Etiology

In 1987, clusters of bacteria confined within cytoplasmic vacuoles of circulating leukocytes (morulae), particularly mononuclear leukocytes, were detected in the peripheral blood of a severely ill patient with suspected Rocky Mountain spotted fever (RMSF). The etiologic agent of this case and other similar cases was found to resemble a canine pathogen in the genus Ehrlichia. In 1990, Ehrlichia chaffeensis was cultivated and identified as the predominant cause of “human ehrlichiosis.” Seroepidemiologic investigations showed that E. chaffeensis infections are transmitted by ticks and occur more often than RMSF in some geographic areas.

In 1994, the observation of other cases in which morulae were found only within circulating neutrophils and serology for E. chaffeensis was negative led to the recognition of another species. In these cases, serologic reactions were strongest to Ehrlichia phagocytophila and Ehrlichia equi, pathogens of ruminant and horse granulocytes, respectively. DNA of these bacteria was also found in the blood of infected persons. In 1996, the agent was cultivated in vitro; in 2001, the human agent and the 2 veterinary pathogens were unified into a single species and placed into the genus Anaplasma under the name Anaplasma phagocytophilum on the basis of genetic studies.

In 1996, a veterinary pathogen of canine neutrophils, Ehrlichia ewingii, was identified as the causative agent of some human infections initially thought to be due to E. chaffeensis because of the presence of morulae within circulating neutrophils. The infection is generally milder, but it can cause severe disease in children and adults with pre-existing immunosuppression, including organ transplant recipients or persons with HIV infection. Although not yet cultivated in vitro, it is serologically cross reactive with E. chaffeensis.

Although these infections are caused by bacteria assigned to various genera, the name ehrlichiosis has been applied to all. Human monocytic ehrlichiosis (HME) is used to describe disease characterized by infection of predominantly monocytes caused by E. chaffeensis, human granulocytic anaplasmosis (HGA) to describe disease of circulating neutrophils caused by Anaplasma phagocytophilum, and ewingii ehrlichiosis caused by E. ewingii (see Table 220-1).

All are tick-transmitted, small, obligate intracellular bacteria with gram-negative–type cell walls and are now classified in the Anaplasmataceae family. Neorickettsia (formerly Ehrlichia) sennetsu is another related bacterium that rarely causes human disease and is not transmitted by ticks. E. chaffeensis alters host signaling and transcription to cause the endosome to enter a receptor recycling pathway that avoids phagosome-lysosome fusion and allows the growth of a morula, an intravacuolar aggregate of bacteria. Little is known about the vacuoles in which A. phagocytophilum and E. ewingii grow. These bacteria are pathogens of phagocytic cells in mammals, and characteristically each species has a specific host cell affinity: E. chaffeensis and N. sennetsu infect mononuclear phagocytes, and A. phagocytophilum and E. ewingii infect neutrophils. Infection leads to direct modifications in function of the host cell that protect the bacterium from host defenses; yet, host immune and inflammatory reactions might in part account for many of the clinical manifestations seen in all forms of ehrlichiosis.

Epidemiology

Infections with E. chaffeensis occur across the southeastern, south central, and mid-Atlantic states in a distribution that parallels that of RMSF; cases have also been reported in northern California. Suspected cases with appropriate serologic and occasionally molecular evidence have been reported in Europe, Africa, and the Far East, including China and Korea. Human infections with E. ewingii have only been identified in the USA in areas where E. chaffeensis also exists, perhaps owing to a shared tick vector. Canine infections are documented in both sub-Saharan Africa and in South America.

Although the median age of patients with ehrlichiosis and anaplasmosis is generally older (>42 yr), many infected children have been identified. Little is known about the epidemiology of E. ewingii infections, although many patients have also been children. All infections are strongly associated with tick exposure and tick bites and are identified predominantly during May through September. Although both nymphal and adult ticks can transmit infection, nymphs are more likely to transmit disease, because they are most active during the summer.

Transmission

The predominant tick species that harbors E. chaffeensis and E. ewingii is Amblyomma americanum, the Lone Star tick. Additional vectors such as Dermacentor variabilis, the American dog tick, have not been proved but might explain the presence of HME outside the known range of A. americanum (see Fig. 220-1). The tick vectors of A. phagocytophilum are Ixodes, including I. scapularis (black-legged or deer tick) in the eastern USA (Fig. 220-1), I. pacificus (western black-legged tick) in the western USA, I. ricinus (sheep tick) in Europe, and I. persulcatus in Eurasia. Ixodes species ticks also transmit Borrelia burgdorferi, Babesia microti, and, in Europe, tick-borne encephalitis-associated flaviviruses. Co-infections with these agents and A. phagocytophilum have been documented in children and adults.

Ehrlichia and Anaplasma species are maintained in nature predominantly by horizontal transmission (tick to mammal to tick), because the organisms are not transmitted to the progeny of infected adult female ticks (transovarial transmission). The major reservoir host for E. chaffeensis is the white-tailed deer (Odocoileus virginianus), which is found abundantly in many parts of the USA. A reservoir for A. phagocytophilum in the eastern USA appears to be the white-footed mouse, Peromyscus leucopus. Deer or domestic ruminants may also have persistent asymptomatic infections, but the genetic variants in these reservoirs might not be infectious for humans. Efficient transmission requires persistent infections of mammals, long recognized in dogs with Ehrlichia canis, ruminants with A. phagocytophilum, and other hosts of various ehrlichial species. Although E. chaffeensis and A. phagocytophilum can cause persistent infections in animals, documentation of chronic infections in humans is exceedingly rare. Transmission of Ehrlichia can occur within hours of tick attachment, in contrast to the 1-2 days of attachment required for transmission of B. burgdorferi to occur. Transmission of A. phagocytophilum is via the bite of the small nymphal stage of Ixodes spp., including I. scapularis (see Fig. 220-1), which is very active during late spring and early summer in the eastern USA.

Pathology and Pathogenesis