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Symptoms, Diagnosis, and Treatment

Symptoms 

In the United States, the term “ehrlichiosis” may be broadly applied to several different infections. Ehrlichia chaffeensis and Ehrlichia ewingii are transmitted by the lonestar tick in the southeastern and southcentral United States. In addition, a third Ehrlichia species provisionally called Ehrlichia muris-like (EML) has been identified in a small number of patients residing in or traveling to Minnesota and Wisconsin; a tick vector for the EML organism has not yet been established. The symptoms caused by infection with these Ehrlichia species usually develop 1-2 weeks after being bitten by an infected tick.  The tick bite is usually painless, and about half of the people who develop ehrlichiosis may not even remember being bitten by a tick. 

 The following is a list of symptoms commonly seen with this disease, however, it is important to note that the combination of symptoms varies greatly from person to person.

  • Fever
  • Headache
  • Chills
  • Malaise
  • Muscle pain
  • Nausea / Vomiting / Diarrhea
  • Confusion
  • Conjunctival injection (red eyes)
  • Rash (in up to 60% of children, less than 30% of adults)

Ehrlichiosis is a serious illness that can be fatal if not treated correctly, even in previously healthy people.  Severe clinical presentations may include difficulty breathing, or bleeding disorders. The estimated case fatality rate (i.e. the proportion of persons who die as a result of their infection) is 1.8%. Patients who are treated early may recover quickly on outpatient medication, while those who experience a more severe course may require intravenous antibiotics, prolonged hospitalization or intensive care. 

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Rash

Skin rash is not considered a common feature of ehrlichiosis, and should not be used to rule in or rule out an infection. Ehrlichia chaffeensis infection can cause a rash in up to 60% of children, but is reported in fewer than 30% of adults. Rash is not commonly reported in patients infected with Ehrlichia ewingii or the Ehrlichia muris-like organism.  The rash associated with Ehrlichia chaffeensis infection may range from maculopapular to petechial in nature, and is usually not pruritic (itchy). The rash usually spares the face, but in some cases may spread to the palms and soles.  A type of rash called erythroderma may develop in some patients.  Erythroderma is a type of rash that resembles a sunburn and consists of widespread reddening of the skin that may peel after several days.  Some patients may develop a rash that resembles the rash of Rocky Mountain spotted fever making these two diseases difficult to differentiate on the basis of clinical signs alone.

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Immune-compromised Individuals

The severity of ehrlichiosis may depend in part on the immune status of the patient. Persons with compromised immunity caused by immunosuppressive therapies (e.g., corticosteroids , cancer chemotherapy, or longterm immunosuppressive therapy following organ transplant), HIV infection, or splenectomy appear to develop more severe disease, and may also have higher case-fatality rates (i.e. the proportion of patients that die from infection.)  

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Blood Transfusion and Organ Transplant Risks Associated with Ehrlichia species

Because Ehrlichia organisms infect the white blood cells and circulate in the blood stream, these pathogens may pose a risk to be transmitted through blood transfusions. Ehrlichia chaffeensis has been shown to survive for more than a week in refrigerated blood. Several instances of suspected E. chaffeensis transmission through solid organ transplant have been investigated, although to date no cases have been confirmed that can be attributed to this route of transmission. Patients who develop ehrlichiosis within a month of receiving a blood transfusion or solid organ transplant should be reported to state health officials for prompt investigation. Use of leukoreduced blood products may theoretically decrease the risk of transfusion-associated transmission of these pathogens. However, the filtration process does not remove all leukocytes or bacteria not associated with leukocytes from leukoreduced blood; therefore, this process may not eliminate the risk completely.

For more in-depth information about signs and symptoms of ehrlichiosis, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

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Diagnosis

 

The diagnosis of ehrlichiosis must be made based on clinical signs and symptoms, and can later be confirmed using specialized confirmatory laboratory tests.  Treatment should never be delayed pending the receipt of laboratory test results, or be withheld on the basis of an initial negative laboratory result.

Physician Diagnosis

There are several aspects of ehrlichiosis that make it challenging for healthcare providers to diagnose and treat.  The symptoms vary from patient to patient and can be difficult to distinguish from other diseases.  Treatment is more likely to be effective if started early in the course of disease. Diagnostic tests based on the detection of antibodies will frequently be negative in the first 7-10 days of illness.

For this reason, healthcare providers must use their judgment to treat patients based on clinical suspicion alone. Healthcare providers may find important information in the patient’s history and physical examination that may aid clinical suspicion. Information such as recent tick bites, exposure to areas where ticks are likely to be found, or history of recent travel to areas where ehrlichiosis is endemic can be helpful in making the diagnosis.  The healthcare provider should also look at routine blood tests, such as a complete blood cell count or a chemistry panel. Clues such as a low platelet count (thrombocytopenia), low white blood cell count (leukopenia), or elevated liver enzyme levels are helpful predictors of ehrlichiosis, but may not be present in all patients depending on the course of the disease.   After a suspect diagnosis is made on clinical suspicion and treatment has begun, specialized laboratory testing should be used to confirm the diagnosis of ehrlichiosis.

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Laboratory Detection

During the acute phase of illness, a sample of whole blood can be tested by polymerase chain reaction (PCR) assay to determine if a patient has ehrlichiosis. This method is most sensitive in the first week of illness, and quickly decreases in sensitivity following the administration of appropriate antibiotics. Although a positive PCR result is helpful, a negative result does not completely rule out the diagnosis.

During the first week of illness a microscopic examination of blood smears (known as a peripheral blood smear) may reveal morulae (microcolonies of ehrlichiae) in the cytoplasm of white blood cells in up to 20% of patients.

Image: a microscopic image of Morulae detected in a monocyte

Figure 1: Morulae detected in a monocyte on a peripheral blood smear, associated with E. chaffeensis infection.

The type of blood cell in which morulae are observed may provide insight into the infecting species: E. chaffeensis most commonly infects monocytes, whereas E. ewingii more commonly infect granulocytes. However, the observance of morulae in a particular cell type cannot conclusively identify the infecting species. Culture isolation of Ehrlichia is only available at specialized laboratories; routine hospital blood cultures cannot detect Ehrlichia.

When a person develops ehrlichiosis, their immune system produces antibodies to the Ehrlichia, with detectable antibody titers usually observed by 7-10 days after illness onset.  It is important to note that antibodies are not detectable in the first week of illness in 85% of patients, and a negative test during this time does not rule out ehrlichiosis as a cause of illness. 

The gold standard serologic test for diagnosis of ehrlichiosis is the indirect immunofluorescence assay (IFA) using E. chaffeensis antigen, performed on paired serum samples to demonstrate a significant (four-fold) rise in antibody titers.  The first sample should be taken as early in the disease as possible, preferably in the first week of symptoms, and the second sample should be taken 2 to 4 weeks later. In most cases of ehrlichiosis, the first IgG IFA titer is typically low, or “negative,” and the second typically shows a significant (four-fold) increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG near the end of the first week of illness and remain elevated for months or longer.  Also, IgM antibodies are less specific than IgG antibodies and more likely to result in a false positive.  For these reasons, physicians requesting IgM serologic titers should also request a concurrent IgG titer.

Serologic tests based on enzyme immunoassay (EIA) technology are available from some commercial laboratories. However, EIA tests are qualitative rather than quantitative, meaning they only provide a positive/negative result, and are less useful to measure changes in antibody titers between paired specimens. Furthermore, some EIA assays rely on the evaluation of IgM antibody alone, which may have a higher frequency of false positive results. 

Antibodies to E. chaffeensis may remain elevated for months or longer after the disease has resolved, or may be detected in persons who were previously exposed to antigenically related organisms.  Up to 12% of currently healthy people in some areas may have elevated antibody titers due to past exposure to Ehrlichia species or similar organisms. Therefore, if only one sample is tested it can be difficult to interpret, while paired samples taken weeks apart demonstrating a significant (four-fold) rise in antibody titer provides the best evidence for a correct diagnosis of ehrlichiosis. 

For more in-depth information about the diagnosis of ehrlichiosis, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

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Treatment

Doxycycline is the first line treatment for adults and children of all ages and should be initiated immediately whenever ehrlichiosis is suspected.

Use of antibiotics other than doxycycline and other tetracyclines is associated with a higher risk of fatal outcome for some rickettsial infections. Doxycycline is most effective at preventing severe complications from developing if it is started early in the course of disease. Therefore, treatment must be based on clinical suspicion alone and should always begin before laboratory results return.

If the patient is treated within the first 5 days of the disease, fever generally subsides within 24-72 hours.  In fact, failure to respond to doxycycline suggests that the patient’s condition might not be due to ehrlichiosis. Severely ill patients may require longer periods before their fever resolves. Resistance to doxcycline or relapses in symptoms after the completion of the recommended course have not been documented. 

Recommended Dosage

Doxycycline is the first line treatment for adults and children of all ages:

  • Adults: 100 mg every 12 hours
  • Children under 45 kg (100 lbs): 2.2 mg/kg body weight given twice a day

Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 7 to 14 days.  Some patients may continue to experience headache, weakness and malaise for weeks after adequate treatment.

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Treating children

The use of doxycycline to treat suspected ehrlichiosis in children is standard practice recommended by both CDC and the AAP Committee on Infectious Diseases. Unlike older generations of tetracyclines, the recommended dose and duration of medication needed to treat ehrlichiosis has not been shown to cause staining of permanent teeth, even when five courses are given before the age of eight.  Healthcare providers should use doxycycline as the first-line treatment for suspected ehrlichiosis in patients of all ages. 

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Other Treatments

In cases of life threatening allergies to doxycycline and in some pregnant patients for whom the clinical course of ehrlichiosis appears mild, physicians may need to consider alternate antibiotics. Although recommended as a second-line therapeutic alternative to treat Rocky Mountain spotted fever (RMSF), chloramphenicol is not recommended for the treatment of either ehrlichiosis or anaplasmosis, as studies have shown a lack of efficacy. Rifampin appears effective against Ehrlichia in laboratory settings. However, rifampin is not effective in treating RMSF, a disease that may be confused with ehrlichiosis. Healthcare providers should be cautious when exploring treatments other than doxycycline, which is highly effective in treating both. Other antibiotics, including broad spectrum antibiotics are not considered highly effective against ehrlichiosis, and the use of sulfa drugs during acute illness may worsen the severity of infection. 

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Prophylaxis (Preventive Treatment)

Antibiotic treatment following a tick bite is not recommended as a means to prevent ehrlichiosis. There is no evidence this practice is effective, and this may simply delay onset of disease. Instead, persons who experience a tick bite should be alert for symptoms suggestive of tickborne illness and consult a physician if fever, rash, or other symptoms of concern develop. 

For more in-depth information about treatment, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

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Other Considerations

The clinical presentation for ehrlichiosis can resemble other tickborne diseases, such as Rocky Mountain spotted fever and anaplasmosis. Similar to ehrlichiosis, these infections respond well to treatment with doxycycline. Healthcare providers should order diagnostic tests for additional agents if the clinical history and geographic association warrant. For more in-depth about other similar tickborne diseases, please visit http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5504a1.htm

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