Ehrlichiosis

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Ehrlichiosis is a tickborne,^[1] bacterial infection,^[2] caused by bacteria of the family Anaplasmataceae, genera Ehrlichia and Anaplasma. These obligate intracellular bacteria infect and kill white blood cells. Ehrlichiae are transmitted to humans by the bite of an infected tick. Usually, symptoms occur within 1-2 weeks following a tick bite. ^[3]

Ehrlichiosis was first observed in the 19th century by the German microbiologist, Paul Ehrlich. Originally it was classified under the genus Rickettsia, however further observation led to a reclassification of the bacteria as a separate genus, Ehrlichia. The first Ehrlichia based infection was reported in South Africa in 1900. In the 1980’s, Ehrlichiosis was recognized as a disease present in the United States. By 1999, Ehrlichia became a disease reportable to the Centers for Disease Control and Prevention.

Three strains of Ehrlichia (E. ewingii, E. chaffeensis, and E. Muris) are responsible for human infection. These resulting infections present themselves with very similar, if not the same, clinical manifestations. Endemic regions are different among the different diseases which may be used to diagnose the organism of infection.^[4]

The pathophysiological process of ehrlichiosis begins with the inoculation of the disease from a tick vector. Following inoculation ehrlichiae and anaplasmosis enter the circulatory system in an attempt to infect a target cell. The infectious agents will then enter the cell via a receptor-mediated endocytosis. This particular endocytosis process is facilitated by a glycophoshoinositol anchored receptor. Both the Ehrlichiae and Anaplasma complete their reproduction process within the host cell’s endosome.Infectious agents of both disease are then able to reprogram a host cell’s defense mechanisms in order to silently proliferate.

Ehrlichiosis must be differentiated from other diseases that cause fever, chills, headaches, body ache, and rash. When trying to differentiate Ehrlichiosis from other infections, it is important to recognize that the clinical manifestations of Ehrlichiosis greatly resemble those of other tick-borne illnesses, especially those caused by the Rickettsiae family. Examples of misdiagnoses, with the umbrella of tick-borne diseases include typhus-spotted fevers and Colorado tick fever.

Ehrlichiosis was deemed a reportable disease by the United States Center for Disease Control and Prevention in 1999. Since the year 2000 the number of reported cases has increased from 200 (in 2000) to 961 in 2008. However it should be noted that amount of reported cases was lessened in 2010. The majority of cases are currently reported in Oklahoma, Missouri, and Arkansas. Other endemic areas include the South central and Southeastern United States. Incidents are highest among males and adults between the ages of 60 to 64 years of age. Cases have also been reported at higher rates among individuals with compromised immune systems.

The primary risk factors associated with Ehrlichiosis are exposure to endemic environment and the time of that exposure. Lone Star ticks have been identified as the primary vector of E. ewingii and E. chaffeensis infections, thus being bitten in an endemic area may result in the contraction of the disease. (The primary vector of E. muris has not yet been verified.)^[4]

The prognosis is usually good for human granulocytotropic anaplasmosis (HGA). Individuals suffering from HGA should fully recover without treatment in 2 months. However, proper treatment of HGA will expedite the recovery process. Symptoms that are commonly associated with HGA include sudden onset of fever and intense pains. Progression of the disease may lead to serious complications including neurological disorders and ARDS. Co-infection remains the greatest threat associated with death as a result of HGA. Thus individuals with compromised immune systems or the elderly should be closely monitored in order to reduce the likelihood of an opportunistic infection. Human monocytotropic ehrlichiosis (HME) presents a very different scenario than that of HGA. HME is far more dangerous as well as deadly. An incubation period of 7-10 days will often follow an infected tick bite. Initial symptoms include fever, headache, and malaise. Further complications will follow the onset of infection, these complications may prove to be extremely dangerous and should be closely monitored for the patients safety.

Clinical manifestations will present themselves differently depending on the infectious agent. HME will display far more severe symptoms than HGE, and thus requires immediate and more closely monitored medical attention. However both have overlapping symptoms including fever, headache, and nausea.

Patients with Ehrlichiosis will often display a fever and myalgia, along with heightened blood pressure and an increase heart rate. Some populations of patients have displayed a mauculopapular rash which is often indicative of an HME infection. It is important for the physician to differentiate between different Ehrlichiosis infection agents since certain strains of Ehrlichiae result in a higher degree of infection severity.

There are three primary laboratory methods to diagnose an ehrlichiosis infection, polymerase chain reaction (PCR), peripheral blood smear, and an immunofluorescence assay (IFA). Polymerase chain reaction and peripheral blood smear exams are most effective when conducted early on in the diagnoses. The gold standard serologic test for ehrlichiosis is the immunofluorescence assay. The test is most effective when conducted once early on in the infection and a second time, later in the infection. Infection rates will show in increase within an IFA as the illness progresses. ^[5]

A chest x-ray may be helpful in the diagnosis of ehrlichiosis. Findings on a chest x-ray indicating acute respiratory distress syndrome may be suggestive of an ehrlichiosis infection.

There are no further diagnostic studies associated with Rocky Mountain spotted fever.

The mainstay of therapy in ehrlichiosis is antimicrobial therapy. Doxycycline is the drug of choice to treat ehrlichiosis.^[6]

Ehrlichiosis prevention strategies are based on avoiding potential, infected, tick bites. Avoiding tick bites may be accomplished through limited exposure to endemic areas. However if it is impossible or impractical to avoid these areas, several preventative strategies may be implemented. These strategies are indicated within the Prevention microchapter. Other prevention strategies include a proper removal of the tick. This process is also outlined under the title, the best way to remove a tick, within the ehrlichiosis, prevention, microchapter.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Ehrlichiosis was first observed in the 19th century by the German microbiologist, Paul Ehrlich. Originally it was classified under the genus Rickettsia, however further observation led to a reclassification of the bacteria as a separate genus, Ehrlichia. The first Ehrlichia based infection was reported in South Africa in 1900. In the 1980’s, Ehrlichiosis was recognized as a disease present in the United States. By 1999, Ehrlichia became a disease reportable to the Centers for Disease Control and Prevention.

Early History

• Paul Ehrlich is the German microbiologist credited with the discovery of Ehrlichia, the microbiological agent responsible for Ehrlichiosis.
• In the 19th century, the first case of an Ehrlichial based disease was discovered in South Africa.
• Ehrlichiosis was established as a tick-borne disease in the early 1900’s.
• Originally the organism was classified under the genus Rickettsia, termed Rickettsia ruminatum.
• Later it was classified under the genus Ehrlichia.
• In 1991, Dr. Aileen Marty of the AFIP was able to demonstrate the bacteria in human tissues using standard stains, and later proved that the organisms were indeed Ehrlichia using immunoperoxidase stains. ^[1][2]

Recent History

• In the 1980’s, Ehrlichiosis was first recognized as a disease present in the United States.
• In 1999, Ehrlichiosis was considered a reportable disease to the Centers for Disease Control and Prevention.
• In 2008, human infection by Panola Mountain (Georgia, USA) Ehrlichia species was reported.^[3]

• On August 3, 2011, infection by a yet-unnamed bacterium in the genus Ehrlichia carried by deer ticks that has caused flu-like symptoms in at least 25 people in Minnesota and Wisconsin was reported; human ehrlichiosis was thought to be very rare or absent in Minnesota and Wisconsin.^[2] The new species, which is very similar genetically to an Ehrlichia species found in Eastern Europe and Japan called E. muris, was identified at Mayo Clinic Health System’s Eau Claire hospital.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Four species (E. ewingii, E. chaffeensis, E. Muris, and A. phagocytophilum) are responsible for human ehrlichiosis infections. ehrlichiosis infections present themselves with very similar, if not the same, clinical manifestations. Differences may be highlighted in the heightened fatality rate and neurological based clinical manifestations of HME versus other types of ehrlichiosis. Endemic regions are different among the different diseases which may be used to diagnose the organism of infection.^[1]

• Ehrlichiosis is a broadly used medical term for multiple bacterial infections.
• Four species have been identified in human ehrlichiosis infections (each disease is associated with a specific bacterial strain):

1. Ehrlichia ewingii
2. Ehrlichia chaffeensis
3. Ehrlichia muris^[2]
4. Anaplasma phagocytophilum

• Infections with the above organism have similar or the same clinical presentation.
• HME however has proven to be more fatal than other Ehrlichia infections, including CNS and neurological disorders inflicting nearly 20% of all infected patients.

^[1][3][2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

The pathophysiological process of ehrlichiosis begins with the inoculation of the disease from a tick vector. Following inoculation ehrlichiae and anaplasmosis enter the circulatory system in an attempt to infect a target cell. The infectious agents will then enter the cell via a receptor-mediated endocytosis. This particular endocytosis process is facilitated by a glycophoshoinositol anchored receptor. Both the ehrlichiae and anaplasma complete their reproduction process within the host cell’s endosome. Infectious agents of both disease are then able to reprogram a host cell’s defense mechanisms in order to silently proliferate.

• E. chaffeensis enter into the mononuclear phagocytes.
• Phagolysosome fusion is inhibited while host genes are suppressed and induced to enable intracellular replication.
• Cytokines IL-12 and IL-18 are downregulated in THP-1 cells.
• Genes that are responsible for upregulation of apoptosis such as SNAP 23, Rab5A and STX16 are downregulated in correlation to the downregulation of IL-12 and IL-18.
• E. chaffeensis secretes an immunoreactive ankyrin protein (200kDa) into the host’s nucleus in an attempt to manipulate the gene regulation of the host cell.
• Other methods of E. chaffeensis include inhibiting the signal transduction pathway and circumventing host cell defense mechanisms.
• Organ failure and other pathogenic manifestations resulting in complications or death is a result of immune mediated pathology.

• A.phagocytophilum successfully resides within the host cells (PMN cells) cytoplasmic vacuoles.
• Apoptosis is suppressed due to the upregulation of bfl-1 and inhibiting anti-FAS. Both of which are responsible for inducing apoptosis within neutrophils.
• Host cell gene transcription is controlled through a secreted protein, AnkA, that travels into the host cell’s nucleus.
• Research into the pathogensis of HGA has also shown upregulation of pro-inflammatory and IL-8 chemokines.
• The pathogenesis of HGA causes immunosuppression and thus fatality may be attributed to opportunistic pathogens.

• Ehrlichia are transported between cells through the host cell filopodia during initial stages of infection, whereas, in the final stages of infection the pathogen ruptures the host cell membrane.^[1]
• Most of the symptoms of ehrlichiosis can likely be ascribed to the immune dysfunction that it causes.
• Early in infection, production of TNF-alpha, a cellular product that promotes inflammation and immune response, is suppressed.
• Experiments in mouse models further supports this hypothesis, as mice lacking TNF-alpha I/II receptors are resistant to liver injury caused by ehrlichia infection.
• Late in infection, however, production of this substance can be upregulated by 30 fold, which is likely responsible for the “toxic shock-like” syndrome seen in some severe cases of ehrlichiosis.^[2]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Ehrlichiosis is a tickborne^[1] bacterial infection,^[2] caused by bacteria of the family Anaplasmataceae, genera Ehrlichia and Anaplasma. These obligate intracellular bacteria infect and kill the white blood cells. Ehrlichiae are transmitted to humans by the bite of an infected tick. Usually, symptoms occur within 1-2 weeks following a tick bite. ^[3]

• Small intracellular bacteria
• Infect vacuoles of host eukaryotic cells
• Gram-negative cell wall
• Grow within a host cells endosomes in morulae clusters
• Manipulate the endosomes mechanical function in order to resist lysosomal fusion
• Ehrlichiae exits the cell as morulae attaches to cell wall
• Target cells include neutrophils, platelets, erythrocytes, and endothelium

• A tick’s life cycle is composed of four stages: hatching (egg), nymph (six legged), nymph (eight legged), and an adult.
• Ticks require blood meal to survive through their life cycle.
• Hosts for tick blood meals include mammals, birds, reptiles, and amphibians. Ticks will most likely transfer between different hosts during the different stages of their life cycle.
• Humans are most often targeted during the nymph and adult stages of the life cycle.
• Life cycle is also dependent on seasonal variation.
• Ticks will go from eggs to larva during the summer months, infecting bird or rodent host during the larval stage.
• Larva will infect the host from the summer until the following spring, at which point they will progress into the nymph stage.
• During the nymph stage, a tick will most likely seek a mammal host (including humans).
• A nymph will remain with the selected host until the following fall at which point it will progress into an adult.
• As an adult, a tick will feed on a mammalian host. However unlike previous stages, ticks will prefer larger mammals over rodents.
• The average tick life cycle requires three years for completion.
• Different species will undergo certain variations within their individual life cycles.

• Ehrlichia are transported between cells through the host cell filopodia during initial stages of infection, whereas, in the final stages of infection the pathogen ruptures the host cell membrane.^[7]
• Most of the symptoms of ehrlichiosis can likely be ascribed to the immune dysfunction that it causes.
• Early in infection, production of TNF-alpha, a cellular product that promotes inflammation and immune response, is suppressed.
• Experiments in mouse models further supports this hypothesis, as mice lacking TNF-alpha I/II receptors are resistant to liver injury caused by ehrlichia infection.
• Late in infection, however, production of this substance can be upregulated by 30 fold, which is likely responsible for the “toxic shock-like” syndrome seen in some severe cases of ehrlichiosis.^[8]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

There are four primary illnesses linked to an Ehrlichia infection, they are: Human ehrlichiosis ewingii (HEE), Human Monocytotropic Ehrlichiosis, Ehrlichiosis muris-like (EML), Human Granulocytotropic Anaplasmosis. Although clinical manifestations appear similar, certain characteristics will differ and may be helpful in an accurate differential diagnosis. Ehrlichiosis infections must also be differentiated from other tick-borne diseases that cause fever, chills, headaches, body ache, and rash. When trying to differentiate ehrlichiosis from other infections, it is important to recognize that the clinical manifestations of ehrlichiosis greatly resemble those of other tick-borne illnesses, especially those caused by the Rickettsiae family.

• Differentiating between ehrlichia diseases:

• Examples of tick-borne diseases that may be misdiagnosed for ehrlichiosis may be found in the table below:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Ehrlichiosis was deemed a reportable disease by the United States Center for Disease Control and Prevention in 1999. Since the year 2000 the number of reported cases has increased from 200 (in 2000) to 961 in 2008 with an overall in 2010. The majority of cases are currently reported in Oklahoma, Missouri, and Arkansas. Other endemic areas include the South central and Southeastern United States. Incidence are highest among males and adults between the ages of 60 to 64 years of age. Cases have also been reported at higher rates among individuals with compromised immune systems.

• First recognized as a reportable disease by the United States Center for Disease Control and Prevention in the late 1999.
• Numbers of reported cases have increased from 200 in 2000 to 961 in 2008.
• Incidence has fluctuated between 200-2010:
  • 2000- 1 case per million persons
  • 2008- 3.4 cases per million persons
  • 2010- 2.5 cases per million persons ^[1]

• The lone star tick (Amblyomma americanum) is the primary vector of both Ehrlichia chaffeensis and Ehrlichia ewingii in the United States.
  • E. chaffeensis is most common in the south central and southeastern states.
  • E. ewingii is most common in the south central and southeastern states.
  • A. muris is endemic to Missouri and Wisconsin.

• Ehrlichiosis is most prominent in Oklahoma, Missouri, and Arkansas, accounting for 30% of all national incidences.
• However incidences have been reported through the United States.^[1]

• The highest incidence rate of ehrlichiosis is observed among males and patients above the age of 50 years. (Highest rate of incidence reported among patients between the ages of 60 and 64.^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

The primary risk factors associated with Ehrlichiosis are exposure to an endemic environment and the season of exposure. Lone Star ticks have been identified as the primary vector of E. ewingii and E. chaffeensis infections, thus being bitten in an endemic area may result in the contraction of the disease. (The primary vector of E. muris has not yet been verified.)^[1]

• Individuals with frequent exposure to wooded areas or areas with high grass may be at increased risk of infection.

• The highest incidence rates have been reported in Oklahoma, Missouri, and Arkansas. (Accounting for 30% of all reported cases)
• E.ewingii and E.chaffeensis organisms have been responsible for cases that have been reported in the Southeastern and South central United States
• E.muris is responsible for infections reported in Missouri and Wisconsin.

• Ehrlichiosis may be contracted year-round, however the highest incidence rates have been reported during the months of June and July.^[2]

• Elderly are more prone to infection
• Immuno-compromised patients are more likely to experience severe symptoms or death by an opportunistic pathogen

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ilan Dock, B.S.

Early symptoms that are commonly associated with human granulocytotropic anaplasmosis (HGA) include sudden onset of fever and intense pains. Progression of the disease may lead to serious complications including neurological disorders and ARDS. Co-infection remains the greatest threat associated with death as a result of HGA. Human monocytotropic ehrlichiosis (HME) presents a very different scenario than that of HGA. HME is far more dangerous as well as deadly. An incubation period of 7-10 days will often follow an infected tick bite. Initial symptoms include fever, headache, and malaise. Further complications will follow the onset of infection, these complications may prove to be extremely dangerous and should be closely monitored for the patients safety. Unlike HME, the prognosis is usually good for human granulocytotropic anaplasmosis (HGA). Individuals suffering from HGA should fully recover without treatment in 2 months. However, proper treatment of HGA will expedite the recovery process.

Infection varies according to the Ehrlichiae agent responsible for the infection. Listed below are the progressive pathways of each infection:

• Sudden onset of fever with rigors
• Severe Myalgia
• Early Symptoms such as pain, nausea, vomiting, weight loss, cough, and confusion

• Toxic-like Syndrome
• ARDS
• Neurological disorders
• Liver complications

• Usually achieve a full recovery in 2 months
• Immuno-compromised individuals may suffer severe infections or even death as a result of an opportunistic co-infection.

• Incubation of 7-10 days
• Initial presenting symptoms include fever, headache, and malaise.
• More severe infections will include myalgia, diaphoresis, weight loss, maculopapular rash, and confusion.

• Progression of symptoms requires hospitalization
• Majority of infected patients require intensive care
• Even with medical therapy 2.7% of infected patients die

• HME remains a life-threatening disease
• Without proper treatment patients may suffer from hypotension, respiratory failure, acute renal failure, and hemorrhagic manifestations
• Death

Common complications associated with an ehrlichiosis infection are listed below:

• Respiratory distress syndrome
• Hepatitis
• Seizure
• Candidiasis
• Opportunistic nosocomial infections^[1]
• Death

• The prognosis for HGE is usually good.
• With proper treatment, patients should fully clear infection
• About Half of infected individuals will require 6 days of hospitalization
• Even in the absence of treatment, infected patients should clear infection within 2 months
• Death associated with opportunistic co-infection.

• HME is a severe illness with many complications
• Even in the presence of proper medical therapy, nearly 2.7% of infected patients will die
• Infection must be closely monitored in order to reduce the amount of possible complications