Human Granulocytic Anaplasmosis and Anaplasma phagocytophilum

J. Stephen Dumler; Kyoung-Seong Choi; Jose Carlos Garcia-Garcia; Nicole S. Barat; Diana G. Scorpio; Justin W. Garyu; Dennis J. Grab; Johan S. Bakken

Disclosures

Emerging Infectious Diseases. 2005;11(12) 

In This Article

Abstract and Introduction

Human granulocytic anaplasmosis is a tickborne rickettsial infection of neutrophils caused by Anaplasma phagocytophilum. The human disease was first identified in 1990, although the pathogen was defined as a veterinary agent in 1932. Since 1990, US cases have markedly increased, and infections are now recognized in Europe. A high international seroprevalence suggests infection is widespread but unrecognized. The niche for A. phagocytophilum, the neutrophil, indicates that the pathogen has unique adaptations and pathogenetic mechanisms. Intensive study has demonstrated interactions with host-cell signal transduction and possibly eukaryotic transcription. This interaction leads to permutations of neutrophil function and could permit immunopathologic changes, severe disease, and opportunistic infections. More study is needed to define the immunology and pathogenetic mechanisms and to understand why severe disease develops in some persons and why some animals become long-term permissive reservoir hosts.

Human granulocytic anaplasmosis (HGA) was first identified in 1990 in a Wisconsin patient who died with a severe febrile illness 2 weeks after a tick bite.[1] During the terminal phases of the infection, clusters of small bacteria were noted within neutrophils in the peripheral blood (Figure 1), assumed to be phagocytosed gram-positive cocci. A careful review of the blood smear suggested the possibility of human ehrlichiosis, an emerging infection with similar bacterial clusters in peripheral blood monocytes among infected patients in the southeast and south-central United States. All blood cultures were unrevealing, and specific serologic and immunohistochemical tests for Ehrlichia chaffeensis, the causative agent of human monocytic ehrlichiosis (HME) were negative. Over the ensuing 2 years, 13 cases with similar intraneutrophilic inclusions were identified in the same region of northwestern Wisconsin and eastern Minnesota.[2] Aside from the bacterial clusters, common features among these persons included fever, headache, myalgia, malaise, absence of skin rash, leukopenia, thrombocytopenia, and mild injury to the liver.

Anaplasma phagocytophilum in human peripheral blood band neutrophil (A. Wright stain, original magnification ×1,000), in THP-1 myelomonocytic cell culture (B, LeukoStat stain, original magnification, ×400), in neutrophils infiltrating human spleen (C, immunohistochemistry with hematoxylin counterstain; original magnification ×100), and ultrastructure by transmission electron microscopy in HL-60 cell culture (D; courtesy of V. Popov; original magnification ×21,960).

In 1994, through application of broad range molecular amplification and DNA sequencing, the causative agent was recognized as distinct from E. chaffeensis. The agent was initially named HGE agent,[1,2] although morphologic and serologic studies indicated a close or identical relationship to the veterinary pathogens of neutrophils, E. equi and E. (Cytoecetes) phagocytophila. During the process of classification of the human agent, phylogenetic studies showed taxonomic disarray among organisms broadly referred to as ehrlichiae, and a careful reorganization now places those bacteria previously classified as E. phagocytophila, E. equi, and the HGE agent into a different genus as a single species, A. phagocytophilum (Figure 2).[1,3] The fallout from the reclassification of these organisms is the proposal for a complete revision of the families Rickettsiaceae and Anaplasmataceae. Under the proposed revision, the tribe structure of the Rickettsiaceae would be abolished, and species in the Ehrlichieae tribe would be assigned to the family Anaplasmataceae, with several placed into the genera Ehrlichia (Cowdria ruminantium), Anaplasma (E. equi, E. phagocytophila, HGE agent, E. platys, E. bovis), and Neorickettsia (E. sennetsu and E. risticii). The genera Ehrlichia and Anaplasma possess all pathogens in the family that are transmissible by ticks and that generally infect peripheral blood cellular elements, including leukocytes, platelets, and erythrocytes.

Current phylogeny and taxonomic classification of genera in the family Anaplasmataceae. The distance bar represents substitutions per 1,000 basepairs. E. coli, Escerichia coli.

HGA is increasingly recognized as an important and frequent cause of fever after tick bite in the Upper Midwest, New England, parts of the mid-Atlantic states, northern California, and many parts of Europe, all areas where Ixodes ticks bite humans.[4,5,6] The ecology of A. phagocytophilum is increasingly understood. The bacterium is maintained in a transmission cycle with Ixodes persulcatus complex ticks, including I. scapularis in the eastern United States, I. pacificus in the western United States, I. ricinus in Europe, and probably I. persulcatus in parts of Asia. Tick infection is established after an infectious blood meal, and the bacterium is transstadially but not transovarially passed.[3] The major mammalian reservoir for A. phagocytophilum in the eastern United States is the white-footed mouse, Peromyscus leucopus, although other small mammals and white-tailed deer (Odocoileus virginianus) can also be infected. White-footed mice have transient (1-4 weeks) bacteremia; deer are persistently and subclinically infected. Human infection occurs when humans impinge on tick-small mammal habitats.[4,5,6,7]

HGA is clinically variable, but most patients have a moderately severe febrile illness with headache, myalgia, and malaise. Among 10 clinical studies that describe the findings in HGA across North America and Europe and that comprise up to 685 patients ( Table ), the most frequent manifestations are malaise (94%), fever (92%), myalgia (77%), and headache (75%); a minority have arthralgia or involvement of the gastrointestinal tract (nausea, vomiting, diarrhea), respiratory tract (cough, pulmonary infiltrates, acute respiratory distress syndrome [ARDS]), liver, or central nervous system.[4,5,6,7] Rash is observed in 6%, although no specific rash has been associated with HGA and co-infection with Borrelia burgdorferi, which can cause simultaneous erythema migrans, is not infrequent. Frequent laboratory abnormalities identified in up to 329 patients include thrombocytopenia (71%), leukopenia (49%), anemia (37%), and elevated hepatic transaminase levels (71%).

Recent seroepidemiologic data suggest that many infections go unrecognized, and in endemic areas as much as 15% to 36% of the population has been infected.[16,17] In Wisconsin, the yearly incidence of HGA from 1990 to 1995 was as high as 58 cases/100,000 in 1 county (Lyme disease incidence in the same region was 110 cases/100,000).[5] The overall yearly Connecticut incidence rate from 1997 to 1999 was 24 to 51 cases/100,000 population.[18] Symptomatic infection in Europe appears to be rare; 66 cases have been reported, despite a median seroprevalence rate of 6.2% among 35 published reports, with rates as high as 21% in some European studies. Similarly, the median infection prevalence in European I. ricinus ticks is 3% (45 publications), a figure close to that observed among North American I. scapularis and I. pacificus ticks (median 4.7% among 42 publications).

What is unclear from these data is whether the discrepancy between the seroprevalence and symptomatic rate results from underdiagnosis of infection, asymptomatic serologic reactions, or even infections that produce cross-reactive serologic responses. In any case, symptomatic infection can occur often in tick-endemic regions and varies in severity from mild, self-limited fever to death. Severity sufficient for hospitalization is observed in half of symptomatic patients and is associated with older age, higher neutrophil counts, lower lymphocyte counts, anemia, the presence of morulae in leukocytes, or underlying immune suppression.[5] Approximately 5%-7% of patients require intensive care, and at least 7 deaths have been identified,[2,4,5,7,19] in which delayed diagnosis and treatment were risk factors. Severe complications include a septic or toxic shock-like syndrome, coagulopathy, atypical pneumonitis/acute respiratory distress syndrome (ARDS), acute abdominal syndrome, rhabdomyolysis, myocarditis, acute renal failure, hemorrhage, brachial plexopathy, demyelinating polyneuropathy, cranial nerve palsies, and opportunistic infections. At least 3 of the deaths resulted from opportunistic fungal or viral infections or hemorrhage that occurred immediately after HGA. In 2 cases, the patients had reasons for preexisting immunocompromise, which suggests that an intact immune system is important for recovery and that HGA further antagonizes immune dysfunction.[2,4,5,7] Unlike results of animal observations,[20] no evidence has shown A. phagocytophilum persistence in humans.

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