Ehrlichiosis and Anaplasmosis

Ehrlichiosis and anaplasmosis are two closely related diseases, caused by different bacteria. They are tickborne or acquired by humans from the bite of tick that is itself infected with these bacteria. Although both diseases concentrate east of the Rocky Mountains, they usually occur in different areas. Ehrlichiosis, also called human monocytic ehrlichiosis (HME), is found mainly in the mid-Atlantic, southeastern, and south central states. Anaplasmosis (formerly called human granulocytic ehrlichiosis, or HGE) occurs more often in the Northeast and upper Midwest. Ehrlichiosis and anaplasmosis are emerging infectious diseases in the United States and other countries. (Emerging infectious diseases are diseases first described by researchers within the last two decades.) In 2005, 786 cases of anaplasmosis and 506 cases of HME were reported to the Centers for Disease Control and Prevention (CDC). Neither HME nor anaplasmosis were reported from states west of the Continental Divide, though some cases of an unknown ehrlichiosis-like disease were reported in California.



Signs and Symptoms
Symptoms usually begin at least five days after being bitten by an infected tick and can include


 * Fever
 * Chills
 * Headache
 * Muscle pain
 * Nausea
 * Tiredness
 * Rash

The symptoms of ehrlichiosis resemble nonspecific signs and symptoms of various other infectious and non-infectious diseases, that is, they are flu-like symptoms. It is unclear if everybody who is infected with Ehrlichia will become ill. It is possible that many infected persons develop an illness so mild they do not seek medical attention or perhaps have no symptoms at all.

Patients with ehrlichiosis generally visit a physician in their first week of illness, following an incubation period of about 5-10 days after the tick bite. Initial symptoms generally include fever, headache, malaise, and muscle aches. Other signs and symptoms may include nausea, vomiting, diarrhea, cough, joint pains, confusion, and occasionally rash. In contrast to Rocky Mountain spotted fever, rash is relatively uncommon in adult patients with HME, and is rarely reported with Anaplasmosis. However, rash has been described in approximately 60% of pediatric patients infected with E. chaffeensis.

Ehrlichiosis can be a severe illness, especially if untreated, and as many as half of all patients require hospitalization. Severe manifestations of the disease may include:
 * prolonged fever
 * renal failure
 * disseminated intravascular coagulopathy
 * meningoencephalitis
 * adult respiratory distress syndrome
 * seizures
 * coma

It is estimated that 2%-3% of patients die from the infection. Preliminary evidence suggests that E. chaffeensis infection may become more severe than other ehrlichial infections.

The severity of ehrlichiosis may be related in part to the immune status of the patient. Persons with compromised immunity caused by immunosuppresive therapies (e.g., cortiocosteroids or cancer chemotherapy), HIV infection, or splenectomy appear to develop more severe disease, and case-fatality ratios for these individuals are characteristically higher than case-fatality ratios reported for the general population.

Causes
Ehrlichiosis is caused by several bacterial species in the genus Ehrlichia which have been recognized since 1935. Over several decades, veterinary pathogens that caused disease in dogs, cattle, sheep, goats, and horses were identified. Currently, three species of Ehrlichia in the United States and one in Japan are known to cause disease in humans; others could be recognized in the future as methods of detection improve.

Anaplasmosis is caused by the bacterium Anaplasma phagocytophilum. Ehrlichia are small, Gram-negative bacteria that primarily invade leukocytes (white blood cells), the same cells which fight disease by destroying microorganisms that enter the body. Ehrlichiae typically appear as minute, round bacteria (cocci), ranging from 1 to 3 µm (micrometers) in diameter. In the leukocytes, ehrlichiae divide to form vacuole-bound colonies known as morulae (plural for morula, which is the Latin word for mulberry, referring to the mulberry-like clustering of the dividing organisms). The formation of morulae is a defining characteristic of this group of bacterial pathogens. The genus Ehrlichia is currently classified as a member of the family Rickettsiaceae, in the order Rickettsiales. The genus includes seven recognized species: E. canis, E. chaffeensis, E. equi, E. phagocytophila, E. risticii, E. ewingii, and E. sennetsu. A number of other named ehrlichiae, such as "E. platys," "E. bovis," E. ovina," and "E. ondiri," also cause disease in animals.

The ehrlichiae were initially grouped according to the type of blood cell most commonly infected (granulocyte, lymphocyte, monocyte, platelet), and disease classes have been termed "granulocytic (or granulocytotropic) ehrlichiosis" or "monocytic (or monocytotropic) ehrlichiosis." However, this type of classification may be misleading because some of the Ehrlichia species have been found in cells other than their chief target cell type.

Diagnosis
Ehrlichial infections are often difficult to diagnose. Fundamental understanding of the signs, symptoms, and epidemiology of the disease is crucial in guiding requests for tests for ehrlichiosis and interpretation of testing results. Routine clinical laboratory tests indicative of ehrlichiosis include:
 * low white blood cell count
 * low platelet count, and
 * elevated liver enzymes

Ehrlichia can be demonstrated in blood smears by staining with Diff-Quik or Giemsa stains.

Laboratory confirmation of ehrlichiosis requires serologic, molecular, or culture-based methods. Serologic evaluations are conducted by using the indirect immunofluorescence assay (IFA). Antibodies in the serum bind to the organisms on a slide and are detected by a fluorescent-labeled conjugate. Although IFA remains the principal diagnostic tool for the detection of ehrlichial infection, there is no standardized antigen, conjugate, or agreement on what constitutes a positive result among the various laboratories providing these tests. Individual laboratories should be consulted as to their test threshold levels. Blood specimens taken early (acute) and late (convalescent) in the disease course represent the preferred specimens for evaluation.

After serologic methods, amplification of the ehrlichial DNA by polymerase chain reaction (PCR) is the next most frequently used method for detecting infection. This test is available through CDC and some state health laboratories, as well as a number of research and commercial laboratories. PCR tests remain unstandardized, and analytical and diagnostic sensitivity and specificity may vary among individual assays. In Anaplasmosis, the organism has been detected by PCR from the blood of clinically ill patients 3-5 weeks following the onset of symptoms. In persons infected with E. chaffeensis, ehrlichial DNA has been detected by PCR from febrile, untreated patients as long as 7 weeks into the illness.

Direct isolation of the organism remains the gold standard for confirmatory diagnosis, but is the most difficult and time-consuming approach. Both E. chaffeensis and Anaplasma phagocytophilum have been recovered from the blood of acutely ill patients by using a variety of cell lines, most frequently canine DH82 and human HL-60 cells, respectively.

New techniques, including enzyme immunoassays using recombinant ehrlichial antigens and fluorometric PCR, are currently under investigation, and these tests may eventually have broader application in public health laboratories.

Treatment
Appropriate antibiotic treatment should be initiated immediately when there is a strong suspicion of ehrlichiosis on the basis of clinical and epidemiologic findings. Treatment should not be delayed until laboratory confirmation is obtained. Fever generally subsides within 24-72 hours after treatment with doxycycline or other tetracyclines. In fact, failure to rapidly respond to a tetracycline antibiotic argues against a diagnosis of ehrlichiosis. Preventative therapy in non-ill patients who have had recent tick bites is not warranted.

Doxycycline (100 mg twice daily for adults or 4.4 mg/kg body weight per day in two divided doses for children under 45.4 kgs (100 lbs)) is the drug of choice for patients with ehrlichiosis. The optimal duration of therapy has not been established, but current regimens recommend continuation of treatment for at least 3 days after the fever subsides and until evidence of clinical improvement, for a minimum total course of 5 to 7 days. Severe or complicated disease may require longer treatment courses. Because tetracyclines are contraindicated in pregnancy, rifampin has been used successfully in a limited number of pregnant women with documented Anaplasmosis.

Prevention
To help prevent ehrlichiosis and anaplasmosis, you should avoid walking in areas of tall grass and brush where there may be ticks. If you do go into these areas, be sure to


 * Wear light-colored clothing.
 * Tuck your pants legs into your socks so ticks can't climb up the inside of your pants legs.
 * Wear a long-sleeved shirt and tuck it inside your pants.
 * Spray insecticide containing permethrin on boots and clothing. The effects will last several days.
 * Apply insect repellent containing DEET to your skin. Because DEET lasts only a few hours, you may need to reapply it.
 * Look for ticks on your body, including in your hair, when you return from hiking or walking.
 * Check children and pets for ticks.

Generally, a tick needs to be attached to your body for at least 24 hours before it can infect you. You should remove it with fine-tipped tweezers.

To remove attached ticks, use the following procedure:

1. Use fine-tipped tweezers or shield your fingers with a tissue, paper towel, or rubber gloves.

2. Grasp the tick as close to the skin surface as possible and pull upward with steady, even pressure. Do not twist or jerk the tick; this may cause the mouthparts to break off and remain in the skin. (If this happens, remove mouthparts with tweezers. Consult your healthcare provider if infection occurs.)

3. Do not squeeze, crush, or puncture the body of the tick because its fluids (saliva, hemolymph, gut contents) may contain infectious organisms.

4. Do not handle the tick with bare hands because infectious agents may enter through mucous membranes or breaks in the skin. This precaution is particularly directed to individuals who remove ticks from domestic animals with unprotected fingers. Children, elderly persons, and immunocompromised persons may be at greater risk of infection and should avoid this procedure.

5. After removing the tick, thoroughly disinfect the bite site and wash your hands with soap and water.

6. You may wish to save the tick for identification in case you become ill within two to three weeks. Your doctor can use the information to assist in making an accurate diagnosis. Place the tick in a plastic bag and put it in your freezer. Write the date of the bite on a piece of paper with a pencil and place it in the bag.

Note: Folklore remedies such as petroleum jelly or hot matches do little to encourage a tick to detach from skin. In fact, they may make matters worse by irritating the tick and stimulating it to release additional saliva, increasing the chances of transmitting the pathogen. These methods of tick removal should be avoided. In addition, a number of tick removal devices have been marketed, but none are better than a plain set of fine tipped tweezers.

How is Spread
Only one of the three tick families, Ixodidae (hard ticks), is associated with ehrlichiae. These ticks have four stages in their life cycle: egg, larva, nymph, and adult. After the eggs hatch, each stage must feed once to develop into the next stage. Larvae are uninfected with ehrlichiae when they begin to look for a bloodmeal. Ticks become infected with ehrlichiae while feeding on blood from the host in either the larval or nymphal stage. After the tick develops into the next stage, the ehrlichiae may be transmitted to the following host during the feeding process. Both male and female ticks may bite humans but it is the females that are responsible for most transmission. In the United States, it appears that both the nymphal and adult stages are responsible for transmission of ehrlichiae, but one stage may be more important for each Ehrlichia species.

Both ehrlichiosis and anaplasmosis are transmitted by the bite of an infected tick. The most important carriers of anaplasmosis in the United States are the western blacklegged tick and the deer tick, both of which also transmit Lyme disease. HME is transmitted by the lone star tick and possibly other species.

Ehrlichia chaffeensis is principally transmitted by the lone star tick (Amblyomma americanum). White-tailed deer are a major host of lone star ticks and appear to represent one natural reservoir for E. chaffeensis. Antibody to E. chaffeensis has been found throughout deer populations in the southeastern and midwestern United States, and the organism has been cultured from deer blood. Anaplasma has been associated with the blacklegged tick (Ixodes scapularis) in the northeastern and upper midwestern United States. The western blacklegged tick (Ixodes pacificus) is a vector in northern California. Ixodes ricinus has been shown to be a vector of E. phagocytophila in Europe. Deer, elk, and wild rodents are likely reservoirs.

The natural history of Ehrlichia ewingii is not completely known. However, dogs may be a reservoir host and the lone star tick (Amblyomma americanum) may be an important vector. Canine granulocytic ehrlichiosis caused by E. ewingii has been described in south central and southeastern states, including Arkansas, Georgia, Mississippi, Missouri, North Carolina, Oklahoma, Tennessee, and Virginia. To date, human cases have been observed in Missouri, Oklahoma, and Tennessee. It has been demonstrated experimentally that the lone star tick is able to transmit the disease among dogs. Other potential reservoirs and vectors remain to be identified.

Complications
Ehrlichiosis can become a severe, life-threatening illness, especially if left untreated. It can damage many organ systems, especially the lungs and kidneys. Other complications can include seizures and coma.

Possible complications of anaplasmosis include sepsis (infection in blood or tissues). Anaplasmosis also can damage organ systems including the lungs, heart, kidneys, and nerves.

History
Toward the end of the 19th century, scientists began to understand the important potential for ticks to act as transmitters of disease. In the last decades of the 20th century, several tick-borne diseases have been recognized in the United States, including babesiosis, Lyme disease, and ehrlichiosis.

In 1953, the first ehrlichial pathogen of humans was identified in Japan. Sennetsu fever, caused by Ehrlichia sennetsu, is characterized by fever and swollen lymph nodes. The disease is very rare outside the Far East and Southeast Asia, and most cases have been reported from western Japan.

In the United States, human diseases caused by Ehrlichia species have been recognized since the mid-1980s. The ehrlichioses represent a group of clinically similar, yet epidemiologically and etiologically distinct, diseases caused by Ehrlichia chaffeensis, E. ewingii, and a bacterium extremely similar or identical to E. phagocytophila. The remainder of the information on this web page will focus on the types of ehrlichiosis that occur in the United States.

Human ehrlichiosis due to Ehrlichia chaffeensis was first described in 1987. The disease occurs primarily in the southeastern and south central regions of the country and is primarily transmitted by the lone star tick, Amblyomma americanum.

The disease human anaplasmosis was first recognized during 1993 in several patients from Minnesota and western Wisconsin; the disease was known as human granulocytic ehrlichiosis (HGE) at that time. A human monocytic form of ehrlichiosis caused by Ehrlichia chaffeensis is found throughout much of southeastern and southcentral United States but does not appear to be an important vector-borne disease in Minnesota. Human granulocytic ehrlichiosis (HGE) was renamed as human anaplasmosis in 2003.

Epidemiology
Ehrlichial pathogens are distributed globally, primarily in temperate regions. Patients with serologic evidence of infection with E. chaffeensis or, more likely, with a species antigenically related to E. chaffeensis have been identified in several other countries, including Argentina, Belgium, Israel, Italy, Mali, Mexico, Portugal, and Thailand. Similarly, human infections with E. phagocytophila have been confirmed in Belgium, Denmark, Hungary, Slovenia, and Sweden, and persons with antibodies reactive to granulocytic ehrlichiae have been identified in Germany, Israel, Italy, Norway, Switzerland, and the United Kingdom.

Most cases of ehrlichiosis are reported within the geographic distribution of the vector ticks. Occasionally, cases are reported from areas outside the distribution of the tick vector. In most instances, these cases have involved persons who traveled to areas where the diseases are endemic, and who had been bitten by an infected tick and developed symptoms after returning home. Therefore, if you traveled to an ehrlichiosis-endemic area 2 weeks prior to becoming ill, you should tell your doctor where you traveled.

Research
The National Institute of Allergy and Infectious Diseases (NIAID) supports research on ehrlichiosis and anaplasmosis as well as other tickborne diseases. Research ranges from studying the basic biology of the microbes that cause these diseases to developing vaccines and better ways to diagnose, treat, and prevent the diseases.

Two years after anaplasmosis was first described in people, researchers supported by NIAID identified the bacterium that causes the disease. More recently, NIAID-supported researchers helped complete the genome sequences of both Anaplasma phagocytophilum and Ehrlichia chaffeensis. This information should facilitate efforts to develop preventive vaccines as well as new and improved diagnostics and treatments.