Human Granulocytic Anaplasmosis

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Tick-borne infections have been recognized in the United States for more than a century. Patients who present with nonspecific fever after exposure to ticks should be evaluated by clinical examination and routine laboratory testing to determine if the illness is potentially a tick-borne infection. This article focuses on the diagnosis and management of human granulocytic anaplasmosis (HGA) caused by Anaplasma phagocytophilum.

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Microbiology

Anaplasma species are obligate, intracytoplasmic bacteria that belong to the order Rickettsiales, family Anaplasmataceae. Like other members of the genus Anaplasma and the closely related genus Ehrlichia, electron microscopy studies of A phagocytophilum demonstrate a characteristic bi-lamellar outer cell wall structure that is typical of Gram-negative bacteria [8]. However, the genome lacks gene-encoding biosynthetic pathways for lipopolysaccharides, peptidoglycan, glycolysis, and glutamate;

Epidemiology

Ticks in the Ixodes persulcatus-complex serve as competent vectors for multiple pathogens that may infect humans including A phagocytophilum[12], Borrelia burgdorferi (the agent of Lyme borreliosis) [13], and Babesia microti (the agent of babesiosis) [14]. HGA is a zoonosis, since the A phagocytophilum lifecycle involves both nonhuman vertebrate and invertebrate hosts. The vector-ticks in their endemic habitats in North America include Ixodes scapularis in the northeastern and upper Midwest

Clinical presentation

Patients with HGA frequently present with a nonspecific febrile illness. The clinical range of HGA spans from asymptomatic infection to fatal disease; there is a direct correlation between patient age and/or comorbid illnesses and the severity [22]. Most symptomatic patients report exposure to ticks one to two weeks before the onset of illness and they often complain of shaking chills, myalgia, and headache (Table 2). HGA can be severe with nearly half of patients requiring hospitalization and

Pathogenesis

A phagocytophilum binds to surfaces of neutrophils via fucosylated platelet selectin glycoprotein ligand-1 (PSGL-1), and possibly other surface structures [48]. The bacterial adhesin is uncertain, but likely involves Msp2, its major immunodominant protein [11]. Binding occurs at locations of lipid rafts, and host cholesterol seems to be a critical factor [49]. Once internalized, A phagocytophilum inhibits maturation of the parasitophorous vacuole, where it inserts type IV secretion proteins

Diagnosis

Most patients present with nonspecific changes in routine hematological and chemistry blood tests. Permutations of leukopenia, a left shift (sometimes reaching 50% or even higher), thrombocytopenia, and mild to moderate elevation of hepatic transaminase activities are present in the majority of patients and provide suggestive clues to the diagnosis [22], [57]. Although both leukopenia and thrombocytopenia are present in many patients at the initial presentation, these abnormalities usually

Differential diagnosis

Owing to the undifferentiated presentation of HGA, the differential diagnosis can be vast. With the common manifestations of fever, headache, myalgia, and malaise, viral syndromes such as enterovirus infection, Epstein-Barr virus infection, human herpes virus-6 infection, human parvovirus B19 infection, viral hepatitis, and West Nile fever should be included on the list of differential diagnoses. Acute bacterial infections to consider include disseminated gonococcal infection, endocarditis,

Treatment

In vitro investigations indicate that A phagocytophilum is uniformly susceptible to the tetracycline antibiotics [66], [67], [68]. Doxycycline hyclate has traditionally been the agent of choice because of its good patient tolerance and favorable pharmacokinetic properties compared with other tetracycline derivatives. For the most part, HGA is a mild illness, but there is a known direct relationship between serious infection, including cases with a fatal outcome, and patient variables such as

Prognosis and long-term outcome

More than 2963 patients were diagnosed with HGA and reported to state and federal health agencies since 1994 [71], although informal compilations document almost twice that number [77]. Only eight patients are known from published literature to have died during the active phase of HGA [15], [43], [46], [78]. Thus, the case fatality rate for HGA is likely between 0.2% and 1.0% [78], Published case-report series indicate that HGA most often is a mild, self-limited illness that resolves even

Immunity and reinfection

Most patients acquire HGA in the geographic region where they live, work, or recreate [15], [19], [25], [26], [79], [80]. It is therefore reasonable to assume that those individuals remain at risk for future bites by infected Ixodes ticks and potential HGA re-infection. Nevertheless, only a single patient is known to have been infected with A phagocytophilum more than once [83]. Although unproven, it is likely that patients who develop and maintain high antibody titers to A phagocytophilum are

Prevention

Avoidance of tick bites and prompt removal of attached ticks remain the best disease prevention strategy. Individuals who are exposed in tick habitats should wear protective clothing, including long-sleeved shirt, long-legged pants, socks wrapped outside the pant legs and close-toed shoes to make it harder for ticks to reach bare skin and attach (bite). Light-colored pants make it easy to see and remove crawling ticks. Chemoprophylactic agents to such as DEET (N,N-diethyl-m-toluamide) repel

Summary

Patients who present with nonspecific fever after exposure to ticks should be evaluated by clinical examination and routine laboratory testing to determine if the illness is potentially a tick-borne infection. Laboratory abnormalities such as leukopenia with relative granulocytosis and a left shift, thrombocytopenia, and mild increases in serum hepatic transaminase activities warrant consideration for treatment with doxcycline. These patients should also undergo specific laboratory testing to

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    This article was supported by grants R01 AI44102 and R56 AI41213.

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