AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Ehrlichiosis is more properly considered as 2 distinct, but related, diseases caused by different tick-borne bacteria. The Rickettsiae family was reorganized in 2001 to rename some of the Ehrlichia as Anaplasma to reflect this fact. Ehrlichiosis and anaplasmosis differ in the pathophysiology of the disease, laboratory findings, and the geographic distribution of the vector species.

Ehrlichia and Anaplasma species are obligate intracellular coccobacilli that historically have been recognized as veterinary pathogens, usually with ticks as vectors. The genus Ehrlichia was established in honor of the German microbiologist Paul Ehrlich, who discovered it in the United States in 1945. The first incident of human ehrlichiosis was reported in Japan in 1954. The first incident of human ehrlichiosis in the United States was documented in 1986. In 1991, Ehrlichia chaffeensis was isolated from a military recruit stationed at Fort Chaffee, Arkansas. In 1994, Anaplasma phagocytophilum was isolated from 12 patients in Minnesota and Wisconsin.

The disease and organism names have changed in the last few years, making the situation confusing to some degree. The 2 diseases are best thought of as affecting either macrophages (human monocytic ehrlichiosis [HME], caused by E chaffeensis) or granulocytes (human granulocytic anaplasmosis [HGA], caused by A phagocytophilum).

HGA was formally known as human granulocytic ehrlichiosis (HGE), and Anaplasma phagocytophilum was formally known as Ehrlichia phagocytophilum and Ehrlichia equi; the species were combined in the reorganization. Because the tick vector and geographic range for HGA is the same as that of Lyme disease, the 2 may coexist, and care should be taken because amoxicillin can treat early Lyme disease but is not effective against HGA; doxycycline is an effective therapy for both.

In 1999, Buller et al reported 4 incidents of ehrlichiosis in Missouri due to Ehrlichia ewingii.¹ 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.

Characteristics of Ehrlichiosis Versus Anaplasmosis

	Ehrlichiosis	Anaplasmosis
Cell type Affected	Macrophage	Granulocyte
Organism	E chaffeensis	A phagocytophilum
Vector	Amblyomma americanum (Lone Star tick)	Ixodes scapularis (black-legged tick), Ixodes pacificus (the western black-legged tick) in California, Ixodes ricinus in Europe, and probably Ixodes persulcatus in parts of Asia
Location	Southeastern and south-central United States	Wisconsin and Minnesota, less active in New York and Connecticut, also California
Rash	30% of adults, 60% of children	Rare
Prognosis	~3% mortality	<1% mortality

Both ehrlichiosis and anaplasmosis are reportable diseases in the United States.

Pathophysiology

The primary target cell for HME is the macrophage, and the primary target for 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.

Ehrlichia species proceed through elementary bodies, initial bodies, and morulae (distinctive membrane-bound, intracytoplasmic bacterial aggregates).

Potential pathology findings believed to be associated with HME include the following:

• Focal necrosis of the liver, spleen, and lymph nodes
• Multiorgan perivascular lymphohistiocytic infiltrates
• Hemophagocytosis of the liver, spleen, lymph nodes, and bone marrow
• Intersitial pneumonitis and pulmonary hemorrhage
• Frequent granulomas observed in bone marrow biopsy
• Suppression or dysregulation of the immune system

Frequency

United States

Both HME and HGA are underreported but are now subject to national reporting requirements. State health departments reported 742 cases of HME and 449 cases of HGA during 1986-1997, but 1,176 for the year 2001-2002.^{2, 3} Annual incidence overall was 0.6 HGA cases per million population for and 1.4 HME cases per million population. This rising incidence is likely due to a mixture of improved recognition and reporting, as well as increased encroachment of humans into areas where the vectors are located.

HME was reported most commonly from the southeastern and south-central states, whereas HGA was reported most often in Wisconsin and Minnesota. Approximately 66% of HME cases have occurred in rural areas, and 68% of cases have been reported from May-July.

International

Evidence of human ehrlichiosis has been reported in residents of Western Europe, Scandinavia, and Africa.

Mortality/Morbidity

Ehrlichiosis is a severe disease, with more than 60% of patients requiring hospitalization; however, some hospitalizations are to rule out other potentially life-threatening conditions.

• Of all patients with HME, 25% required intensive care therapy.
• Case fatality rates are 2-3% for HME and 1% for HGA.

Race

No racial predilection has been reported.

Sex

Ehrlichiosis is predominantly reported in males (75%), most likely due to a high rate of high-risk outdoor activities.

Age

A median age of 44 years is reported. Older patients are more likely to have a more severe course of illness.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Approximately 68% of patients with human monocytic ehrlichiosis (HME) reported 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. Symptoms are nonspecific and resemble those of Rocky Mountain spotted fever.

• Fever: All patients have a fever of more than 38°C.
• Headache
• Myalgia and arthralgia
• Anorexia and nausea
• Malaise and photophobia
• Skin rash
• • Rash is less common in ehrlichiosis than in Rocky Mountain spotted fever. Rash is rare in patients with anaplasmosis.
  • Skin rash is more common in children than adults (approximately 60% in children vs 30% in adults).
  • Rash usually occurs on the trunk, legs, arms, or face and may be macular, maculopapular, and/or petechial.
  • Rash on the palms or the soles is found in fewer than 10% of patients.
• Immunosuppression: Pre-existing immunosuppression is a risk factor in 12% of patients with HME and 6% of patients with human granulocytic anaplasmosis (HGA)

Physical

Physical findings vary. The patient may be confused. Physical examination may reveal the following:

• Rash
• Hepatosplenomegaly
• Systolic murmur
• Nuchal rigidity (if meningitis is present)
• Cervical or inguinal adenopathy
• Conjunctivitis
• Strawberry tongue
• Pharyngitis or tonsillar exudate
• Genital or oral ulcers
• Abnormal gait

Causes

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.

• Different species are identified by sequencing and analysis of 16S ribosomal RNA (rRNA).
• A americanum (Lone Star tick) is the putative vector of HME.
• I scapularis (black-legged tick) is the principal vector of HGA. I pacificus (the western black-legged tick) is the main vector in California.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Tick-borne Diseases, Colorado
Relapsing Fever
Acute or chronic gonococcemia
Typhoid fever
Collagen vascular disease
Idiopathic thrombocytopenic purpura
Malaria
Miliary tuberculosis
Erythema multiforme/nodosum
Neoplastic diseases
Haverhill and rat-bite fever (Streptobacillus moniliformis)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Dr E. Dale Everett stated, "The problem is not so much that ehrlichiosis is specifically difficult to diagnose, it is more that some physicians are still unaware of it and thus do not recognize the clinical syndrome."
• Case definition depends on a positive serologic test or positive polymerase chain reaction (PCR) assay. An alternative may be a single immunofluorescence antibody (IFA) titer of 64 or higher in conjunction with morulae on microscopy (see below).
• • A positive serologic test demonstrates a 4-fold or greater change in antibody titer in blood sera obtained at 4-week intervals following onset of symptoms.
  • 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 human monocytic ehrlichiosis (HME) and 20%-80% of patients with human granulocytic anaplasmosis (HGA) may demonstrate this in the first week of infection. A negative result should not be taken as proof of noninfection.
  • Individual laboratories vary as to their specific positive criteria for indirect IFA testing. A probable infection is one with an IFA titer of 64 or higher or morulae on microscopy. Some laboratories are able to perform an enzyme-linked immunoassay (ELISA).
  • The Centers for Disease Control and Prevention (CDC), certain state health laboratories, and a limited number of research and commercial laboratories offer the PCR test. A peripheral blood test is sufficient to perform this because these pathogens infect circulating lymphocytes.
  • Abnormal liver enzymes are found in 86% of patients.
  • Leukopenia is found in 60% of patients.
  • Thrombocytopenia is found in 68% of patients.
  • Abnormal cerebrospinal fluid also can be observed.
  • Hyponatremia (<130 mEq/L) is found in 40% of patients.
  • Elevated C-reactive protein (CRP) levels are common in the first week of illness and typically resolve by the end of the second week.

Imaging Studies

• An abnormal chest radiograph is observed in 50% of patients with ehrlichiosis and respiratory symptoms.

Histologic Findings

Buffy coat examination may reveal intracytoplasmic inclusions (morulae), which are characteristic of ehrlichiosis. Morulae are observed in the cytoplasm of neutrophils in patients with HGA and in mononuclear cells in patients with HME. Only a minority of patients with HME have detectable morulae.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Early treatment is critical. Consider the possibility of ehrlichiosis when patients have a febrile illness and history of recent tick exposure.

• Doxycycline remains the drug of choice for persons with ehrlichiosis.
• Current data recommend continuation of treatment until the patient has been afebrile for at least 3 days and for a minimum of 5-7 days.

Consultations

Treat patients with ehrlichiosis in consultation with an infectious diseases specialist.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The American Academy of Pediatrics recommends doxycycline as first-line therapy for suspected or proven human granulocytic anaplasmosis (HGA) and human monocytic ehrlichiosis (HME).  Ordinarily, tetracyclines are not administered to children younger than 8 years; however, chloramphenicol is the alternative treatment option and is associated with aplastic anemia.  Additionally, oral chloramphenicol is no longer available in the United States. Chloramphenicol has also been associated with treatment failures and is inactive against A phagocytophilum in vitro.

Several case reports have detailed successful treatment of mild, non–life-threatening anaplasmosis (not ehrlichiosis) with rifampin in patients in whom doxycycline was contraindicated (eg, allergy, pregnancy).

Drug Category: Antibiotics

Doxycycline is considered the DOC for ehrlichiosis. Use rifampin only as an alternative treatment for mild anaplasmosis if doxycycline is contraindicated. For these indications, age younger than 8 years is not considered a contraindication for doxycycline.

Drug Name	Rifampin (Rifadin)
Description	Inhibits RNA synthesis in bacteria by binding to beta subunit of DNA-dependent RNA polymerase, which, in turn, blocks RNA transcription.
Adult Dose	300 mg PO/IV bid; not to exceed 600 mg/d
Pediatric Dose	10 mg/kg PO/IV bid; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
Interactions	Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid or pyrazinamide may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFT findings occur)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Avoidance of tick bites in infested areas is the first line of defense against ehrlichiosis.
• No role exists for the use of antimicrobial prophylaxis after a tick bite in the prevention of human monocytic ehrlichiosis (HME) or human granulocytic ehrlichiosis (HGE) due to the low rate of subsequent infection.
• If tick-infested areas cannot be avoided, wearing light-colored shirts and trousers that fit tightly around the waist and ankles can minimize the risk of tick bites.
• 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.
• Perform a body search for attached ticks with emphasis on areas containing hair.
• If ticks are found, any of several commercial removal devices should be used, if possible. 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 identify what (if any) infection may have 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.

Complications

• Renal failure
• Respiratory failure
• Intravascular coagulopathy
• Cardiomyopathy
• Meningitis
• Seizures
• Encephalopathy
• Coma

Prognosis

See Mortality/Morbidity.

Patient Education

For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to recognize that ehrlichiosis is a life-threatening disease
• Failure to give meticulous attention in treating these patients
• Failure to recognize that signs and symptoms of ehrlichiosis can mimic other diseases and, thus, failure to obtain an essential history of travel to endemic areas, tick bite, or exposure
• Failure to recognize that a negative history does not exclude the diagnosis
• Failure to administer antibiotics promptly if a high index of clinical suspicion is observed

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Buller RS, Arens M, Hmiel SP, et al. Ehrlichia ewingii, a newly recognized agent of human ehrlichiosis. N Engl J Med. Jul 15 1999;341(3):148-55. [Medline].
2. McQuiston JH, Paddock CD, Holman RC, Childs JE. The human ehrlichioses in the United States. Emerg Infect Dis. Sep-Oct 1999;5(5):635-42. [Medline].
3. Demma LJ, Holman RC, McQuiston JH, Krebs JW, Swerdlow DL. Human monocytic ehrlichiosis and human granulocytic anaplasmosis in the United States, 2001-2002. Ann N Y Acad Sci. Oct 2006;1078:118-9. [Medline].
4. Bakken JS, Krueth J, Wilson-Nordskog C, et al. Clinical and laboratory characteristics of human granulocytic ehrlichiosis. JAMA. Jan 17 1996;275(3):199-205. [Medline].
5. Chapman AS, Bakken JS, Folk SM, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichioses, and anaplasmosis--United States: a practical guide for physicians and other health-care and public health professionals. MMWR Recomm Rep. Mar 31 2006;55(RR-4):1-27. [Medline]. [Full Text].
6. Committee on Infectious Diseases. Ehrlichiosis. In: Red Book. 2006:281-4.
7. Dumler JS, Barbet AF, Bekker CP, et al. Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia, descriptions of six new species combinations and designation of Ehrlichia equi and 'HGE agent' as subjective synonyms of Ehrlichia phagocytophila. Int J Syst Evol Microbiol. Nov 2001;51(Pt 6):2145-65. [Medline].
8. Dumler JS, Choi KS, Garcia-Garcia JC, et al. Human granulocytic anaplasmosis and Anaplasma phagocytophilum. Emerg Infect Dis. Dec 2005;11(12):1828-34. [Medline].
9. Glushko GM. Human ehrlichiosis. Postgrad Med. Jun 1997;101(6):225-30. [Medline].
10. Jacobs RF, Schutze GE. Ehrlichiosis in children. J Pediatr. Aug 1997;131(2):184-92. [Medline].
11. Laudicina RJ, Hilger AE. Human ehrlichiosis: a case review. Clin Lab Sci. 1997;10(3):149-66.
12. Ogden NH, Woldehiwet Z, Hart CA. Granulocytic ehrlichiosis: an emerging or rediscovered tick-borne disease?. J Med Microbiol. Jun 1998;47(6):475-82. [Medline].
13. Schaffner W, Standaert SM. Ehrlichiosis--in pursuit of an emerging infection. N Engl J Med. Jan 25 1996;334(4):262-3. [Medline].
14. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. Nov 1 2006;43(9):1089-134. [Medline]. [Full Text].

Article Last Updated: Nov 1, 2007