Ehrlichiosis and Anaplasmosis

Etiology

Ehrlichiosis in humans was 1st described in 1987, when clusters of bacteria confined within cytoplasmic vacuoles of circulating leukocytes (morulae), particularly mononuclear leukocytes, were detected in the peripheral blood of a patient with suspected Rocky Mountain spotted fever (RMSF). The etiologic agent, Ehrlichia chaffeensis, was cultivated from blood of an infected patient in 1990 and identified as the predominant cause of human ehrlichiosis. Investigations showed that infection by E. chaffeensis is transmitted by Amblyomma americanum ticks and occurs more often than RMSF in some geographic areas. By 1994, other cases in which morulae were found only in neutrophils and lacked serologic evidence for E. chaffeensis infection led to the recognition of the species classified as Anaplasma phagocytophilum , which encompasses several previously described veterinary pathogens on at least 2 different continents and causing anaplasmosis .

Since these 1st discoveries in humans, additional species in the Anaplasmataceae family were identified as human pathogens, including (1) Ehrlichia ewingii in 1996, a veterinary pathogen of canine neutrophils transmitted by A. americanum ticks; (2) the Ixodes scapularis –transmitted Ehrlichia muris subsp . euclairensis in 2009, only present so far in patients from Minnesota and Wisconsin in the United States; (3) infections by Candidatus Neoehrlichia mikurensis, presumably Ixodes spp. or Haemaphysalis concinna tick-transmitted, recognized in 2010 as a cause of sepsis-like infections of immune compromised patients in Europe, and later as a cause of mild febrile illness in healthy individuals in China; (4) Panola Mountain Ehrlichia , a bacterium rarely associated with infections in human but present in A. americanum ticks in the United States and with genetic features of the ruminant pathogen Ehrlichia ruminantium ; (5) Ehrlichia canis, the established canine pathogen that has infected humans in Venezuela; and (6) Anaplasma capra , the cause of mild fever after Ixodes persulcatus tick bites, so far only identified in China . The latter 5 have not yet been established as causes of infection in children.

Although the infections caused by these various genera have been called ehrlichiosis, further study has identified substantial differences in biology and diagnostic approaches such that the CDC now generally separates these into ehrlichiosis, anaplasmosis, or undetermined ehrlichiosis/anaplasmosis. Human monocytic ehrlichiosis (HME) describes disease characterized by infection of predominantly monocytes and is caused by E. chaffeensis , human granulocytic anaplasmosis (HGA) describes disease related to infection of circulating neutrophils by Anaplasma phagocytophilum , and ewingii ehrlichiosis is caused by infection of granulocytes by E. ewingii (see Table 255.1 in Chapter 255 ).

All of these organisms are tick-transmitted and are small, obligate intracellular bacteria with gram-negative-type cell walls. Neorickettsia sennetsu is another related bacterium that is rarely recognized as a cause of human disease and is not transmitted by ticks. E. chaffeensis alters host signaling and transcription once inside the cell. It survives in an endosome that enters a receptor recycling pathway to avoid phagosome-lysosome fusion and growth into a morula , an intravacuolar aggregate of bacteria. A. phagocytophilum survives in a unique vacuole that becomes decorated by microbial proteins that prevent endosomal trafficking and lysosome fusion. Little is known about the vacuoles in which E. ewingii and E. muris subsp. euclairensis grow. These bacteria are pathogens of phagocytic cells in mammals, and characteristically each species has a specific host cell affinity: E. chaffeensis infects mononuclear phagocytes, and A. phagocytophilum and E. ewingii infect neutrophils. Infection leads to direct modifications in function, in part the result of changes in intracellular signal transduction or modulation of transcription of the host cell that diminishes host defenses toward the bacterium. Yet, host immune and inflammatory reactions are still activated and in part account for many of the clinical manifestations in ehrlichiosis, such as overlaps with macrophage activation or hemophagocytic lymphohistiocytosis syndromes.

Epidemiology

Infections with E. chaffeensis occur across the southeastern, south central, and mid-Atlantic states of the United 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, South America, and the Far East, including China and Korea. Human infections with E. ewingii have only been identified in the United States in areas where E. chaffeensis also exists, perhaps owing to the shared tick vector. Canine infections are documented in both sub-Saharan Africa and in South America.

Although the median age of patients with HME and HGA is generally older (>51 yr), many infected children have been identified, and for HME the case fatality rate is 4% in those <5 yr of age. Little is known about the epidemiology of E. ewingii infections; although infections in children occur, they are recognized at a rate 100-fold less than for E. chaffeensis . 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 A. americanum, the Lone Star tick (see Fig. 255.1D in Chapter 255 ). The tick vectors of A. phagocytophilum are Ixodes spp . , including I. scapularis (black-legged or deer tick) in the eastern United States (see Fig. 255.1 in Chapter 255 ), Ixodes pacificus (western black-legged tick) in the western United States, Ixodes ricinus (sheep tick) in Europe, Ixodes persulcatus in Eurasia, and Haemaphysalis concinna in China. The Ixodes spp. ticks also transmit Borrelia burgdorferi, Borrelia miyamotoi, Babesia microti, and tick-borne encephalitis-associated flaviviruses in Europe, Powassan viruses, and E. muris subsp. eauclairensis in North America. Co-infections with these agents and A. phagocytophilum are 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 for E. chaffeensis is the white-tailed deer (Odocoileus virginianus) , which is found abundantly in many parts of the United States. A reservoir for A. phagocytophilum in the eastern United States appears to be the white-footed mouse, Peromyscus leucopus. Deer or domestic ruminants can sustain persistent asymptomatic infections, but the genetic variants in these reservoirs might not be infectious for humans. Efficient transmission requires persistent infections of mammals. Although E. chaffeensis and A. phagocytophilum can cause persistent infections in animals, the 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. 255.1 A in Chapter 255 ), which is very active during late spring and early summer in the eastern United States.