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Ehrlichiosis

Last Updated: August 25, 2006
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Synonyms and related keywords: ehrlichiosis, "spotless" Rocky Mountain spotted fever, Ehrlichia, Ehrlichia chaffeensis, (human monocytic ehrlichiosis, HME), Anaplasmosis phagocytophilium, (human granulocytic anaplasmosis, HGA), Ehrlichia ewingii (human granulocytic ehrlichiosis, HGE)

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Author: Burke A Cunha, MD, MACP, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD, MACP, is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Editor(s): Thomas J Marrie, MD, Chair, Professor, Department of Medicine, Division of Infectious Diseases, University of Alberta College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael Stuart Bronze, MD, Chairman, Professor, Department of Medicine, University of Oklahoma Health Science Center; Eleftherios Mylonakis, MD, PhD, Assistant Professor of Medicine, Harvard Medical School, Assistant in Medicine, Division of Infectious Disease, Massachusetts General Hospital; and Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice

Disclosure


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Background: Ehrlichiosis is an infection of white blood cells that affects various mammals, including mice, cattle, dogs, deer, horses, sheep, goats, and humans.

Ehrlichia are obligate, intracytoplasmic bacteria that infect mononuclear cells and granulocytes. Ehrlichia resemble Rickettsia and are tiny gram-negative organisms (0.2-2.0 mm) that divide by binary fission and multiply within the cytoplasm of infected white cells. Clusters of Ehrlichia multiply in host cell vacuoles to form large aggregates that are mulberry shaped and called morulae.

Ehrlichia inclusion bodies, such as morulae, are visible in the cytoplasm of infected mononuclear phagocytic cells after 5-7 days. The varieties of ehrlichiosis that infect humans include Ehrlichia chaffeensis (human monocytic ehrlichiosis [HME]), Anaplasma phagocytophilum (human granulocytic anaplasmosis [HGA]), and Ehrlichia ewingii (human granulocytic ehrlichiosis [HGE]), which primarily infects human monocytes and/or macrophages. The Ehrlichia equi/E equi cluster usually infects human granulocytes and is the agent of HGE. Ehrlichia species that infect human monocytes are referred to as HME. Ehrlichia and Anaplasma species that infect granulocytes are called HGE or HGA.

The clinical manifestations of HGE, HGA, and HME are the same. Therefore, ehrlichiosis refers to infection due to HGA, HGE, or HME.

Pathophysiology: The pathophysiology of ehrlichiosis is not completely understood. Like Rickettsia, Ehrlichia gain access to the blood via a bite from an infected tick. Amblyomma americanum (Lone Star tick) is the principle tick vector of E chaffeensis and is the primary vector of HME. HGE may be transmitted from Ixodes persulcatus ticks and possibly Dermacentor variabilis (dog tick/wood tick).

The major antigenic determinants of Ehrlichia are surface membrane proteins. These antigenic proteins are complex and consist of both thermolabile and thermostable components. In terms of kilodalton (kD) molecular weight, the key protein bands associated with HME are the 27-, 29-, and 44-kD bands. The major antigenic determinants associated with HGE include the 40-, 44-, and 65-kD bands.

Frequency:

  • In the US: The distribution of ehrlichiosis in the United States mirrors the tick distribution and appropriate mammalian vectors, eg, the white-footed mouse, the white-tailed deer. Ehrlichiosis occurs where mammalian hosts are in contact with the appropriate tick vector, ie, A americanum, D variabilis, Ixodes ticks. Hundreds of cases of HME and HGE have been reported, but ehrlichiosis is not a reportable disease; therefore, many more cases exist than are reported.

    Most cases of ehrlichiosis in the United States occur in California, Texas, the Southeast, and the Northeast, with some cases occurring in the north central states west of the Great Lakes.

  • Internationally: Ehrlichiosis occurs essentially worldwide, and the incidence parallels the distribution of the appropriate tick vectors for the transmission of Ehrlichia and the mammalian hosts.

Mortality/Morbidity: The great majority of cases of ehrlichiosis are asymptomatic. Most cases present as mild-to-moderate acute febrile illnesses. In immunocompromised hosts, ehrlichiosis may be severe, manifesting as a Rocky Mountain spotted fever (RMSF)–like illness and may be fatal.

Sex: Males are affected more commonly than females (male-to-female ratio is 4:1).

Age: Ehrlichiosis occurs in all age groups but is most common in young adults.


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History:

  • Patients with ehrlichiosis usually present with severe headache, myalgias, and fever. Shaking chills often are present. Nausea, vomiting, and abdominal pain are uncommon and mild.
  • Patients usually develop clinical manifestations of ehrlichiosis approximately 1 week after a tick bite.

Physical:

  • In contrast to RMSF, rash is rare in ehrlichiosis. When present in ehrlichiosis, the rash is maculopapular and not petechial. Evidence for vasculitis is not observed in ehrlichiosis as it is in RMSF.
  • Physical findings with ehrlichiosis are minimal. Occasionally, slight hepatomegaly may be present.
  • Lymphadenopathy is observed in less than 25% of cases and splenomegaly is not common.
  • Patients with severe ehrlichiosis may develop thrombocytopenia or disseminated intravascular coagulation (DIC), which can result in hemorrhage into the skin.

Causes:

  • Ehrlichia are obligate, intracytoplasmic bacteria that infect mononuclear cells and granulocytes.
  • Ehrlichia resemble Rickettsia and are tiny gram-negative organisms (0.2-2 mm) that divide by binary fission and multiply within the cytoplasm of infected white cells.
  • Clusters of Ehrlichia (called morulae) multiply in the vacuoles of cells, forming large mulberry-shaped aggregates.
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Babesiosis
Malaria
Meningitis
Rocky Mountain Spotted Fever
Typhoid Fever


Other Problems to be Considered:

Ehrlichiosis is a difficult infectious disease to diagnose because it presents as an acute undifferentiated febrile RMSF-like illness with few/no physical findings. The majority of patients previously diagnosed with RMSF without rash, in fact, probably had ehrlichiosis.

Ehrlichiosis has the same distribution as RMSF and is transmitted by the same tick species (eg, Amblyomma, Dermacentor). Both RMSF and ehrlichiosis present as acute, febrile, undifferentiated infectious diseases. RMSF has physical findings that are not present in ehrlichiosis, ie, bilateral periorbital edema, edema of the dorsum of the hands/feet, and conjunctival suffusion. The petechial rash of RMSF is conspicuous by its absence in ehrlichiosis.

Laboratory findings in RMSF and ehrlichiosis are similar (eg, thrombocytopenia, lymphopenia, increased serum transaminases, atypical lymphocytes). However, neutropenia is more common in ehrlichiosis than RMSF.

Because most patients with ehrlichiosis present with fever and a severe headache, meningitis may be in the differential diagnosis in these patients. Patients with ehrlichiosis do not have nuchal rigidity in contrast to patients with aseptic or bacterial meningitis. The cerebral spinal fluid (CSF) profile in patients with ehrlichiosis is normal, in contrast to those patients with viral or bacterial meningitis.

Other diagnostic possibilities include typhoid fever, malaria, and babesiosis. All of these infectious diseases present as acute, undifferentiated, febrile illnesses with a paucity of physical signs. The diagnosis of typhoid fever and malaria are suggested by an appropriate epidemiological/travel history. Exposure to large Dermacentor ticks would suggest RMSF, whereas exposure to small Ixodes ticks would suggest the possibility of babesiosis.

Co-infections of various tick-borne pathogens transmitted by the same vector are uncommon, but they do occur.
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Babesiosis

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Lab Studies:

  • The diagnosis of HME, HGA, or HGE rests on a single elevated immunoglobulin G (IgG) immunofluorescent antibody (IFA) Ehrlichia titer or by demonstrating a 4-fold or greater increase between acute and convalescent IFA Ehrlichia titers.
  • The diagnosis of ehrlichiosis also may be made by demonstrating characteristic morulae in the cytoplasm of leukocytes. Morulae are diagnostic of ehrlichiosis and occur more frequently in HGE than HME.
  • The microbiology laboratory should be alerted to look carefully in the blood smear for cytoplasmic inclusions (morulae), which, if found, are diagnostic of ehrlichiosis.
  • Nonspecific laboratory tests in patients with acute febrile illnesses may suggest a variety of tick-borne infectious diseases, including ehrlichiosis.
  • A complete blood count (CBC) should be obtained for possible neutropenia, lymphocytopenia, or thrombocytopenia. Anemia is not a usual feature of ehrlichiosis and, if present, is not a hemolytic anemia as in babesiosis.
  • Atypical lymphocytes have been reported in patients with ehrlichiosis. The erythrocyte sedimentation rate (ESR) is variably elevated in ehrlichiosis.
  • Serum transaminases should be obtained because they frequently are mildly elevated in ehrlichiosis as well as in other tick-borne transmitted infectious diseases.
  • For patients who present with a cutaneous bleeding diathesis, DIC may be diagnosed if thrombocytopenia is present and schistocytes are observed in the peripheral smear.
  • If other infectious diseases are suspected, appropriate tests should be ordered to rule out these diagnoses. If co-infection with RMSF or babesiosis is suspected, then appropriate serology should be ordered to diagnose each of these infectious diseases.

Other Tests:

  • Lumbar puncture (LP) may be necessary in patients with fever and severe headache to rule out meningitis.
Histologic Findings: The method of attachment of Ehrlichia to white cells is not understood, but, after intracellular multiplication in mononuclear phagocytic cells, the cells burst, releasing ehrlichial cells into the circulation and infecting other white blood cells.

Ehrlichia are obligate, intracytoplasmic bacteria that infect mononuclear cells and granulocytes. Ehrlichia resemble Rickettsia and are tiny gram-negative organisms (0.2-2 mm) that divide by binary fission and multiply within the cytoplasm of infected white cells. Clusters of Ehrlichia multiplying in the phagolysosomal vacuole of cells form large aggregates that are mulberry shaped and are called morulae. Ehrlichia inclusion bodies (morulae) are visible in the cytoplasm of infected mononuclear phagocytic cells after 5-7 days.

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Medical Care:

Consultations:

Diet:

Activity:


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The preferred drug for HME and HGE is doxycycline. In contrast to RMSF, chloramphenicol is not effective in ehrlichiosis. Although experience is limited, in vivo data suggest that rifampin may be useful in patients unable to take doxycycline (eg, children <8 y, pregnant females). Fluoroquinolones may be useful against Ehrlichia, but experience is limited.

Drug Category: Antibiotics -- Empiric antimicrobial therapy should cover the most likely pathogens in the context of the clinical setting.
Drug Name
Doxycycline (Vibramycin) -- Second-generation tetracycline. More active than tetracycline against many pathogens. Different adverse effect profile and pharmacokinetics compared to tetracycline. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Adult Dose100-200 mg IV/PO q12h
Pediatric Dose<8 years: Not recommended
>8 years: Administer as in adults
ContraindicationsDocumented hypersensitivity; severe hepatic dysfunction
InteractionsBioavailability minimally decreased with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate
Pregnancy D - Unsafe in pregnancy
PrecautionsPhotosensitivity may occur rarely; tetracycline use during tooth development (last one-half of pregnancy through age 8 y) can cause permanent discoloration of teeth
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Deterrence/Prevention:

Prognosis:

Patient Education:

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Medical/Legal Pitfalls:

  • Clinicians should remember that doxycycline is the preferred antimicrobial agent for all treatable tick-borne infectious diseases.
  • Avoid using chloramphenicol in patients with possible ehrlichiosis because it is ineffective in HME and in HGE.
  BIBLIOGRAPHY Section 10 of 10   Click here to go to the previous section in this topic Click here to go to the top of this page
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