or babesiosis. It has been reported that approximately 10% to 50% of I. scapularis ticks are infected with A. phagocytophilum in endemic areas.3 The animal reservoirs for A. phagocytophilum are primarily small mammals with humans serving as dead end host. Cases do occur year-round, with a peak incidence during June and July.3,4 There are also case reports of transmission occurring perinatally and through blood transfusion.9,10
HME Ehrlichiosis was first characterized in humans in 1986 and there are 3 known species: Ehrlichia chaffeensis (HME), E. ewingii, and Ehrlichia muris-like (EML).3,4 E. chaffeensis and E. ewingii are transmitted by Amblyomma americanum (lone star tick) and E. muris-like (EML) has been identified in a small number of patients residing in or traveling to Minnesota and Wisconsin.11 A tick vector for EML has not yet been established. HME is the most frequently diagnosed tick-borne human illness in the southern US from the eastern seaboard extending westward to Texas.12,13 Three states (Oklahoma, Missouri, Arkansas) account for 35% of all reported E. chaffeensis infections.13 Animal reservoir for E. chaffeensis is the white-tailed deer, which can sustain infections for extended periods and infecting ticks without the development of illness.4 E. chaffeensis has been isolated from other ticks in North America, including the American dog tick (Dermacentor variabilis). The natural cycle of E. ewingii is not well defined but likely includes domestic dogs and deer.3,4 The ehrlichioses are nationally notifiable diseases.3 The incidence of human disease depends on the percentage of infected ticks. In a study in Tennessee, E. chaffeensis was detected in 2.6% and E. ewingii in 0.8% of lone star ticks.14 A higher prevalence was found in Missouri ticks and Oklahoma dogs.12 Approximately 3400 cases of HME were reported to the Centers for Disease Control from 2003 to 2008 (Fig 2). During 2000-07, the reported incidence rate of E. chaffeensis in348
DM, June 2012
FIG 2. Reported cases of ehrlichiosis by state, USA, 2008. (Reprinted with permission from Centers for Disease Control and Prevention. Annual reported incidence (per million population) for Ehrlichia in the USA for 2008. Available at: http://www.cdc.gov/ehrlichiosis/stats/ index.html. Accessed February 17, 2012.) (Color version of figure is available online.).
creased from 0.80 to 3.0 cases/million persons/year.13 This probably reflects better reporting. A seroprevalence study in Tennessee found a 12.5% seroprevalence of antibodies to E. chaffeensis in an asymptomatic population.15 Human transmission can occur anytime from spring to fall; however, infection is most common during the late summer and fall when the lone star ticks are most active. More infections occur in men, which may reflect greater recreational or occupational exposure.4,15 Generally, successful transmission happens in a dose-dependent fashion and an adequate inoculum may occur if the tick is attached and feeding for at least 24 hours. DM, June 2012
349
Clinical Presentation HME HME is a more severe disease than HGA with 40% of cases requiring hospitalization and a case fatality rate of 3%, with up to 17% of patients developing life-threatening complications, including acute renal failure, myocarditis, disseminated intravascular coagulopathy, and adult respiratory distress syndrome.3-5 HME and HGA may be more severe infections in patients who are immunocompromised, including those with advanced human immunodeficiency virus, malignancy, or advanced age, those who are asplenic, and those receiving immunosuppressive agents.3 HME can manifest as a multisystem disease resembling toxic shock or Rocky Mountain spotted fever, except for the infrequent occurrence of rash. Fever is an almost universal symptom followed by headache, myalgias, and arthralgias. A rash, which may be present in approximately 10% to up to 30% of cases, typically occurs 5 days after the onset of symptoms and can be maculopapular, petechial, or diffuse erythroderma, typically sparing the palms and soles. Gastrointestinal symptoms, including nausea, vomiting, and diarrhea, are sometimes present.3,4 Neurologic symptoms, including meningitis and meningoencephalitis, have been reported in approximately 20% of patients with HME. In some cases, seizures and coma have been reported.16
HGA HGA generally tends to be a less severe illness than HME, although life-threatening complications can occur, including hemodynamic collapse and respiratory failure. The case-fatality rate has been reported to be about 0.6% with a hospitalization rate of 36%.3,5 HGA resembles HME with respect to the frequency of fever, headache, and myalgia; however, rash is uncommon, present in less than 10% of infected patients.3,4 Central nervous system involvement is also less common compared to HME with meningitis reported in approximately 1% of cases. In contrast, peripheral nerve involvement has been more frequently described, including brachial plexopathy, polyneuropathy, and cranial nerve palsies, including bilateral facial nerve palsy3,4,17 (Table 1).
Diagnosis HME and HGA Laboratory findings in HME and HGA are generally nonspecific, often characterized by leukopenia (50%), and thrombocytopenia (94%). Ele350
DM, June 2012
TABLE 1. Comparison of clinical characteristics of HME and HGA Tick-Borne Illness Cell preferentially infected Presence of rash Morulae visible on peripheral blood smear Treatment Case fatality
Human Monocytic Ehrlichiosis
Human Granulocytic Anaplasmosis
Monocyte 60% children ⬍30% adults 20%
Granulocyte Generally not present 80%
Doxycycline
Doxycycline 0.6%
1.9%
vated liver-associated enzymes may be seen in over 90% of cases.3,4,12,17 In patients with HME who have neurologic symptoms and undergo lumbar puncture, a cerebrospinal fluid pleocytosis (cerebrospinal fluid ⬍100 cells/mm3) is identified in approximately 60% with a lymphocytic predominance in most instances, although a neutrophilic predominance may also be seen.16 Because of the limited availability of rapid diagnostic testing like PCR testing and the absence of antibodies at the time of presentation, diagnosis often rests on clinical signs, symptoms, and disease occurring in an endemic region with seasonality. Treatment should not be delayed while waiting for diagnostic test results.3,4 Confirmatory assays should be used retrospectively to validate the accuracy of diagnosis. A review of a Wright- or Giemsa-stained peripheral blood smear may provide early diagnosis. Although this method is rapid, it is relatively insensitive compared to other diagnostic tests and should be performed by an experienced microscopist. Its highest sensitivity is during the first week of illness when morulae may be seen in monocytes in 1% to 20% of patients with HME; however, it may be more useful in HGA where 20% to 80% of patients may have morulae detected in neutrophils3,18 (Figs 3 and 4). Serology has long been relied on for diagnosis. Indirect immunofluorescence antibody assay is used most but there is no standardized definition of positivity. Antibody levels only begin to rise after the clinical illness is established so serology may be negative during the first week of illness. Sensitivity of the immunofluorescence antibody is 94% to 100% 14 days after onset of illness. Testing of 2 sequential serum samples taken at least 2 to 3 weeks apart to examine for a 4-fold or greater rise in antibody titers is recommended.3,4,12,17,18 Diagnosis of ehrlichial infections by PCR, when available, is becoming the test of choice for confirming HME and HGA infection because of its specificity (60%-85%) and sensitivity (60%-85%) for E. chaffeenis and 67% to 90% for A. phagocytophilum. PCR is becoming more widely DM, June 2012
351
FIG 3. Morulae within a monocyte. (Reprinted with permission from Centers for Disease Control and Prevention. Morulae detected in a monocyte on a peripheral blood smear, associated with E. chaffeensis infection. Available at: http://www.cdc.gov/Ehrlichiosis/symptoms/index.html. Accessed February 17, 2012). (Color version of figure is available online.).
commercially available.3,4,19 It is particularly important for detection of infection at early stages when antibody levels are very low or undetectable. A negative PCR does not rule out the diagnosis. Treatment with antimicrobials will decrease sensitivity of PCR amplification. Isolation of these organisms through cell culture is labor-intensive, more timeconsuming than other diagnostic testing, and rarely used.3
Treatment The drug of choice for both HME and HGA in adults as well as in children is doxycycline.3 Therapy is most effective when started early in the disease course and should be initiated when diagnosis is suspected. Therapy should never be delayed while awaiting diagnostic workup. The adult dose of doxycycline is 100 mg orally every 12 hours and the dose for children under 45 kg is 2.2 mg/kg orally every 12 hours for 7-14 days and for 3 days after fever resolves. Some advocate treating longer if central nervous system involvement is present. In children, the usual dose and duration of doxycycline for treatment of HGA or HME does not cause tooth discoloration. Doxycycline is highly efficacious, and posttherapy relapse has not been reported. There is generally a rapid response to treatment with a marked clinical improvement within 24 to 48 hours. A lack of this response should prompt consideration for an alternative diagnosis. In those with HGA who do not respond to doxycycline, infection with Babesia should be considered.3 352
DM, June 2012
FIG 4. Morulae within a granulocyte. (Reprinted with permission from Centers for Disease Control and Prevention. Morulae detected in a granulocyte on a peripheral blood smear, associated with A. phagocytophilium infection. Available at: http://www.cdc.gov/anaplasmosis/symptoms/ index.html. Accessed February 20, 2012). (Color version of figure is available online.)
Guidelines do not exist for treatment of HGA or HME in pregnancy; however, if the disease is life-threatening, therapy with doxycycline may be warranted.3,9 A possible alternative for patients with a doxycycline allergy or with mild disease during pregnancy is rifampin.3,9 Other antibiotics, such as quinolones, cephalosporins, penicillins, and macrolides, are ineffective.3,12 There is some evidence that the use of sulfonamides may worsen the disease course.20 Prophylaxis is not recommended after a tick bite, even in endemic regions. Preventive measures include tick avoidance, early removal of attached ticks, and use of insecticides and are discussed in depth elsewhere in this monograph.3
REFERENCES 1. 2. 3.
Schneider JG. Human ehrlichiosis: a case study. Clin Lab Sci 2009;22(1):3-8. Fishbein DB, Sawyer LA, Holland CJ, et al. Unexplained febrile illnesses after exposure to ticks. Infection with an Ehrlichia? JAMA 1987;257(22):3100-4. Center for Disease Control. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis—United States. MMWR Morb Mortal Wkly Rep 2006;55(RR04):1-27.
DM, June 2012
353
4. 5.
6.
7. 8.
9.
10.
11. 12. 13. 14.
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