Human Granulocytic Ehrlichiosis (HGE) is a rare infectious disease that belongs to a group of diseases known as the Human Ehrlichioses. The Ehrlichioses are infectious diseases caused by bacteria in the "Ehrlichia" family. Several forms of Human Ehrlichial infection have been identified including Human Granulocytic Ehrlichiosis (HGE), Sennetsu Fever, and Human Monocytic Ehrlichiosis (HME). Though caused by different strains of Ehrlichia bacteria, the disorders are all characterized by similar symptoms.
The symptoms of Human Granulocytic Ehrlichiosis (HGE) may include a sudden high fever, headache, muscle aches (myalgia), chills, and a general feeling of weakness and fatigue (malaise) within a week or so after initial infection. In most cases, abnormal laboratory findings may occur including an abnormally low number of circulating blood platelets (thrombocytopenia), a decrease in white blood cells (leukopenia), and an abnormal increase in the level of certain liver enzymes (hepatic transaminases). In some cases, symptoms may progress to include nausea, vomiting, cough, diarrhea, loss of appetite (anorexia), and/or confusion. If Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms, such as kidney failure and/or respiratory problems, may develop in some cases. Human Granulocytic Ehrlichiosis is caused by a bacterium of the Ehrlichiosis family that has not yet been named. The Ehrlichial bacterium is carried and transmitted by certain ticks (vectors), such as the deer tick (Ixodes scapularis) and the American dog tick (Dermacentor variabilis).
In individuals with Human Granulocytic Ehrlichiosis (HGE), the onset of symptoms usually occurs approximately one week after an individual has been bitten by a tick carrying the Ehrlichia bacterium. The particular strain of Ehrlichia bacterium responsible for HGE has not yet been named. In almost all cases, symptoms include fever, chills, muscle pain (myalgia), a general feeling of weakness and fatigue (malaise), and/or headaches. Some affected individuals may also experience coughing, nausea, vomiting, joint pain (arthralgia), and/or confusion. In extremely rare cases, a rash may appear on the skin.
In addition, most individuals with HGE exhibit an abnormal increase in the level of certain liver enzymes (hepatic transaminases); low levels of the protein albumin in the blood (hypoalbuminemia); and/or an abnormal decrease in circulating blood platelets (thrombocytopenia), red blood cells (anemia), and/or certain granular white blood cells (granulocytopenia) that play a role in removing bacteria from the blood and destroying them.
In some severe cases, if Human Granulocytic Ehrlichiosis is left untreated, life-threatening symptoms may develop, such as respiratory insufficiency, severe gastrointestinal bleeding, kidney (renal) failure, and/or liver damage.
According to the medical literature, in rare cases, individuals with HGE may be simultaneously infected with Lyme disease, a more common bacterial disease that is transmitted by deer ticks (which are also known tick vectors for HGE). In such cases, affected individuals may experience symptoms and physical findings often associated with both HGE and Lyme disease such as headache, fever, muscle aches, weakness, joint pain (arthralgia), and/or abnormalities of liver function. They may also experience certain symptoms and findings specific to one disorder yet rarely found in the other, such as the appearance of a characteristic red skin lesion (erythema chronicum migrans), which is often associated with Lyme disease, and/or a cough, thrombocytopenia, and/or granulocytopenia, which often occur in those with HGE. According to the medical literature, it is not yet clear whether coinfection with HGE and Lyme disease may result in more serious disease than that typically associated with infection with HGE or Lyme disease alone. (For more information on Lyme disease, please see the “Related Disorders” section of this report below.)
The human ehrlichioses, including Human Granulocytic Ehrlichiosis (HGE), are caused by bacteria belonging to the “Ehrlichia” family. These bacteria are transmitted to humans through the bite of infected ticks. (The ticks serve as “vectors”, the name for any organism that is infected with and later transmits a particular disease agent (e.g., bacterium or virus) to another organism, which may then become infected). Ticks that may transmit the bacterium responsible for HGE include the deer tick (Ixodes scapularis) and the American dog tick (Dermacentor variabilis).
Human Granulocytic Ehrlichiosis (HGE) is caused by a species of the ehrlichial bacterium that is genetically similar to, or identical with, the species that causes Ehrlichiosis in horses (Ehrlichia equi) as well as another strain that causes Ehrlichial infection in cattle, deer, and sheep (Ehrlichia phagocytophila).
In HGE, the Ehrlichial bacteria invade and, if untreated, eventually destroy (phagocytosis) certain white blood cells (granulocytes) that play a role in infection protection. The invading bacteria form distinctive membrane-bound bacterial aggregates (morulae) within the cytoplasm of the host cell.
Until recently, the Ehrlichioses were known primarily as veterinary disorders. However, two forms of the infection are found in humans: Human Granulocytic Ehrlichiosis (HGE) and Human Monocytic Ehrlichiosis (HME). First recognized in the United States in 1986, the human ehrlichioses are considered emerging zoonotic diseases (diseases of animals that may be transmissible to man under natural conditions), according to the Centers for Disease Control and Prevention.
National incidence rates have not been determined because of wide variability in reporting. The CDC has urged improved national surveillance for Ehrlichiosis. Meanwhile, from 1986 through 1997, 1,223 cases (742 HME, 449 HE, and 32 not ascribed to a specific agent) were reported by state health departments, according to a 1999 CDC report.
HGE has been reported more frequently from the northeastern and upper midwestern states, while HME has been reported more from the southeastern and southcentral states. The distinct geographic distributions of the human ehrlichioses may result from differences in the distribution of the different species of ticks which act as the vectors for the bacteria.
Although infection with HGE may occur at any time of the year, infection is most common during the months of June and July. In theory, this disease affects males and females in equal numbers. However, in observed cases, approximately 80 percent of affected individuals are male, while about 20 percent are female. Infection tends to occur when individuals participate in recreational or occupational activities that expose them to tick vectors.
In rare cases, individuals with HGE may be simultaneously infected with Lyme disease, an infectious disease caused by the spirochete bacterium Borrelia burgdorferi. Coinfection may occur because a percentage of deer ticks in certain geographic areas may be infected with the bacterial agents for both HGE and Lyme disease. In a suburban county of New York it was found that from 2.2% to 26% of deer ticks were coinfected with the agents for HGE and Lyme disease.
Human Granulocytic Ehrlichiosis (HGE) may be diagnosed based upon a thorough clinical evaluation, characteristic findings, and specialized laboratory tests.
Recently, a test developed at the Yale University School of Medicine and Connecticut Agricultural Experiment Station has been shown to be an appropriate diagnostic tool. It employs recombinant HE-44 antigen used in an ELISA (a type of enzyme immunoassay). When a team of scientists evaluated this method of diagnosis by testing normal serum samples from healthy individuals as well as serum samples from patients known to have HEG, they found that it correctly identified 87 percent of the samples from subjects with confirmed HGE.
Blood tests may reveal findings often associated with the Human Ehrlichioses such as abnormally low levels of circulating blood platelets (thrombocytopenia), low levels of certain white blood cells (leukopenia), and/or elevated levels of certain liver enzymes (such as aspartate aminotransferase [AST] and alanine aminotransferase [ALT]). In some cases, laboratory tests may reveal abnormalities of the cerebrospinal fluid. In addition, chest X-rays may reveal abnormalities in the lungs (e.g., pulmonary infiltrates, increased fluid in the lungs).
Examination of blood smears under a microscope that uses an electron beam (electron microscopy) may reveal clusters of bacteria in membrane-bound cavities (vacuoles) within certain cells (i.e., peripheral neutrophils); however, such clusters may not be apparent early in the course of infection. In some cases, additional specialized laboratory tests may then be conducted to help determine and/or to confirm a diagnosis of a specific bacterial infection.
Specialized laboratory tests may include Indirect Immunofluorescence Assays (IFA) conducted on the fluid portion of an affected individual's blood (serum). Antibodies, which are proteins manufactured by certain white blood cells, help the body fight toxins and invading microorganisms. In Indirect Immunofluorescence Assays, human antibodies are marked with special fluorescent dyes and a microscope with ultraviolet light is used, enabling researchers to observe antibody response to certain microorganisms.
IFA testing has been used in confirming a diagnosis of all known types of Human Ehrlichial infection. The bacterium that causes Human Granulocytic Ehrlichiosis (HGE) was isolated in 1996, a discovery that may lead to improved diagnostic tests. HGE may be confirmed by IFA testing, observing antibody response to the bacterium responsible for an Ehrlichial infection in horses, E. equi, a bacterium that is almost genetically identical to the bacterium causing HGE.
Measurable diagnostic rises in antibody response to the Ehrlichia bacteria may not occur until several weeks after the onset of Human Granulocytic Ehrlichiosis. As a result, initial IFA blood serum results may be negative in some cases. Therefore, more sensitive testing techniques that can help establish early diagnosis may be used in some cases.
One such process, called Polymerase Chain Reaction (PCR), is a laboratory technique in which sequences of DNA (which contains the organism's genetic information) may be quickly and repeatedly copied. This enables close analysis of the DNA, aiding in the identification of the organism in question. PCR conducted on certain bacterial DNA sequences obtained from patients' blood samples may confirm Human Ehrlichial infection due to a particular strain of Ehrlichia. PCR has been used to establish an early diagnosis of Human Granulocytic Ehrlichiosis.
Information in the medical literature indicates that because it may be difficult to differentiate Human Ehrlichial infection, such as Human Granulocytic Ehrlichiosis, from other illnesses that are also characterized by high fever (febrile illnesses), Ehrlichiosis should be considered in any patient with high fever, thrombocytopenia, and leukopenia who has recently been exposed to ticks. If HGE is suspected, treatment should not be delayed until diagnosis has been confirmed by IFA testing, since a positive antibody response may not occur until several weeks after initial infection. Therapy should begin as soon as possible after the onset of symptoms.
In rare cases, individuals who have symptoms and physical findings associated with HGE may also demonstrate certain symptoms typically associated with Lyme disease, such as the appearance of a red skin lesion (erythema chronicum migrans). In such rare cases, coinfection with HGE and Lyme disease should be considered. According to the medical literature, coinfection with the bacterial agents for HGE and Lyme disease may be confirmed by isolating both organisms from blood specimens.
The treatment of Human Granulocytic Ehrlichiosis usually entails standard doses of tetracycline or, alternatively, doxycycline. When individuals with HGE are unable to take tetracycline antibiotics (contraindicated), chloramphenicol may be effective. In severe cases of Human Granulocytic Ehrlichiosis, hospitalization may be required. Other treatment is symptomatic and supportive.
According to the medical literature, in rare cases when affected individuals have a confirmed diagnosis of coinfection with HGE and early Lyme disease, doxycycline treatment should be considered in those who can tolerate tetracycline medications.
Individuals in geographic areas who risk exposure to tick vectors for Ehrlichial infection should consider taking certain steps to prevent infection. Such steps should include wearing long-sleeved shirts, long pants, and hats; wearing light-colored clothing to make ticks more visible; using insect repellents; and carefully checking their clothing and skin (particularly the scalp and the back of the neck) after being in fields or wooded areas.
In early 1996, researchers at the University of Minnesota isolated the bacterium that causes Human Granulocytic Ehrlichiosis (HGE). Now that researchers understand how to promote the growth of this bacteria in cell culture, they can further study the nature of the organism, potentially leading to improved diagnosis and treatment of HGE. Researchers are currently working to develop a blood test that will aid in faster, more accurate diagnosis of Human Granulocytic Ehrlichiosis.
Research on tropical and other infectious diseases such as the Human Ehrlichioses is ongoing. For more information about these disorders, please contact the World Health Organization (WHO) listed in the Resources section below.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Harrison’s Principles of Internal Medicine, 13th Ed.: Kurt J. Isselbacher, M.D. et al., Editors; McGraw-Hill, Inc., 1994. P. 756.
Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 4th Ed.: Gerald L. Mandell, M.D. et al., Editors; Churchill Livingstone Inc., 1995. Pp. 1747-52, 2143.
Infectious Diseases: Sherwood L. Gorbach, John G. Bartlett, and Neil R. Blacklow, Editors; W.B. Saunders Company, 1992. Pp. 1312-14.
Ehrlichiosis: Ticks, Dogs and Doxycycline. J.L. Goodman; New Eng J Med (Jul 15 1999; 341(3)). Pp. 195-96.
Ehrlichia Ewingii, A Newly Recognized Agent of Human Ehrlichiosis. R.S. Buller et al.; New Eng J Med (Jul 15 1999; 341(3)). Pp. 148-55.
Ehrlichiosis: Ticks, Dogs and Doxycycline (editorial). J.L. Goodman; New Eng J Med (Jul 15 1999; 341(3)).
The Human Ehrlichioses in the United States. J.H. McQuiston et al.; Emerging Infectious Diseases (1999;5(5). Centers for Disease Control.
Deer Ticks (Ixodes Scapularis) and the Agents of Lyme Disease and Human Granulocytic Ehrlichiosis in a New York City Park. T.J. Daniels et al.; Emerging Infectious Diseases (1997; 3(3)). Pp. 353-55.
Simultaneous Human Granulocytic Ehrlichiosis and Lyme Borreliosis. R.B. Nadelman et al.; New Eng J Med (Jul 3 1997; 337(1)). Pp. 27-30.
Prevalence of the Rickettsial Agent of Human Granulocytic Ehrlichiosis in Ticks from a Hyperendemic Focus of Lyme Disease (letter). I. Schwartz et al.; New Engl J Med (Jul 3 1997; 337(1)). Pp. 49-50.
Direct Cultivation of the Causative Agent of Human Granulocytic Ehrlichiosis. J.L. Goodman et al.; New Eng J Med (Jan 25 1996; 334(4)). Pp. 209-15.
Ehrlichiosis – In Pursuit of an Emerging Infection (editorial). W. Schaffner et al.; New Eng J Med (Jan 25 1996; 334(4)). Pp. 262-63.
A Case of Concurrent Presentation of Human Ehrlichiosis and Lyme Disease in Connecticut. F.M. Mazzella et al.; Conn Med (1996; 60). Pp. 515-19.
The Clinical Spectrum of Early Lyme Borreliosis in Patients with Culture-Confirmed Erythema Migrans. R.B. Nadelman et al.; Am J Med (1996; 100). Pp. 502-08.
Human Granulocytic Ehrlichiosis: A Case Series from a Medical Center in New York State. M.E. Aguero-Rosenfeld et al.; Ann Intern Med (1996; 125). Pp. 904-08.
Emergence of the Ehrlichioses as Human Health Problems. D.H. Walker et al.; Emerging Infectious Diseases (Jan-Mar 1996; 2(1)). Pp. 1-16.
Seroepidemiology of Infections due to Spotted Fever Group Rickettsiae and Ehrlichia Species in Military Personnel Exposed in Areas of the United States Where Such Infections are Endemic. S.J. Yevich et al.; J Infect Dis (May 1995; 171(5)). Pp. 1266-73.
Serologic Cross-Reactions among Ehrlichia Equi, Ehrlichia Phagocytophila and Human Granulocytic Ehrlichia. J.S. Dumler et al.; J Clin Microbiol (May 1995; 33(5)). Pp. 1098-103.
Ehrlichiosis In A Golf-Oriented Retirement Community. S.M. Standaert et al.; New Eng J Med (Aug 17 1995; 333(7)). Pp. 420-25.
Ixodes Dammini as a Potential Vector of Human Granulocytic Ehrlichiosis. P. Pancholi et al.; J Infect Dis (1995; 172). Pp. 1007-12.
Human Granulocytic Ehrlichiosis in the Upper Midwest United States. A New Species Emerging? J.S. Bakken et al.; JAMA (Jul 20 1994; 272(3)). Pp. 212-18.
Identification of a Granulocytotropic Ehrlichia Species as the Etiologic Agent of Human Disease. S.M. Chen et al.; J Clin Microbiol (Mar 1994; 32(3)). Pp. 589-95.
Human Ehrlichiosis in Adults After Tick Exposure. Diagnosis Using Polymerase Chain Reaction. E.D. Everett et al.; Ann Intern Med (May 1 1994; 120(9)). Pp. 730-35.
Serologic Evidence for Human Ehrlichiosis in Africa. P. Brouqui et al.; Eur J Epidemiol (Dec 1994; 10(6)). Pp. 695-98.
A Case of Human Ehrlichiosis Acquired in Mali: Clinical and Laboratory Findings. I.J. Uhaa et al.; Am J Trop Med Hyg (Feb 1992; 46(2)). Pp. 161-64.
In Vitro Antibiotic Susceptibility of the Newly Recognized Agent of Ehrlichiosis in Humans, Ehrlichia Chaffeensis. P. Brouqui et al.; Antimicrob Agents Chemother (Dec 1992; 36(12)). Pp. 2799-803.
Detection of the Etiologic Agent of Human Ehrlichiosis by Polymerase Chain Reaction. B.E. Anderson et al.; J Clin Microbiol (Apr 1992; 30(4)). Pp. 775-80.
In Vitro Susceptibility of Ehrlichia Sennetsu to Antibiotics. P. Brouqui et al.; Antimicrob Agents Chemother (Aug 1990; 34(8)). Pp 1593-96.
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