CHAPTER 42 Anaplasma phagocytophila
ETIOLOGY
Anaplasma phagocytophila (also A. phagocytophilum, formerly Ehrlichia equi) is the etiologic agent of equine granulocytic ehrlichiosis (EGE). A. phagocytophila has recently been classified based on genetic analysis in the genus Anaplasma, with Anaplasma marginale, which causes infectious anemia in cattle by infecting erythrocytes, and Anaplasma platys, which causes canine cyclic thrombocytopenia by infecting platelets.1
Because 16S ribosomal ribonucleic acid (rRNA) gene sequences differ only up to three bases (99.1% homology) among former E. equi, Ehrlichia phagocytophila (cause of tick-borne fever in Europe), and the recently discovered human granulocytic ehrlichiosis (HGE) agent, these organisms are now all considered strains of A. phagocytophila. E. equi, E. phagocytophila, and the HGE agent are also closely related on the basis of morphology, host cell tropism, and antigen analysis by indirect fluorescent antibody tests.2 The deoxyribonucleic acid (DNA) sequences of the 16S rRNA gene from the peripheral blood of naturally infected horses in Connecticut and California are identical with those of the HGE agent.3 Moreover, blood derived from HGE patients causes typical EGE when injected into horses. In turn, the blood from these horses can transmit disease to other horses. The HE agent also induces protection in horses to subsequent challenge with E. equi.4,5 These data suggest that the agent of EGE and HGE are conspecific. A. phagocytophila has been cultured in vitro using the tick-embryo cell line IDE86 and a human promyelocytic leukemia cell line HL60.7
EPIDEMIOLOGY
Equine granulocytic ehrlichiosis occurs during late fall, winter, and spring. The horse represents an aberrant host, and it seems unlikely that infected horses could serve as effective reservoirs of A. phagocytophila, because the presence of the organism in an affected animal is limited to the acute phase of the disease. Horses of any age are susceptible, but the clinical manifestations are less severe in horses younger than 4 years.8 Horses from endemic areas have a higher seroprevalence of antibody to A. phagocytophila than horses from nonendemic areas, suggesting the occurrence of subclinical infection in some animals.9 Further, horses introduced into an endemic area are more likely to develop EGE than native horses.
In recent years, EGE has been experimentally transmitted by the western black-legged tick (Ixodes pacificus)10 and the deer tick (Ixodes scapularis).11 Further, an epidemiologic study in California showed that the spatial and temporal pattern of EGE cases closely paralleled the well-characterized life history and distribution of I. pacificus, but not other ticks typically associated with horses.12 In the eastern and midwestern United States, I. scapularis is the vector of granulocytic ehrlichiosis, and small rodents such as white-footed mice, chipmunks and voles, as well as the white-tailed deer, are potentially important reservoirs.13 In California, white-footed mice, dusky-footed wood rats, cervids, lizards, and birds have been proposed as reservoirs.14 In Europe, where granulocytic ehrlichiosis is transmitted by the sheep tick (Ixodes ricinus), the reported reservoir hosts are wild rodents, deer, and sheep.15
PATHOGENESIS
The pathogenesis of EGE is poorly understood. Clearly, after entering the dermis by tick-bite inoculation and spread, presumably through lymphatics or blood, ehrlichiae invade target cells of the hematopoietic and lymphoreticular systems. Ehrlichiae replicate within vacuoles of professional phagocytes. Whether or how these granulocytic ehrlichiae directly injure cells is not known, despite clear evidence of cytolytic activity in vitro.7 Granulocytic ehrlichiae are suspected to initiate a cascade of localized pathologic inflammatory events after invading organs such as spleen, liver, and lungs. Subsequent tissue injury is thought to be mediated locally by accumulating inflammatory cells and systematically by induction of proinflammatory responses.16 The mechanism by which sufficient cells are removed to cause pancytopenia is unknown. However, the presence of normal cellularity or diffuse hyperplasia of bone marrow, combined with hemophagocytosis in spleen and lymph nodes, and the presence of infected granulocytes in spleen and lung support peripheral sequestration, consumption, and destruction of normal blood elements as the major mechanisms for ehrlichia-induced pancytopenia.16
Granulocytic ehrlichioses caused by A. phagocytophila are diseases that trigger dysfunction or suppression of host defenses. It is well established that horses infected with A. phagocytophila are predisposed, as are humans and sheep, to develop opportunistic infections and secondary infections with bacteria, fungi, and viruses.17 These animals develop defects in both humoral and T-cell–mediated immunity and abnormalities in normal neutrophil phagocytic and migratory functions.18
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