Ehrlichiosis and Anaplasmosis

Ehrlichiosis and anaplasmosis are tick-borne bacterial infections. The most common causative species include Ehrlichia chaffeensis and Anaplasma phagocytophilum, which infect and multiply within monocytes and granulocytes, respectively. The clinical presentation can vary widely, but often includes fever, malaise, headache, myalgia, and arthralgias. A maculopapular or petechial rash occurs in some patients. Gastrointestinal, neurologic, and respiratory symptoms are also possible. The diagnosis is based on clinical suspicion and confirmed PCR or antibody testing. Management is with doxycycline.

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General Characteristics

Basic features of Ehrlichia and Anaplasma

  • Gram negative
  • Obligate intracellular bacteria
  • Coccobacilli
  • Grow in membrane-bound vacuoles in leukocytes, particularly:
    • Monocytes
    • Granulocytes 
  • Light microscopy:
    • Individual organisms are difficult to appreciate.
    • Frequently visualized as morulae (microcolony of organisms within a vacuole)
    • Stains: 
      • Wright
      • Giemsa

Microscopic images of Giemsa-stained cells infected with anaplasmosis:
Cell nuclei are labeled “N” and the arrows point to Anaplasma morulae.

Image: “Giemsa stained cells infected with Ap.” by University of Minnesota, Department of Entomology, Saint Paul, Minnesota 55108, USA. License: CC BY 2.0

Clinically relevant species

The most notable species are:

  • Ehrlichia chaffeensis human monocytic ehrlichiosis (HME)
  • Anaplasma phagocytophilum → human granulocytic anaplasmosis (HGA)

Rare causes of ehrlichiosis in humans:

  • E. ewingii
  • E. muris eauclairensis

Epidemiology and Risk Factors

Epidemiology

  • Incidence in the United States:
    • HME: 3.2 cases per million per year
    • HGA: 6.3 cases per million per year
  • Endemic areas in the United States:
    • HME:
      • Southeast
      • South Central
    • HGA:
      • Northeast
      • Upper Midwest and Great Lakes
  • Endemic areas outside the United States:
    • Europe
    • Southeast Asia
    • South America
  • Incidence is higher in men than women.
  • Commonly occurs between April and September

Risk factors

For ehrlichiosis/anaplasmosis:

  • Travel to or living in an endemic area
  • Owning pets
  • Participating in outdoor activities in wooded areas:
    • Camping
    • Hiking
    • Hunting

For severe disease:

  • Immunosuppression:
    • HIV infection
    • Chemotherapy
    • Organ transplant
  • The elderly and young children

Pathogenesis

Transmission

  • Tick vectors:
    • E. chaffeensis is transmitted by Amblyomma americanum (Lone Star tick).
    • A. phagocytophilum is transmitted by Ixodes ticks.
  • Iatrogenic (rare):
    • Blood transfusion 
    • Solid organ transplantation

Reservoirs

A wide range of wild and domestic animals can serve as reservoirs. The most notable are:

  • White-tailed deer (E. chaffeensis)
  • White-footed mice (A. phagocytophilum)

Virulence factors

  • Surface proteins:
    • Allow binding to host cells for entry
    • Antigenic variation helps with evading a host’s immune system.
  • Bacterial effector proteins:
    • Translocate into a host cell
    • Modify the cell’s cytoskeleton to allow bacterial entry
    • Allow bacteria-containing vacuoles to avoid lysosome fusion
    • Alter gene expression in the host cell nucleus

Pathophysiology

Human monocytic ehrlichiosis:

  • E. chaffeensis is introduced into the skin during a tick bite.
  • Infects monocytes and macrophages
  • Spreads through the lymphatics or blood to:
    • Bone marrow
    • Liver
    • Lymph nodes
    • Spleen
  • The clinical presentation is due to the effects of the host’s inflammatory response.

Human granulocytic anaplasmosis:

  • A. phagocytophilum is introduced into the skin during a tick bite → neutrophil recruitment 
  • A. phagocytophilum enters neutrophils:
    • Alters intracellular killing
    • Induces neutrophil activation and cytokine release → contributes to tissue injury and clinical manifestations
  • Infection spreads hematogenously.

Clinical Presentation

Signs and symptoms

The incubation period is typically 1–2 weeks, and the clinical presentation can vary greatly.

Features of both HME and HGA:

  • Nonspecific symptoms: 
    • Fever 
    • Malaise 
    • Headache 
    • Myalgia
    • Arthralgia
  • GI symptoms: 
    • Abdominal pain 
    • Nausea
    • Vomiting
    • Diarrhea
  • Respiratory symptoms: 
    • Cough
    • Shortness of breath

Findings more commonly seen in HME:

  • Rash:
    • Macular, maculopapular, or petechial
    • More common in children
  • Neurological symptoms:
    • Change in mental status 
    • Neck stiffness
    • Clonus
    • Meningoencephalitis

Complications

  • Seizures
  • ARDS
  • Myocarditis and heart failure
  • Pericardial effusion and tamponade
  • Renal failure
  • Coagulopathy
  • Septic shock
  • Hemophagocytic lymphohistiocytosis (rare, severe complication of HGA)

Diagnosis and Management

Diagnosis

Definitive studies:

  • Indirect fluorescent antibody testing
  • ELISA antibody testing
  • PCR to detect organism DNA
  • Buffy coat or peripheral blood smear examination: Intracytoplasmic morulae are seen in peripheral blood leukocytes.

Supporting laboratory studies:

  • Thrombocytopenia
  • Leukopenia
  • Anemia
  • ↑ AST and ALT
  • ↑ Alkaline phosphatase
  • ↑ Lactate dehydrogenase
  • ↑ Creatinine

Peripheral blood smear evaluations for ehrlichiosis and anaplasmosis:
These blood smears show intracellular morulae of A. phagocytophilum (1) and E. chaffeensis (2).

Image: “Etiologic agents of ehrlichioses” by CDC/NCID. License: Public Domain

Management

Doxycycline is the antibiotic of choice.

  • Treatment should be initiated in patients with suspected HME or HGA while laboratory testing is pending.
  • If patients do not improve with therapy, they should be evaluated for a concurrent Babesia infection.

Prevention

Avoiding tick bites is key to preventing these diseases.

  • Wearing appropriate protective clothing
  • Using tick repellents
  • Inspecting for ticks after outdoor activity
  • Removing any attached ticks to reduce the risk of infection
  • Tick control on domestic animals
  • Doxycycline prophylaxis after a tick bite is not recommended.

Comparison of Gram-negative Tick-borne Bacteria

Table: Comparison of several clinically relevant gram-negative tick-borne bacteria
OrganismEhrlichia chaffeensisAnaplasma phagocytophilumRickettsia rickettsiiBorrelia burgdorferi
DiseaseHMEHGARocky Mountain spotted feverLyme disease
Micro
  • Obligate intracellular
  • Coccobacilli
  • Obligate intracellular
  • Coccobacilli
  • Obligate intracellular
  • Pleomorphic
  • Poor Gram staining
  • Microaerophilic
  • Spirochete
  • Difficult to visualize on Gram stain
VectorLone Star tickIxodes tickDermacentor tickIxodes tick
ReservoirWhite-tailed deerWhite-footed mouseDermacentor tick
  • Rodents
  • Deer
Geographical distribution in the United StatesSoutheast and South Central statesNortheast and upper Midwest statesSoutheast and South Central statesNortheast and Midwest states
Diagnosis
  • PCR
  • ELISA
  • Immunofluorescent antibody (IFA)
  • Blood smear
  • PCR
  • ELISA
  • IFA
  • Blood smear
  • Clinical
  • Skin biopsy
  • IFA
  • PCR
  • Clinical
  • ELISA
  • Western blot
ManagementDoxycycline
  • Doxycycline
  • Amoxicillin
  • Ceftriaxone

IFA: immunofluorescent antibody

Differential Diagnosis

  • Babesiosis: a tick-borne infection caused by Babesia. Patients can be asymptomatic or develop fever, fatigue, malaise, and arthralgias. Asplenic, immunocompromised, and elderly patients are at risk for severe disease, causing hemolytic anemia, thrombocytopenia, hepatosplenomegaly, renal failure, and death. Diagnosis is confirmed with a peripheral blood smear, serologic testing, and PCR. Management includes antimicrobials such as atovaquone plus azithromycin.
  • Rocky Mountain spotted fever: a disease caused by Rickettsia rickettsii that presents with fever, fatigue, headache, and a rash following a tick bite. However, this disease is associated with the Dermacentor tick, and the rash presents more frequently than in HME or HGA. Diagnosis is made based on the clinical features, biopsy of the rash, and serologic testing. Management involves antibiotics, including doxycycline.
  • Viral hepatitis: liver inflammation caused by an infection with the hepatitis virus. Patients may present with a viral prodrome of fever, anorexia, and nausea. Right upper quadrant abdominal pain, jaundice, and transaminitis also occur. The diagnosis is made with viral serologic testing and will differentiate hepatitis from HME or HGA. Management of acute hepatitis is supportive.
  • Mononucleosis: a disease caused by the Epstein-Barr virus that is characterized by fever, fatigue, lymphadenopathy, and pharyngitis. These latter 2 features are less commonly seen in HME or HGA. Diagnosis is based on clinical features and testing, such as a heterophile antibody test or serology. Management is supportive. 
  • Lyme disease: an infection caused by B. burgdorferi, which is transmitted by the Ixodes tick. Presentation depends on the stage of the disease and may include a characteristic erythema migrans rash. Neurological, cardiac, ocular, and joint manifestations are also common in later stages. Diagnosis relies on clinical findings and tick exposure and is supported by serological testing. Antibiotics are used for treatment. 
  • Brucellosis: an infection caused by Brucella, which spreads predominantly after the ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Diagnosis is based on clinical manifestations, exposure history, serology, and culture studies. Management involves a combination of antibiotics, including doxycycline, rifampin, and aminoglycosides.

References

  1. Summary of notifiable diseases–United States, 2010. (2010). Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2012;59(53):1. https://pubmed.ncbi.nlm.nih.gov/22647710/
  2. Everett ED, Evans KA, Henry RB, McDonald G. Human ehrlichiosis in adults after tick exposure. Diagnosis using polymerase chain reaction. (1994). Ann Intern Med. https://pubmed.ncbi.nlm.nih.gov/8147545/
  3. Dawson JE, Fishbein DB, Eng TR, Redus MA, Green NR. Diagnosis of human ehrlichiosis with the indirect fluorescent antibody test: kinetics and specificity. (1990). https://pubmed.ncbi.nlm.nih.gov/2192013/
  4. Dumler JS, Dawson JE, Walker DH. Human ehrlichiosis: hematopathology and immunohistologic detection of Ehrli Humchia chaffeensis. (1993). Hum Pathol. https://pubmed.ncbi.nlm.nih.gov/8491479/
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  6. Guzman, N., Naga, S., Yarrarapu, S., and Beidas, S.O. (2021). Anaplasma phagocytophilum. [online] StatPearls. Retrieved March 18, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK513341/
  7. Petri, W.A. (2020). Ehrlichiosis and anaplasmosis. [online] MSD Manual Professional Version. Retrieved March 18, 2021, from https://www.msdmanuals.com/professional/infectious-diseases/rickettsiae-and-related-organisms/ehrlichiosis-and-anaplasmosis
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  9. Sexton, D.J., and McClain, M.T. (2020). Human ehrlichiosis and anaplasmosis. In Mitty, J. (Ed.), UpToDate. Retrieved March 18, 2021, from https://www.uptodate.com/contents/human-ehrlichiosis-and-anaplasmosis
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