Anaplasmosis and Ehrlichiosis --- Maine, 2008

Anaplasmosis and ehrlichiosis are rickettsial tickborne diseases that have had at least a twofold increase in prevalence in the United States since 2000 (1,2). Despite similar clinical presentations, the causative organisms are carried by different ticks with distinct geographic and ecologic associations (3). Surveillance efforts are complicated by ambiguous terminology and serologic testing with antibody cross-reactivity. Although anaplasmosis historically has been reported in Maine, ehrlichiosis has been reported infrequently. During 2007--2008, the number of physician-reported anaplasmosis cases nearly doubled in Maine, and ehrlichiosis cases increased more than fourfold. To examine this increase, the Maine Department of Health and Human Services (MDHHS) analyzed available data on tick burden and physician-reported cases of anaplasmosis and ehrlichiosis during 2000--2008. This report describes the results of that analysis, which indicated that Ixodes scapularis (the tick vector for Anaplasma phagocytophilum) was broadly distributed in Maine, whereas Amblyomma americanum (the tick vector for Erhlichia chaffeenisis) was scarce. Moreover, 95% of physician-reported ehrlichiosis cases lacked a concurrent serologic assessment to exclude anaplasmosis, suggesting that antibody cross-reactivity might have resulted in misclassification. In 2008, Maine modified case classification to enhance specificity; ehrlichiosis cases that lack a concurrent test for anaplasmosis are now classified as suspect rather than probable and therefore are not included in national surveillance summaries. The accuracy of case classification and surveillance can be improved by educating health-care providers regarding 1) the expected geographic distribution of tick vectors and 2) recommendations for confirmatory testing to distinguish between the causative organisms of anaplasmosis and ehrlichiosis.

In Maine, laboratories electronically report positive anaplasmosis and ehrlichiosis results to the health department (referred to as physician reported). Field epidemiology personnel follow up positive results by interviewing physicians and patients and by obtaining clinical, laboratory, and epidemiologic information required to complete the CDC tickborne rickettsial disease case report form.* MDHHS conducted a review of available data on tick burden in the state and reviewed the clinical and public health surveillance data for physician-reported human ehrlichiosis and anaplasmosis during 2000--2008. Maine classified cases according to Council of State and Territorial Epidemiologists (CSTE) case definition† with the exception that the 2008 cases were classified according to a modified ehrlichiosis case definition that had increased specificity.

Tick Surveillance Data

During 2000--2008, the Vector Borne Disease Laboratory of the Maine Medical Center Research Institute conducted active surveillance of ticks in Maine (through flagging and trapping) and passive surveillance (through receipt of ticks submitted by state residents through the mail) (4). A total of 5,089 I. scapularis were collected, but only 15 A. americanum ticks were detected. All life stages of I. scapularis (larvae, nymphs, and adults) were identified; the tick distribution increased and expanded along the southern coastline and up the river valleys, corresponding to areas of increasing settlement of human populations in this geographic distribution. During 2007--2008, Maine residents submitted 1,968 I. scapularis and only six A. americanum. The surveillance results suggested that A. americanum, the ehrlichiosis vector, had only a sparse and sporadic distribution in Maine.

Human Anaplasmosis Surveillance Data

During 2000--2008, a total of 45 cases of anaplasmosis cases were reported in Maine. Fifteen (33%) cases were confirmed, 30 (67%) were probable, and no suspect cases were reported (Tables 1 and 2). Among the 15 confirmed cases, three (20%) patients were diagnosed by demonstration in paired sera of a fourfold or greater increase in antibodies to A. phagocytophilum in acute versus convalescent samples; 12 (80%) patients were diagnosed by polmerase chain reaction (PCR) detection of A. phagocytophilum DNA, including two patients who also had positive single A. phagocytophilum serologic test. Among the 30 probable cases, 23 (77%) patients were diagnosed only by a single test for antibodies to A. phagocytophilum, including one (3%) patient who also had detection of morulae consistent with A. phagocytophilum on a blood smear. Seven (23%) patients were tested for antibodies to both A. phagocytophilum and E. chaffeensis, and all showed higher antibody titers to A. phagocytophilum. The median patient age among all confirmed and probable cases was 57 years (range: 21--89 years); 28 patients (62%) were males. Seventeen (38%) patients were hospitalized, and one (2%) patient died from renal failure relating to infection. Two (4%) patients were diagnosed with concurrent Lyme disease, and two (4%) with concurrent babesiosis. Reported anaplasmosis cases occurred during April--December; 30 (67%) of 45 patients had onset dates during May--September. Anaplasmosis was reported in six (38%) of 16 counties; the majority occurred in southern coastal Maine. One patient with confirmed anaplasmosis had traveled to New York, an anaplasmosis-endemic state, during the preceding month.

Human Ehrlichiosis Surveillance Data

During 2000--2008, a total of 20 cases of ehrlichiosis were reported in Maine (Tables 1 and 2). The single confirmed case, which was diagnosed by PCR, occurred in a male aged 58 years who worked as an interstate truck driver; therefore, out-of-state exposure to E. chaffeensis was possible. An additional 19 ehrlichiosis cases were reported during this same period (including six cases reported during 2005--2007 and 13 cases reported during 2008). All 19 cases were diagnosed by a single positive Ehrlichia serologic assay, and none had accompanying serologic tests to exclude anaplasmosis. Although all 13 cases reported in 2008 would have met the CSTE case definition for probable ehrlichiosis, beginning in that year, Maine had adopted a modified ehrlichiosis case definition to increase specificity; therefore, these 13 case were classified as suspect. Ten of the 20 cases were in persons who had either concurrent Lyme disease (seven persons) or babesiosis (three persons), which, like Anaplasma, are transmitted by I. scapularis.

2008 Classification of Ehrlichiosis Cases

Based on the lack of evidence for a sustained tick vector population in the state, lack of travel history among patients, and the cross-reactive serologic tests for ehrlichiosis and anaplasmosis, MDHHS implemented a new ehrlichiosis case classification strategy using a modified CSTE case definition in 2008 (5). Probable ehrlichiosis cases were defined as clinically compatible with one positive immunoglobulin G (IgG) serologic result for E. chaffeensis and either a concurrent lower titer serologic test for A. phagocytophilum or visualization of intracytoplasmic morulae in peripheral monocytes or macrophages. For cases having serologic reactivity to both agents, the higher antibody level was used to identify the most likely infection (5). Ehrlichiosis reports that did not meet this new more stringent probable case definition (i.e., those that were only tested for ehrlichiosis) were classified as suspect cases, which are excluded from national notifiable disease surveillance summaries.

Reported by: B Cahill, C Lubelczyk, R Smith, MD, Maine Medical Center Research Institute; K Gensheimer, MD, A Robbins, MPH, S Robinson, MPH, Maine Dept of Health and Human Svcs. ME Eremeeva, MD, PhD, JH McQuiston, DVM, National Center for Zoonotic, Vector-Borne, and Enteric Diseases; A Pelletier, MD, Coordinating Office for Terrorism Preparedness and Emergency Response; J Adjeman, PhD, JE Tongren, PhD, EIS officers, CDC.

Editorial Note:

The findings in this report underscore that the use of cross-reactive serologic assays, which test for ehrlichiosis alone in anaplasmosis-endemic areas, can result in an inaccurately high ehrlichiosis incidence and contribute to underrecognition of actual anaplasmosis cases. Serologic assays for A. phagocytophilum and E. chaffeensis have >50% cross reactivity; thus, differentiating between ehrlichiosis or anaplasmosis based on single serologic assay is not possible (6--8). In 2008, Maine classified 13 ehrlichiosis cases as suspect because they more likely represent infection with A. phagocytophilum given that tick data did not support a sustained ehrlichiosis vector in the state and confirmatory laboratory testing and supporting travel history for ehrlichiosis infection were lacking. The likelihood these suspect cases are anaplasmosis cases is further supported by the fact that 54% of suspect ehrlichiosis cases occurred in persons who had either concurrent Lyme disease or babesiosis, which, like Anaplasma, are transmitted by I. scapularis. Whether the emergence of anaplasmosis in Maine and nationwide is an actual increase in incidence or an increase in awareness and testing is unclear. Reports of anaplasmosis have increased threefold (from 351 cases in 2000 to 1,053 cases in 2008), and reports of ehrlichiosis have increased more than fourfold (from 200 cases in 2000 to approximately 800 cases in 2008) (1; CDC, unpublished data, 2009). Most cases of ehrlichiosis have been reported from the southern and south-central United States, corresponding to the geographic distribution of the tick vector, A. americanum. However, during 2008--2009, a concerning trend of increased ehrlichiosis case reports from some northern-area states, including Maine, has been noted (CDC, unpublished data, 2009). Possible explanations for this increase include expanding geographic ranges of the tick vector A. americanum or misclassification of cases.

Anaplasmosis, referred to as human granulocytic anaplasmosis, is caused by A. phagocytophilum. Before a taxonomic reorganization in 2001, this organism was called Ehrlichia phagocytophilum, and the infection was described as human granulocytic ehrlichiosis. I. scapularis (the black-legged tick), the vector for anaplasmosis, is reported commonly from northern and northeastern states. Ehrlichiosis, known as human monocytic ehrlichiosis, is caused by E. chaffeensis and is transmitted by A. americanum (the lone star tick). E. chaffeensis is commonly reported in the southern and south-central states, where the vector is common. Both anaplasmosis and ehrlichiosis are nationally notifiable diseases. In Maine, the vector A. americanum responsible for transmission of E. chaffeensis is not endemic. Conversely, A. phagocytophilum DNA has been detected in 16% of 94 I. scapularis ticks tested in 2008 (9). The fact that 95% of physician-reported ehrlichiosis cases lacked a concurrent serologic assessment to exclude anaplasmosis supports the likelihood that antibody cross-reactivity could have resulted in misclassification. One factor contributing to this misclassification might have been confusion among physicians regarding the recent change in terminology for A. phagocytophilum infection (from human granulocytic ehrlichiosis to anaplasmosis) and a lack of understanding of appropriate testing strategies. Since taxonomic changes were adopted in 2001, the term "anaplasmosis" has gradually replaced the term "human granulocytic ehrlichiosis" to describe human infections with A. phagocytophilum. However, some medical references and commercial test names still use the term "ehrlichiosis," which might cause confusion among physicians regarding the selection of appropriate diagnostic tests.

Health-care providers should assess clinical and ecologic features and, as indicated, include concurrent confirmatory testing for both anaplasmosis and ehrlichiosis or other tickborne diseases when evaluating patients with suspected tickborne illness. Compared with anaplasmosis patients, ehrlichiosis patients might have a higher potential for severe or fatal outcome, and a higher proportion (up to 30%) of ehrlichiosis patients have rash; thus, these diagnostic clues also can prompt physicians to request concurrent testing for ehrlichiosis (3). If serologic testing is selected to evaluate patients, serology should include 1) concurrent testing for both A. phagocytophilum and E. chaffeensis and 2) testing of paired acute and convalescent sera whenever possible. PCR is considered a confirmatory test and is the recommended diagnostic tool preferred over serology because it can differentiate between the two infections (4,10). Patients with suspected anaplasmosis or ehrlichiosis should be treated promptly with doxycycline, without regard to initial serologic test results, because antibodies in the first week of illness frequently are not detected.

Acknowledgments

This report is based, in part, on contributions by K Bisgard, DVM, Office of Workforce and Career Development, CDC.

References

1. CDC. Final 2000 reports on notifiable diseases. MMWR 2001;50:712.
2. CDC. Final 2007 reports of nationally notifiable infectious diseases. MMWR 2008;57:906.
3. Demma LJ, Holman RC, McQuiston JH, et al. Human monocytic ehrlichiosis and human granulocytic anaplasmosis in the United States, 2001--2002. Am J Trop Med Hyg 2005;73:400--9.
4. Rand PW, Lacombe EH, Dearborn R, et al. Passive surveillance in Maine, an area emergent for tick borne diseases. J Med Entomol 2007;44:1118--29.
5. Council of State and Territorial Epidemiologists. Revision of the national surveillance case definition for ehrlichiosis (ehrlichiosis/anaplasmosis). Available at http://www.cste.org/ps/2007ps/2007psfinal/id/07-id-03.pdf.
6. Wong S, Brady G, Dumler JS. Serologic responses to Ehrlichia equi, Ehrlichia chaffeensis, and Borrelia burgdorferi in patients from New York State. J Clin Microbiol 1997;35:2198--205.
7. Childs JE, Sumner JW, Massung RF, et al. Outcome of diagnostic tests using samples from patients with culture-proven human monocytic ehrlichiosis: implications for surveillance. J Clin Microbiol 1999;37:2997--3000.
8. Comer JA, Nicholson WL, Olson JG, et al. Serologic testing for human granulocytic ehrlichiosis at a national referral center. J Clin Microbiol 1999;37:558--64.
9. Steiner FE, Pinger RR, Vann CN, et al. Infection and co-infection rates of Anaplasma phagocytophilum variants, Babesia spp., Borrelia burgdorferi, and the rickettsial endosymbiont in Ixodes scapularis from sites in Indiana, Maine, Pennsylvania, and Wisconsin. J Med Entomol 2008;45:289--97.
10. CDC. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever, ehrlichiosis, and anaplasmosis---United States. MMWR 2006;55(No. RR-4).

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Date last reviewed: 9/24/2009