Family Anaplasmataceae (Anaplasmosis, Ehrlichiosis, Neorickettsiosis, and Neoehrlichiosis)

Description of the Pathogens

The family Anaplasmataceae is classified in the order Rickettiales and currently contains five genera and two candidate genera of obligate intracellular bacteria. Four of the genera contain members that are known to infect humans: Anaplasma , Ehrlichia , Neorickettsia , and Candidatus Neoehrlichia. These zoonotic bacteria are transmitted by invertebrate vectors and can cause potentially life-threatening diseases in humans and animals. Their natural cycles are maintained through vector transmission among wildlife or domestic animals. Five species in the genus Ehrlichia and at least 4 species in the genus Anaplasma are documented as causes of human disease, and multiple species have been reported from children and adolescent patients worldwide ( Table 170.1 ). Globally, thousands of human cases due to Anaplasmataceae are reported each year, primarily recorded in the US. The dominant species responsible for disease in the US are Ehrlichia chaffeensis, E. ewingii , E. muris eauclairensis , and Anaplasma phagocytophilum . As new pathogens are characterized in the US and worldwide, it is likely that additional Anaplasmataceae capable of causing human disease may be discovered in the future.

Ehrlichia and Anaplasma species are small (0.5–1.5 μm) gram-negative cocci. The genomes of these organisms are relatively small, with a size of 1.18 Mb for E. chaffeensis and 1.47 Mb for A. phagocytophilum. After attachment to membrane receptors on the surface of target cells and subsequent induction of phagocytosis, the organisms multiply in endosomes that fail to develop into mature phagocytic or lysosomal vacuoles. Organisms reside within the cell cytoplasm of infected cells (monocytes, granulocytes, macrophages, erythrocytes, platelets, and endothelial cells, depending on the species). Organisms replicate within membrane-bound vesicles to form microcolonies known as morulae. The morphologic features of morulae vary among the species in size, number of individual organisms, and the presence of a fibrillar matrix ( Fig. 170.1 ). Individual morulae can contain few to many bacteria, which are released into the extracellular space after cell lysis or by exocytosis after fusion of the vacuole membrane with the plasma membrane. Ehrlichia species can spread to uninfected cells by concentration in filopodia in early infection and by host cell membrane rupture in late infection, whereas Anaplasma are released by host cell lysis without loss of host cell cytoplasm. ^, A. phagocytophilum and E. ewingii are found in granulocytes, whereas E. chaffeensis is found in monocytes. Neorickettsia sennetsu is found in monocytic cells of blood and lymph nodes, while the target cell of Candidatus Neoehrlichia mikurensis is vascular endothelial cells. The type(s) of cells infected with E. muris eauclairensis in humans is currently unknown.

Ehrlichia and Anaplasma species have developed a variety of adaptive mechanisms to subvert the host cell response and increase their survival. ^, The host immune response appears to be responsible for the pathology seen in infected patients, and cytokine and chemokine production by infected tissues may lead to more severe damage. Perivascular inflammatory infiltrates become apparent in many organs, and morulae can be visualized within the leukocyte populations present in these infiltrates. Mechanisms of many of the hematologic and biochemical perturbations, such as cytopenia and abnormal serum hepatic enzyme levels, are not completely clear. It is noteworthy that Anaplasma and Ehrlichia infections usually do not cause the vasculitis or endothelial damage characteristic of other rickettsial diseases, such as Rocky Mountain spotted fever .

Epidemiology

Ecologically, the species of Anaplasmataceae are usually maintained in wild or domestic mammalian species and transmitted within that system and to humans through invertebrate vectors, most often through the bite of a hard-bodied tick (Acari: Family Ixodidae). ^, The pathogens are generally distributed within the geographic ranges of their primary invertebrate vectors.

The members of the Anaplasmataceae can infect persons of all ages but are more frequently recognized in older adults. Over half of patients are hospitalized, and infections can result in life-threatening illness. The epidemiology of infections in children is derived from case reports and case series in the literature. Ehrlichia chaffeensis accounts for most Anaplasmataceae infections seen in the pediatric population. In the most recent surveillance summary, the case fatality rate was highest in children aged <5 years and in adults aged ≥70 years. Active surveillance for A. phagocytophilum infection (also called human granulocytic anaplasmosis) indicates that the age-specific incidence is notably low in persons aged <18 years and is highest in adults aged >50 years. Reasons for low case numbers in younger patients remain unclear, and the frequency of asymptomatic infection in children is unknown. Seroprevalence studies using generally accepted cutoff titers suggest that about 5.3% of children aged ≤19 years in an endemic area of the northeastern US had antibodies to A. phagocytophilum . Another study indicated that 13% of children aged ≤17 years in the southcentral and southeastern US had antibodies reactive with E. chaffeensis .

Infections by the Anaplasmataceae occur throughout the world, yet a number of pathogens occur in certain regions or countries (see Table 170.1 ). ^, A. phagocytophilum has been documented in many countries and is thought to be the most prevalent tick-borne infection in Europe. E. chaffeensis is thought to occur primarily in the US, although E. chaffeensis or antigenically similar organisms (some supported by molecular evidence) have been detected in other countries. N. sennetsu generally is limited to Southeast Asia and has more recently re-emerged in Laos. Despite the fact that Candidatus Neoehrlichia mikurensis is widespread in rodents and ticks in Europe and Asia, human cases have not been numerous but do occur in a number of countries. Childhood infection has not been documented. ^, Further study utilizing newly developed culture methods and multiple molecular targets for Anaplasmataceae infections will enhance our knowledge of emerging pathogens and help determine their threat to public health.

In the US, national passive surveillance found a fourfold increase in the number of ehrlichiosis cases reported from 2008–2012 compared with 2000. From 2008–2012, 4613 cases of Ehrlichia chaffeensis were recorded. The incidence rate was 3.2 cases/million person-years, with a 57% hospitalization rate and 1% case fatality rate. The highest case fatality rate (4%) was seen in children aged <5 years. During this same period, 55 cases of E. ewingii were reported to national surveillance. The incidence rate was 0.04 cases per million person-years, with a 77% hospitalization rate. No deaths were reported. Cases occurred across the southeastern and southcentral US and in New Jersey and Indiana. ^, Infections by E. ewingii have been seen in both patients with altered immune status and in previously healthy persons. From 2012–2016, the incidence of Ehrlichia chaffeensis infection increased to 4.47 per million person-years.

The US cases of anaplasmosis also increased in national passive surveillance system reports. From 2008–2012, a total of 8896 cases of A. phagocytophilum infection were reported, with an overall incidence of 6.3 cases per million person-years. Cases were reported from 38 states and the highest incidence was in Minnesota (97 cases per million person-years), Wisconsin (79), and Rhode Island (51). The hospitalization rate was 31% with a case fatality rate of 0.3%. Increasing age was associated with higher incidence, hospitalization, and case fatality rates. In the period of 2012–2016, the annual incidence increased to 7.27 per million person-years.

From 2008–2012, a total of 726 cases of ehrlichiosis or anaplasmosis where the specific etiology could not be determined based on available test results also were reported through national passive surveillance. When active case finding is conducted, both ehrlichiosis and anaplasmosis show incidences a magnitude higher than national passive surveillance.

Human ehrlichiosis and anaplasmosis share certain epidemiologic features. In addition to being reported most commonly in adults, cases are reported most frequently in males. Approximately 60% of the recorded pediatric cases have occurred in boys. Although cases can occur throughout the year, the peak seasonal incidence of disease is in May through August. ^, While generally a sporadic disease, clusters of cases have occurred during recreational activities and occupational exposure. Certain populations may be disproportionately affected by rickettsial diseases. It has been shown that Native Americans in the US had a higher incidence rate of infection than other races. While ehrlichiosis and anaplasmosis generally increase with age, American Indian cases had more cases in the lower age groups. The majority of these cases were reported from geographic regions endemic for ehrlichiosis, which may reflect increased exposure.

The endemic region for specific diseases can be reasonably approximated by the geographic distribution of each agent’s primary tick vector. ^, The pathogens are maintained in a variety of domestic and wildlife animal hosts via tick bite transmission. Infections caused by E. chaffeensis and E. ewingii are associated with the bite of the lone star tick, Amblyomma americanum. ^{, ,} This tick is primarily distributed across central Texas and eastern Oklahoma, eastward throughout the southeastern US and northerly along the Atlantic coastal plain into New England. The greatest number of cases of E. chaffeensis ehrlichiosis and those caused by E. ewingii have been reported from the southeastern and south central US The recognized geographic range of A. americanum is expanding, thus suggesting that the area of risk for ehrlichial pathogens transmitted by this vector should be considered dynamic. ^, Most anaplasmosis cases have occurred in the north central and northeastern states, particularly New York, Connecticut, Minnesota, and Wisconsin. ^{, ,} The principal tick vector is the blacklegged tick, Ixodes scapularis, the same tick that transmits Borrelia burgdorferi. This tick also is expanding its range, and more states reported anaplasmosis cases from 2008 to 2012 compared with previous years. ^, In the western US, Ixodes pacificus is the main vector of A. phagocytophilum to humans and animals . ^, In Europe, Ixodes ricinus has been incriminated, while Ixodes persulcatus is the primary vector in eastern parts of Asia.

Ticks in the genus Ixodes can transmit several other pathogens, including Babesia species, flaviviruses, and Borrelia burgdorferi. Dual infections with A. phagocytophilum and B. burgdorferi have been reported. In some children, the concurrent presence of anaplasmosis and Lyme disease has resulted in more severe disease.

Clinical Manifestations

Children and adults commonly present with fever, malaise, headache, and myalgia. Laboratory abnormalities classically include leukopenia, thrombocytopenia, and increased serum hepatic transaminase levels. These early clinical features may resemble other infectious and noninfectious diseases and a high level of suspicion is important when obtaining a complete epidemiologic and travel history. Outdoor activities (occupational or recreational) can increase the risk for tick bite. Patients may not recall tick bites due to the small size of ticks and the fact that the tick is not often attached at presentation. Clusters of ehrlichiosis or anaplasmosis can occur geographically or temporally, so asking about illness in associates or family can be helpful. History of travel within the US or to other countries will provide valuable clues to the possible etiology of suspected imported Anaplasmataceae infection (see Table 170.1 ).

The incubation period typically is between 5–21 days after a recognized tick bite. Many parents or children (55%–85%) recall a tick bite several days to weeks before the illness. ^{, ,} Common symptoms in children include fever, myalgia, and headache. Additional clinical features include anorexia, nausea or vomiting, and less frequently, hepatomegaly or spenomegaly. ^{, , ,} In adults with E. chaffeensis infections, rash is seen in only about 25%, yet rash occurs in about 66% of children ^{, ,} ; <10% of patients infected by A. phagocytophilum exhibit a rash. ^, When present, rash typically involves the trunk (sparing the hands and feet) and can appear macular, papular, maculopapular, or occasionally petechial. Gastrointestinal tract symptoms, including nausea, vomiting, anorexia, and diarrhea, are observed in approximately 60% of children with ehrlichiosis, slightly greater than that reported in adults with E. chaffeensis infection. ^, Adults with anaplasmosis have gastrointestinal tract symptoms less frequently (<40%). ^,

Moderate to severe headache is a common feature regardless of etiologic agent; however, encephalitis or meningitis is relatively rare and has been more frequently reported with E. chaffeensis . ^, Long-term neurologic sequelae, including bilateral footdrop, speech impairment, and diminished reading and fine motor ability, have been described in children following severe disease. ^{, ,}

Anaplasmosis and ehrlichiosis can both present as severe, life-threatening infections. Infections can result in severe pulmonary disease and may be a cause of acute respiratory distress syndrome in adults or children. ^, Intubation and mechanical ventilation have been required for severe cases of E. chaffeensis ehrlichiosis. ^{, ,} As in adults, the most severe disease in children is associated with infection by E. chaffeensis. Immunosuppressive conditions, including chemotherapy and organ transplantation, may predispose children to more severe disease by E. chaffeensis. ^, Presumably, the same or similar conditions predispose children to infection by E. ewingii . The first report of E. ewingii disease was in an 11-year-old boy receiving immunosuppressive therapy after kidney transplantation, and there have been recent case reports of severe E. ewingii infections in children with acute lymphoblastic leukemia and sickle cell disease. ^{, , ,}

Opportunistic infections may occur in patients as a result of alterations in neutrophil and CD4 ⁺ lymphocyte function. Disseminated candidiasis, invasive pulmonary aspergillosis, Cryptococcus neoformans pneumonia, herpes simplex, and cytomegalovirus infections have been noted. ^{, ,} Reinfection of the same patient with E. chaffeensis has been reported and reinfection with A. phagocytophilum has been documented. ^, Fatalities occur in <1% of A. phagocytophilum cases, often due to opportunistic infections. Case-fatality in Ehrlichia chaffeensis is about 3% and is more common in immunosuppressed patients. There have been no fatal cases of E. ewingii infections. ^,