Ehrlichiosis

Ehrlichiosis is an infection of white blood cells that affects various mammals, including mice, cattle, dogs, deer, horses, sheep, goats, and humans.[1, 2]  

Ehrlichia/Anaplasma are tiny (0.2-2 µm) obligate, intracytoplasmic, gram-negative bacteria that resemble Rickettsia; divide by binary fission; and multiply within the cytoplasm of infected white blood cells. Clusters of Ehrlichia multiply in host monocyte vacuoles (phagosomes) to form large, mulberry-shaped aggregates called morulae.

Ehrlichia inclusion bodies, such as morulae, are visible in the cytoplasm of infected mononuclear phagocytic cells after 5-7 days. The type of ehrlichiosis that develops varies and depends on the infecting species and the type of leukocyte infected. Human granulocytic anaplasmosis (HGA), formerly known as human granulocytic ehrlichiosis (HGE), is caused by Anaplasma phagocytophilum, which infect granulocytes. In contrast, human monocytic ehrlichiosis (HME) is caused by Ehrlichia chaffeensis, which infects monocytes.

HGA and HME cause the same clinical manifestations. Therefore, the term ehrlichiosis is used for both types of infections. The total duration of illness for HME and HGA is unknown. No chronic cases have been reported at this time. 

Table. Characteristics of HME Versus HGA (Open Table in a new window)

 

In 2008, the ehrlichiosis case definition was divided into four classifications:

1. Ehrlichia chaffeensis infection
2. Ehrlichia ewingii infection
3. Anaplasma phagocytophilum infection
4. Undetermined ehrlichiosis/anaplasmosis

In 2009, a new Ehrlichia species was identified in patients in the upper Midwest area.

• This species was previously called  “ E. muris-like agent” (EMLA),  but is now referred to as  E. muris eauclairensis. No death has been reported with infection caused by this species. ^[3]

Because the tick vector and geographic range for HGA is the same as that for Lyme disease, rarely the 2 may coexist in the same patient; doxycycline is effective therapy for both. 

In October 2008, a report was made of an apparent nosocomial infection with A phagocytophilum that was transmitted from blood donated by an infected woman who had spent time in Minnesota just prior to donating.

The major antigenic determinants of Ehrlichia are surface membrane proteins. These antigenic proteins are complex and consist of 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 HGA include the 40-, 44-, and 65-kd bands.

In 1999, Buller et al reported 4 incidents of ehrlichiosis in Missouri due to Ehrlichia ewingii.[4] The associated disease may be clinically indistinguishable from infection caused by E chaffeensis or A phagocytophilum; however, laboratory testing can distinguish these incidents from HGA and HME. 

Go to Tick Removal and Tick-Borne Diseases for complete information on these topics.

See 7 Bug Bites You Need to Know This Summer, a Critical Images slideshow, for helpful images and information on various bug bites.

Patient education

Educate patients in endemic ehrlichiosis areas to take proper precautions when traveling through wooded and/or tick-infested areas.

For patient education information, see Ticks. 

 

Ehrlichia and Anaplasma species, members of the family Rickettsiae, are gram-negative, obligate, intracellular coccobacilli that resemble Rickettsia species. All 3 are forms of Alphaproteobacteria.

Like Rickettsia, Ehrlichia organisms gain access to the blood via a bite from an infected tick. A americanum (Lone Star tick, seen in the image below) is the principle tick vector of E chaffeensis and is the primary vector of human monocytic ehrlichiosis (HME). A phagocytophilum may be transmitted from Ixodes persulcatus ticks and possibly Dermacentor variabilis (dog tick/wood tick).

The primary target cell for HME is the macrophage, and the primary target for human granulocytic anaplasmosis (HGA) is the granulocyte. Intracellular infection is established within phagosomes, most often found in macrophages in the liver, spleen, lymph nodes, bone marrow, lung, kidney, and CNS.

HME and HGA are more severe in those with impaired splenic function.

Individuals considered to be at risk for ehrlichiosis include the following:

• From a review of the national surveillance data, cases of ehrlichiosis are more frequently reported in men than in women.
• People aged 60-69 years account for the highest number of cases.

People with compromised immune systems (eg, resulting from cancer treatments, advanced HIV infection, prior organ transplants, or some medications) might be at increased risk for severe disease.[5]

Occurrence in the United States

The distribution of ehrlichiosis in the United States mirrors the tick distribution and appropriate mammalian vectors (eg, white-footed mouse, white-tailed deer). Ehrlichiosis occurs where mammalian hosts are in contact with the appropriate tick vector (ie, A americanum,D variabilis,Ixodes ticks). 

Most cases of ehrlichiosis in the United States occur in California and Texas and in the southeast and northeast regions of the country, with some cases occurring in the north-central states west of the Great Lakes.

In 2016, 4 states (Missouri, Arkansas, New York, Virginia) accounted for 50% of all reported cases of ehrlichiosis in the United States.[5]

Ehrlichiosis is a seasonal disease observed mainly from April to September. In 1999, ehrlichiosis became reportable to the US Centers for Disease Control and Prevention (CDC). In 2005, 786 cases of human granulocytic anaplasmosis (HGA) were reported. The 3 states that reported the most cases were New York (221 cases), Minnesota (186 cases), and Wisconsin (155 cases).[6, 7] In 2006, 646 cases of HGA were reported. The 3 states that reported the most cases were New York (235 cases), Minnesota (177 cases), and Wisconsin (49 cases).[8]

In the year 2000, only 200 cases of ehrlichiosis were reported, whereas more than 1,377 cases were reported in 2016.[5]

 

 

A 2011 study confirmed that B burgdorferi and A phagocytophilum share the same enzootic life cycle suggesting that it is important to monitor areas endemic for Lyme disease for HGA. In this study, La Crosse, WI is centrally located in a well-documented Lyme disease focus. HGA was identified by PCR in the blood of 53 patients with clinical findings consistent with HGA confirming that this region endemic for Lyme should now also be considered part of the upper Midwestern focus of endemicity for HGA.[9]

In 2005, 506 cases of human monocytic ehrlichiosis (HME) were reported. The 3 states that reported the most cases were New York (85 cases), Oklahoma (79 cases), and New Jersey (64 cases). In 2006, 578 cases of HME were reported. The 3 states that reported the most cases were New York (141 cases), Missouri (73 cases), and New Jersey (67 cases).

A 2011 report identified a new ehrlichia species in 4 patients in the Minnesota and Wisconsin areas. All patients had the traditional clinical syndrome and responded to treatment. On testing, 17 of 697 Ixodes scapularis ticks collected in Minnesota or Wisconsin were positive for the same ehrlichia species by polymerase chain-reaction testing and genetic analyses revealed that this new ehrlichia species was closely related to E muris.[10]

Notably, while cases and incidence rose, the case fatality rate (ie, the proportion of patients with ehrlichiosis who died as a result of infection) has declined since 2000, although the case fatality rate in recent publications is still roughly 1% of cases.

International occurrence

Ehrlichiosis occurs essentially worldwide, and the frequency parallels the distribution of the appropriate tick vectors for the transmission of Ehrlichia bacteria and the mammalian hosts.[11]

Ehrlichia sennetsu causes a mononucleosis-like illness in Japan and Malaysia.

Sex-related demographics

The rates of HME and HGA are higher in males than in females, most likely due to a higher rate of participation in high-risk outdoor activities among males.

In 2006, the CDC reported that of the 646 cases of HGA, 357 were males and 273 were females (16 cases did not specify sex). HME had a similar distribution, with 337 males and 234 females among the 578 cases in 2006 (7 cases did not specify sex).

The incidence rates per 100,000 for males were 0.26 for HGA and 0.24 for HME. For females, the rates were 0.19 for HGA and 0.16 for HME.

Age-related demographics

Ehrlichiosis is reported more frequently in adults than in children. The highest age range is between 40 and 64 years. 

Ehrlichiosis carries an excellent prognosis in healthy hosts. A favorable outcome is associated with the early use of antibiotics.[12]

The mortality rate for human monocytic ehrlichiosis (HME) is reported to be 2-5%, while that for HGA is 7-10%.

Elderly patients (>60 y) are more likely than others to develop severe infections and account for most deaths due to ehrlichiosis. In addition, ehrlichiosis may be severe in immunocompromised hosts, manifesting as a Rocky Mountain spotted fever (RMSF)–like illness that may be fatal. The great majority of cases of ehrlichiosis are asymptomatic. Most cases present as mild-to-moderate acute febrile illnesses, but some cases are severe/life threatening.

HME has a reported hospitalization rate as high as 60%, while that for HGA is 28-54%.

Clinical manifestations of ehrlichiosis usually begin 5-14 days after the tick bite. Approximately 68% of patients with human monocytic ehrlichiosis (HME) report a tick bite, and 83% of patients have a history of tick exposure in the 4-week period before onset of symptoms. Onset is abrupt or subacute.

The histories for HME, human granulocytic anaplasmosis (HGA), and E ewingii infection are similar and may include the following[1, 2] :

• Tick bites or exposure (>90%)
• Fevers (>90%)
• Headaches (>85%)
• Malaise (>70%)
• Myalgias (>70%)
• Rigors (60%)
• Nausea (40%)
• Vomiting (40%)
• Anorexia (40%)
• Confusion (20%)

Skin rash is not considered a common feature of ehrlichiosis and should not be used to rule in or rule out an infection. E chaffeensis infection can cause rash in up to 60% of children, but rash is reported in fewer than 30% of adults. Rash is not commonly reported in patients infected with E ewingii or the E muris-like organism.[13]

Physical findings due to ehrlichiosis are minimal.

Splenomegaly is not uncommon, but some patients develop hepatomegaly. Lymphadenopathy is very uncommon.

Complications of ehrlichiosis include the following:

• Renal failure

• Respiratory failure

• Coagulopathy

• Myocarditis

• Encephalopathy

• Coma

• Seizures

• Septic shock

Lumbar puncture may be necessary in patients with fever and severe headache to rule out meningitis.

Buffy coat examination may reveal morulae, which are diagnostic characteristics of HME/HGA. Morulae are observed in the cytoplasm of neutrophils in patients with HGA and in monocytes in patients with HME. Only a minority of patients with HME have detectable morulae.

The diagnosis of human monocytic ehrlichiosis (HME) or human granulocytic anaplasmosis (HGA) rests on several testing methods:

Serology (2 types): (1) indirect fluorescent antibody and (2) enzyme-linked immunosorbent assays.

A single elevated immunoglobulin G (IgG) immunofluorescent antibody (IFA) Ehrlichia titer or (2) demonstration of a 4-fold or greater increase between acute and convalescent IFA Ehrlichia titers.[1]

Buffy coat examination: Ehrlichiosis may also be diagnosed by demonstrating characteristic morulae in the cytoplasm of leukocytes. Morulae are diagnostic of ehrlichiosis and occur more frequently in HGA than in HME. The microbiology laboratory should be alerted to look carefully in the blood smear for them.

Polymerase chain reaction: Detection of the organism with polymerase chain reaction (PCR) assay is now becoing widely available. Sensitivity and specificity of assays may vary but has been reported as high as 95-100 percent by some laboratories.[15]

Immunohistochemical stains: Although not a preferred method, immunohistochemical stains have been used to make the diagnosis of ehrlichiosis and anaplasmosis in a few patients through bone marrow staining tissue or autopsy tissue such as spleen, lymph nodes, liver, or lung.[16]   

Culture: The infecting organism is extremely difficult to culture from blood and therefore is not recommended.

 

A complete blood cell (CBC) count should be obtained for possible neutropenia, relative lymphopenia, and/or thrombocytopenia. Anemia is not a 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 minimally/moderately elevated in ehrlichiosis.

Elevated C-reactive protein (CRP) levels are common in the first week of illness and typically resolve by the end of the second week.

Serum transaminases are frequently mildly elevated in ehrlichiosis, as well as in other tick-borne infectious diseases. Abnormal liver enzymes are found in 86% of patients.

If other infectious diseases are suspected, appropriate tests should be obtained to rule out these diagnoses. If coinfection with RMSF or babesiosis is suspected, appropriate serology should be obtained to diagnose each of these infectious diseases.

Microscopic examination (by an experienced microbiologist) of blood smears stained with eosin-azure type dyes, such as Wright-Giemsa stain, may reveal morulae in the cytoplasm of leukocytes. As many as 20% of patients with HME and 20-80% of patients with HGA may have morulae in the first week of infection. A negative result should not be taken as proof of no infection.

Hyponatremia (< 130 mEq/L) is found in 40% of patients.

Moderately or severely ill patients may require hospitalization for diagnosis and treatment. Early treatment is critical. Consider the possibility of ehrlichiosis when patients have a febrile illness and a history of recent tick exposure. Doxycycline remains the preferred drug for persons with ehrlichiosis.[1, 2]

Continue treatment until the patient has been afebrile for at least 3 days and for 10-14 days depending on the severity of illness. Guidelines for the diagnosis and management of tick-borne diseases have been established by the CDC.[2]

Deterrence and prevention of ehrlichiosis includes the following:

• Wear light-colored clothes

• Tuck pants into socks

• Use insect repellent

• Regularly examine the body for ticks

Promptly remove ticks; a feeding period of 3-48 h is required before disease is transmitted. Cover exposed areas of the skin with insect repellents containing N,N -diethyl-meta-toluamide (DEET). In children, carefully use insect repellents on exposed skin; avoid the face and hands to prevent systemic absorption.

After returning from wooded and/or tick-infested areas, individuals should check themselves carefully for ticks. If found, ticks should be removed carefully and a physician should be consulted.

Any of several commercial devices should be used, if possible, to remove ticks. Alternatively, ticks can be removed by grasping them with fine tweezers at the point of attachment and pulling slowly and steadily. The aim is to remove the mouthparts from the site of insertion without damaging the insect.

After removal, the skin should be disinfected. Check to make sure that the tick head is not still embedded.

Some have recommended keeping the tick in a jar along with a damp paper towel in the refrigerator for a month or so, in case symptoms develop, as it may help to identify what (if any) infection has been transmitted.

Trying to burn the tick; smothering it in alcohol, petroleum jelly, or similar substance; or twisting or rubbing the tick off is not recommended. These methods have not been shown to decrease the time the tick remains embedded and risk breaking the tick body open and releasing otherwise-contained bacteria.

No role exists for the use of antimicrobial prophylaxis after a tick bite in the prevention of human monocytic ehrlichiosis (HME) or human granulocytic anaplasmosis (HGA) due to the low rate of subsequent infection.

An infectious disease specialist should be consulted for any patient with an acute febrile illness and a recent history of tick exposure.

The drug of choice for infections with human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) in both adults and children is doxycycline. It is also the recommended drug for many other tick-borne infections, such as Rocky Mountain spotted fever. 

Early initiation of doxycycline should be done once there is a high index of suspicion of either human monocytic ehrlichiosis (HME) or human granulocytic anaplasmosis (HGA as delay in treatment is usually associated with increased morbidity especially in immunocompromised hosts. Supportive management such as antipyretics, hydration with intravenous fluids, should also be initiated if indicated.

The American Academy of Pediatrics recommends a short course of doxycycline (< 21 days) as first-line therapy for severe/life threatening suspected or proven HGA and HME in children of all ages. Tetracyclines in general are known to cause teeth discoloration in young children, however, this risk is minimal if a short course of doxycycline is used.[17]

Doxycycline can be administered intravenously in patients who are very sick and are unable to tolerate oral medications or given orally in less sick patients who can tolerate pills. Dose is usually 100mg every 12 hours for a duration of 7 to 10 days or continued for 3 to 5 days after resolution of fever in adults or for 7 to 14 days in children. Treatment should be continued for at least 3 days after resolution of fever.[18, 19]

For patients who are intolerant or have severe allergy to doxycycline, rifampin and chloramphenicol are alternative treatment options.

Rifampin has been used as an alternative agent in both adults and children and even in pregnant women. Children treated with rifampin will need closer monitoring.[18]

There is limited data about the use of Chloramphenicol in this setting although it has been used in a few instances but given its hematological adverse effects, it is usually avoided. Oral chloramphenicol is not readily available in most pharmacies in the United States. 

Prophylaxis

Currently, there is no recommendation for the use of doxycycline or other antibiotics for post tick exposure prophylaxis against HME or HGA. Individuals with potential tick-bite exposure should monitor for development of symptoms such as feeling unwell, fever, new rash within 2 weeks of exposure and contact their healthcare providers for further evaluation.

 

Class Summary

Empiric antimicrobial therapy should cover the most likely pathogens in the context of the clinical setting.

Doxycycline (Vibramycin, Doryx, Adoxa)

This is a second-generation tetracycline. It is more active than tetracycline against many pathogens. Doxycycline has different pharmacokinetics and a different adverse effect profile from tetracycline.

Doxycycline inhibits protein synthesis and thus bacterial growth by binding with 30S and, possibly, 50S ribosomal subunits of susceptible bacteria.

Rifampin (Rifadin)

Rifampin inhibits ribonucleic acid (RNA) synthesis in bacteria by binding to the beta subunit of deoxyribonucleic acid (DNA)-dependent RNA polymerase, which, in turn, blocks RNA transcription.