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Am. J. Trop. Med. Hyg., 73(2), 2005, pp. 400-409
Copyright © 2005 by The American Society of Tropical Medicine and Hygiene

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Right arrow Ehrlichiosis

EPIDEMIOLOGY OF HUMAN EHRLICHIOSIS AND ANAPLASMOSIS IN THE UNITED STATES, 2001–2002

LINDA J. DEMMA*, ROBERT C. HOLMAN, JENNIFER H. MCQUISTON, JOHN W. KREBS, AND DAVID L. SWERDLOW
Viral and Rickettsial Zoonoses Branch and Office of the Director, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia


ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
During 2001 through 2002, 1,176 cases of the tick-borne diseases human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) were reported to the Centers for Disease Control and Prevention (CDC) by 32 states through the National Electronic Telecommunications System for Surveillance. The average reported annual incidences for HME and HGA during 2001–2002 were 0.6 and 1.4 cases per million population, respectively; incidence was highest among men > 60 years of age. During this same interval, a total of 883 cases of HME and HGA were reported to CDC through a passive surveillance system of tick-borne disease case report forms (CRFs). The surveillance information retrieved from CRFs has allowed for qualitative evaluation of ehrlichiosis and anaplasmosis risk factors, severity, and diagnostic accuracy. Although these surveillance systems likely substantially under-represent the true burden of ehrlichiosis and anaplasmosis in the United States due to poor recognition and reporting, they represent the first compilation of national data since these diseases were made nationally notifiable. Continued and improved surveillance activities will progressively reinforce our understanding and awareness of these newly recognized zoonotic infections.


INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Ehrlichiosis and anaplasmosis are zoonotic tick-borne diseases caused by small, gram-negative, obligate intracellular bacteria in the family Anaplasmataceae, order Rickettsiales.1,2 In the United States, human infection with these zoonotic diseases is caused by Ehrlichia chaffeensis, which causes human monocytic ehrlichiosis (HME), Anaplasma phagocytophilum, which causes human granulocytic anaplasmosis (HGA), and Ehrlichia ewingii, which causes a granulocytic form of ehrlichiosis. These agents were all formerly classified within the genus Ehrlichia, and the diseases caused by them were broadly referred to as ehrlichiosis. However, recent taxonomic changes have reclassified the agent formerly called Ehrlichia phagocytophila under the genus Anaplasma, and the disease caused by this agent is better described as anaplasmosis.1

The agents that cause ehrlichiosis and anaplasmosis are transmitted to humans through the bite of infected ticks. In the United States, E. chaffeensis and E. ewingii are primarily transmitted to humans through the bite of the lone star tick (Amblyomma americanum), which is distributed throughout the southeastern and south-central United States.3,4 The western black-legged tick (Ixodes pacificus) and the American dog tick (Dermacentor variabilis) are also known to be infected with these agents, but their role in transmission of the pathogen to humans is not well-defined.5,6 Transmission of A. phagocytophilum to humans in the United States occurs through the bite of the black-legged tick (Ixodes scapularis) in the eastern states and through the bite of the western blacklegged tick (Ixodes pacificus) in the western states.5,7 White-tailed deer (Odocoileus virginianus) are thought to be the major reservoir of E. chaffeensis and E. ewingii, while small mammals, especially the white-footed mouse (Peromyscus leucopus) in the eastern United States are considered the major reservoir of A. phagocytophilum.8–12

The diseases HME and HGA often present as non-specific febrile illnesses that can be difficult to diagnose. The incubation period for HME and HGA in humans is typically one week (range = 1–21 days) after exposure to an infected tick.2,13,14 A rash develops in up to 33% of patients with HME but is rarely reported with HGA.15,16 For HME, patients usually present with undifferentiated fever with specific findings of headache, myalgia and malaise; gastrointestinal, respiratory or central nervous system involvement may also occur.13,16 Specific laboratory findings include leukopenia, thrombocytopenia, and elevated levels of liver enzymes.17 Particularly severe complications or manifestations of HME may include meningoencephalitis, adult respiratory distress syndrome, and a toxic shock-like illness.18–21 Typically less severe than HME,22 HGA may cause undifferentiated fever and non-specific signs such as headache, myalgias, and malaise; during the acute infection, HGA may result leukopenia and thrombocytopenia, usually accompanied by elevations in levels of liver enzymes.17 Severe manifestations of HGA may include prolonged fever, shock, confusion, seizures, pneumonitis, renal failure, hemorrhages, and additional complications such as opportunistic infections.16,23–26 The estimated fatality rate is 3% for ehrlichiosis and 0.7% for anaplasmosis, as determined from surveillance data, and elderly patients are more prone to severe infections and death.27–29 The risk for contracting HME or HGA in immunocompromised patients, such as organ transplant recipients and persons infected with human immunodeficiency virus, is unknown. However, immunocompromised patients infected with HME may develop more severe manifestations than healthy patients.30–33

Because human ehrlichiosis and anaplasmosis have only recently been recognized as zoonotic diseases of public health importance, epidemiologic information on these agents is limited. Case definitions used by state health departments for surveillance for these diseases were first adopted by the Council of State and Territorial Epidemiologists (CSTE) in 1996 and were revised in 2000 to incorporate the use of newer laboratory methods for case confirmation.34 Two earlier national surveillance studies of human ehrlichiosis and anaplasmosis in the United States have been conducted, using data from a limited number of state health departments. From 1986 to 1997, 742 cases of HME and 449 cases of HGA were reported in the United States,28 and from 1997 to 2001, 487 cases of HME and 1,091 cases of HGA were reported.29 Most HME cases were reported from the southeastern and south-central areas of the United States, while HGA cases were reported primarily from the northeast and upper midwest. The median ages of HME and HGA patients and the high proportion of cases among males were consistent with findings in other case reports and less formal surveillance reports.13,35 These studies did not comprehensively describe the epidemiology of HME and HGA because the diseases were not consistently notifiable at the national level and a uniform case definition did not exist during the study periods.

Human ehrlichiosis and anaplasmosis were made nationally notifiable diseases in 1998 and are reported by state health departments to the Centers for Disease Control and Prevention (CDC) through the National Electronic Telecommunications System for Surveillance (NETSS).36 This electronic reporting system collects basic information on HME and HGA. The system also includes a category for other ehrlichioses (OE), which includes E. ewingii infections and any cases that cannot be distinguished based on available test results. The NETSS provides official national counts for ehrlichiosis and anaplasmosis but collects only minimal demographic and epidemiologic data. In 2001, CDC began collecting more specific demographic and epidemiologic information on ehrlichiosis and anaplasmosis by requesting that states submit a tick-borne rickettsial disease surveillance case report form (CRF) on cases. The CRF, which has historically been used to collect additional supplementary demographic and epidemiologic data on Rocky Mountain spotted fever, provides more detailed epidemiologic and diagnostic information than is available through NETSS.

While NETSS and CRFs provide the basis of HME and HGA surveillance in the United States and share considerable overlap, they are separate, and no one system can be regarded as complete. Thus, both systems are essential to provide an overall picture of disease surveillance. Periodically assessing the findings from both surveillance systems is crucial to help define disease-endemic regions and to describe the basic epidemiology of these diseases for more accurate diagnosis and prevention of severe illness. This study provides an analysis of the national occurrence of human ehrlichiosis and anaplasmosis during 2001 and 2002, using data from both NETSS and CRFs.


METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Case definition. The nonspecific clinical presentations of human ehrlichiosis and anaplasmosis preclude an accurate clinical diagnosis. The organisms responsible are difficult to detect and identify with standard laboratory techniques. The current case definition, as defined by CSTE in 1996 and revised in 2000, requires the presence of a clinically compatible illness with laboratory evidence of infection.34,37 A clinically compatible illness is a febrile illness most commonly characterized by acute onset and accompanied by headache, myalgia, rigors and/or malaise, with clinical laboratory findings that may include morulae in leukocytes of a peripheral blood smear, cerebrospinal fluid, or bone marrow aspirate or biopsy; cytopenias (especially thrombocytopenia and leukopenia); and elevated levels of liver enzymes (especially alanine aminotransferase or aspartate aminotransferase). A confirmed case of ehrlichiosis or anaplasmosis is defined as a patient with a clinically compatible illness with one of the following: a four-fold change in antibody titer to Ehrlichia or Anaplasma species antigen by indirect immunofluoresence assay (IFA) in two serum samples, a positive polymerase chain reaction (PCR) assay result, the visualization of morulae in white blood cells with a single positive serum antibody titer by IFA, immunohistochemical staining (IHC) of an antigen in a tissue biopsy or autopsy sample, or isolation and culture of an Ehrlichia or Anaplasma species from a clinical specimen.34,38–43 A probable case of ehrlichiosis or anaplasmosis is defined as a patient with a clinically compatible illness with a single positive antibody titer by IFA or with the visualization of morulae in white blood cells.34 In this analysis, confirmed and probable cases were regarded as cases and analyzed together except where indicated.

National Electronic Telecommunications System for Surveillance. Data analyzed in this study were limited to ehrlichiosis and anaplasmosis cases reported to NETSS36 with an onset date during January 2001 through December 2002. In Figure 1BGo, the numbers of reported cases for 1999–2000 were included to demonstrate recent trends in HME, HGA, and OE reporting. Although ehrlichiosis and anaplasmosis are considered nationally notifiable diseases, not all states require that they be reported to the state health department. In 2001, HME and HGA were not considered reportable in Alaska, Montana, North Dakota, Idaho, Colorado, New Mexico, Louisiana, Mississippi, and Maryland, while in 2002, this was true for only North Dakota and Colorado. In this study, analyses were conducted only for states where the diseases were reported to the state health department. Epidemiologic variables available through NETSS included diagnosis (HME, HGA, or OE), date of disease onset, and patient age, sex, race, ethnicity, and state and county of residence. Race was defined as white, black, American Indian/Alaska Native, Asian/Pacific Islander, and other. State incidence was calculated as the number of cases in each state per 1,000,000 persons, using state census population estimates for 2001 and 2002; national incidence was calculated as the number of cases per 1,000,000 persons using national population estimates for 2001 and 2002.44



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  		    FIGURE 1. A, Number of ehrlichiosis and anaplasmosis cases reported through two national surveillance systems, National Electronic Telecommunications System for Surveillance (NETSS) and the Centers for Disease Control and Prevention case report form (CRF), United States, 2001–2002. B, Number of ehrlichiosis and anaplasmosis cases reported to the NETSS, United States, 1999–2002. HME = human monocytic ehrlichiosis, HGA = human granulocytic anaplasmosis; OE = other ehrlichiosis.

 
Case Report Form Surveillance System. The CRFs for HME, HGA, or OE that were submitted to CDC and showed an illness onset date during January 2001–December 2002 were selected for analysis as of March 2004. Incidence was calculated as above for NETSS data. Variables for which information was collected included the patient’s state and county of residence, sex, date of birth, race, date of symptom onset, presence of any clinically compatible illness, if the patient was immunosuppressed, and whether the patient was hospitalized and/or died. If the date of disease onset was not reported, the earliest known date associated with the case was assigned as the onset date. Life-threatening manifestations, referred to as complications on the CRF and hereafter in the analysis, were specified as follows: adult respiratory distress syndrome (ARDS), disseminated intravascular coagulopathy (DIC), meningitis/encephalitis, renal failure, or other. These data were not accompanied by additional clinical information such as reported symptoms or pertinent laboratory findings that could be used to confirm the accuracy of the clinical diagnosis. Race was reported as white, black, American Indian/Alaska Native, Asian/Pacific Islander, and other. Hispanic ethnicity was also reported. Laboratory data were recorded by indicating positive or negative acute-phase and convalescent-phase antibody titers obtained by IFA. Results of additional diagnostic tests, such as PCR, IHC for morulae visualization, and culture, were indicated on the form. Cases were classified as probable or confirmed, according to accepted case definitions, by the state health department prior to submission. Reported laboratory data for the cases were reviewed at CDC, and the designation of probable and confirmed infection was sometimes reclassified. Data for each variable were not reported for all cases. Because the classification of OE could potentially include unspecified or unconfirmed HME or HGA, we did not conduct a separate epidemiologic analysis for OE cases. Statistical comparisons of categorical variables between HME and HGA were made using the chi-square test or Fisher’s exact test (two-tailed), as appropriate.


RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
National Electronic Telecommunications System for Surveillance. From 2001 to 2002, 1,176 cases of ehrlichiosis and anaplasmosis were reported from 32 states: 358 were HME, 789 were HGA, and 29 were OE cases (Figure 1AGo). Human granulocytic anaplasmosis was the most commonly reported of these infections in the United States, accounting for 67% of the cases reported for 2001–2002. Reports of HME and HGA have increased recently, since only 889 cases (317 HME, 567 HGA, and 5 OE) were reported during the preceding two years of 1999 through 2000 (Figure 1BGo).

During the 2001–2002 study period, the national average annual incidence of HME was 0.6 per million population. The states with the highest average annual incidence of HME were Missouri, Oklahoma, Tennessee, Arkansas, and Maryland. Missouri reported the most cases for 2001 and 2002 (27 and 50, respectively; Figure 2AGo and Table 1Go), and Maryland reported the largest increase in cases (from 0 to 27). The median age of patients with reported cases of HME was 53 years (Table 2Go), and the highest age-specific incidence occurred among persons ≥ 70 years of age (Figure 3AGo). Among HME patients for whom race was known and reported, most were non-Hispanic white males: 95% were white, 3.4% were black, 1.5% were American Indian/Alaska Native, 2.1% were Hispanic, and 61% were male (Table 2Go). Most HME cases had an onset between May and August (Figure 4Go).



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  		    FIGURE 2. Average annual incidence per million population of ehrlichiosis and anaplasmosis, by state, reported to the National Electronic Telecommunications System for Surveillance, in the United States, 2001–2002: A, Human monocytic ehrlichiosis. B, Human granulocytic anaplasmosis. C, Other ehrlichiosis.

 

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TABLE 1
Incidence per million population of human monocytic ehrlichiosis (HME), human granulocytic anaplasmosis (HGA), and other ehrlichiosis (OE) cases reported through the National Electronic Telecommunications System for Surveillance (NETSS), and a Centers for Disease Control and Prevention case report form (CRF), United States, 2001–2002
 

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TABLE 2
Demographic characteristics for human monocytic ehrlichiosis (HME) and human granulocytic anaplasmosis (HGA) cases reported through the National Electronic Telecommunications System for Surveillance (NETSS) United States, 2001–2002*
 


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  		    FIGURE 3. Age-specific incidence of ehrlichiosis and anaplasmosis by cause, reported to the National Electronic Telecommunications System for Surveillance (NETSS). A, Human monocytic ehrlichiosis. B, Human granulocytic anaplasmosis.

 


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  		    FIGURE 4. Month of illness onset for human ehrlichiosis and anaplasmosis reported to National Electronic Telecommunications System for Surveillance, United States, 2001–2002. HME = human monocytic ehrlichiosis; HGE = human granulocytic anaplasmosis.

 
During the 2001–2002 study period, the national average annual incidence of HGA was 1.4 per million population, and the states that reported the highest average annual incidence were Rhode Island, Minnesota, Connecticut, New York, and Maryland; Minnesota reported the greatest number of cases during 2001 (93), and New York reported the greatest number of cases during 2002 (176) (Figure 2BGo and Table 1Go). New York reported the largest increase in cases (from 79 to 176) from 2001 to 2002. The median age of patients with reported cases of HGA was 51 years (Table 2Go). The highest age-specific incidence occurred among persons 60–69 years of age (Figure 3BGo). Among HGA patients for whom race was known and reported, most were non-Hispanic males: 98% of cases were white, 0.5% were black, 1.0% were American Indian/Alaska Native, 0.7% were Asian, 4.3% were Hispanic, and 57% were male (Table 2Go). Most HGA cases had an onset between May and August (Figure 4Go).

During 2001 through 2002, 29 cases of OE were reported from 11 states: Illinois (8), Kentucky (1), Maryland (1), Michigan (1), New York (4), Ohio (1), Pennsylvania (3), Rhode Island (1), Tennessee (5), Virginia (1), and Wisconsin (3) (Figure 1AGo, Figure 2CGo, and Table 1Go).

Case Report Form Surveillance System. During 2001 through 2002, a total of 989 ehrlichiosis and anaplasmosis cases were reported to CDC via CRFs. The number of HME, HGA, and OE cases reported were 175, 708, and 106, respectively. Human granulocytic anaplasmosis accounted for most (72%) of the cases reported via CRFs, a finding similar to that for NETSS. Although CRFs accounted for fewer overall cases of HME and HGA than were reported to NETSS during the corresponding time period, more cases of OE were reported by CRFs than via NETSS. Although Wisconsin reported very few cases of anaplasmosis or ehrlichiosis to CDC via NETSS, the state reported the highest average annual incidence of HGA (3.0 per million population) via CRF. The age, sex, race, and seasonal onset distributions were similar for cases reported by both surveillance systems.

Among HME patients reported by CRFs, 70 (42%) of 166 were hospitalized (9 unknown/not reported). The average time between the onset of HME symptoms and hospitalization was 11 days (range = 0–122). Life-threatening complications were reported for 19 (17%) of 113 patients (62 unknown/not reported), including 1 with ARDS (patient was hospitalized), 2 with DIC (both patients hospitalized), 5 with meningitis/encephalitis (all hospitalized), 2 with renal failure (both patients hospitalized), and 9 with an unspecified life-threatening complication (6 of 9 patients hospitalized). An immunosuppressive condition was reported in 11 (12%) of 94 patients (81 unknown/not reported). Ten of 11 immunosuppressed patients were hospitalized, but none died. Five (3%) of 161 patients with HME died (14 unknown/not reported): 1 each is reported to have died of ARDS and DIC, and the remaining 3 were reported to have no specific life-threatening complication. The average time between onset of symptoms and death for four of the five patients was 9.8 days (range = 8–13).

Among HGA patients, 212 (33%) of 637 were hospitalized (71 unknown/not reported). Life-threatening complications were reported in 30 (7%) of 457 total patients (251 unknown/not reported): 3 had ARDS (2 patients hospitalized), 1 had DIC (patient was hospitalized), 5 had meningitis/encephalitis (all patients hospitalized), 3 had renal failure (all patients hospitalized), and 18 had an unspecified life-threatening complication (12 patients hospitalized). An immunosuppressive condition was reported in 11 (6%) of 180 patients (528 unknown/not reported). It was reported that one immunosuppressed patient with HGA died with a life-threatening complication defined as other. Five immunosuppressed patients survived (for the remaining five, the outcome is unknown). Hospitalization was reported for five immunosuppressed patients, and three were not hospitalized (remaining two unknown). Two (0.34%) of 586 HGA patients for whom outcome information was reported died (122 unknown/not reported); one of these patients had an unspecified life-threatening complication, but no life-threatening complication was reported for the other fatal case. Dates of hospitalization and death were available for only one patient who died: the patient was hospitalized the same day as the onset of symptoms, and died two days later.

Hospitalization, severe complications, and death were used to indicate and compare the severity of HME and HGA. The rates of hospitalization and death for HME cases were greater than those for HGA cases (P = 0.04 and P = 0.006, respectively). There were significantly more HME cases with reported complications compared with HGA cases (P = 0.002). For both HME and HGA, immunosuppressed patients had a significantly higher rate of hospitalization, severe complications, and death than non-immunosuppressed patients (P ≤ 0.001, P = 0.03, and P = 0.002, respectively), but there was no difference in severity for HME immunosuppressed patients compared with those with HGA. In addition, there was no significant difference in the proportion of immunosuppressed patients with HME compared with those with HGA.

Although a specific etiology was not recorded for OE cases, we evaluated the clinical data to determine potential trends. Among OE cases, 56 (54%) of 104 patients were hospitalized (2 unknown/not reported). Immunosuppression was reported in 10 (13%) of 79 patients (5 were hospitalized) for whom information was provided (27 unknown/not reported). Life-threatening complications were reported in 11 (12%) of 90 patients (14 missing/unknown). One case of ARDS, 2 cases of meningitis/encephalitis (all patients hospitalized), and 8 with other life-threatening complications (all hospitalized) were reported. Of 102 cases with a reported outcome, only 1 fatality (1.0%) was reported (4 unknown/not reported). This patient was hospitalized seven days after the onset of symptoms, but it is unknown how soon after hospitalization he or she died.

Information provided on CRFs showed that 32 (18%) HME cases and 192 (27%) HGA cases were categorized as confirmed cases. However, only 108 (57%; 72% for HME and 44% for HGA) of the 224 confirmed cases had supporting laboratory data provided on the CRF. Serologic testing of paired sera and demonstration of a significant change in antibody titer was the most frequent laboratory diagnostic criterion used for confirmation of HME and HGA cases (88 cases, 10%). There was a median of 18.5 and 38 days between collection of paired serum samples for HME and HGA, respectively. Only two cases, both HGA, were confirmed by PCR, and none were confirmed by IHC or culture, which is likely due to the specialized laboratory needs for these assays. Twenty (2.2%) HME and HGA cases were confirmed by visualization of morulae and at least one positive serologic test result. Information provided on CRFs showed that 143 (82%) of HME cases and 516 (73%) of HGA cases were categorized as probable cases, and most (84% for HME and 74% for HGA) had accompanying laboratory data supporting this classification. A single positive serologic test result was used for diagnosis in 393 (45%), and visualization of morulae alone was used to diagnose 107 (16%).

For OE, which is more difficult to classify because a specific etiologic agent may not be identified, 13 (12%) of 106 cases were categorized as confirmed cases using a significant change in antibody titer as the criteria for classification. In addition, one case (0.9%) was categorized as a confirmed case by a single positive antibody titer with visualization of morulae. Fifty-six (53%) were categorized as probable cases based on a positive antibody titer in a single serum specimen, and 16 (15%) were categorized as probable based on visualization of morulae alone. None of the cases reported as OE were specifically identified as E. ewingii based on the accompanying laboratory data.


DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This report provides the first surveillance summary and epidemiologic analysis of HME, HGA, and OE during the period (2001–2002) in which these data were nationally notifiable, and provides demographic and epidemiologic data through the use of CRFs as a new surveillance tool for ehrlichiosis and anaplasmosis. Although these surveillance systems likely still under-represent the true number of ehrlichiosis and anaplasmosis cases in the United States, they are currently our only means of assessing the national burden of these diseases. This report complements two previous national surveillance summaries of ehrlichiosis and anaplasmosis cases in the United States spanning 1986 through 2001, during which time specific demographic and epidemiologic data on cases were more limited.28,29 Consistent with the previous summaries, this current report shows a trend toward increased reporting of human ehrlichiosis and anaplasmosis in the southeastern, south-central, northeastern, and upper mid-western regions where the corresponding tick vectors are prevalent. The increase in national ehrlichiosis and anaplasmosis reporting may be due to enhanced surveillance and physician recognition following the initiation of HME and HGA as reportable diseases. In some circumstances, the diseases may be increasing in specific locations due to changes in environmental conditions, such as increased home building in suburban and rural sites, which results in increased risk of tick exposure. Several prospective epidemiologic studies have recently documented an increasing incidence of human ehrlichiosis.22,45,46 The population growth of the natural reservoirs of ehrlichiosis and anaplasmosis, as well as the expansion of the range and population of vector ticks, are important ecologic factors that may contribute to an increase in cases in some areas.17,43

In this report, analysis of CRF data showed an increase in the number of cases and incidence of ehrlichiosis and anaplasmosis with age, and a higher proportion of cases among males than females. The highest incidence of HME and HGA was reported in male patients over the age of 60 years, suggesting rates of clinical infection may be related to age-specific increased susceptibility to infection and/or greater risk of exposure. Furthermore, risk factors such as outdoor recreation/employment may be different for males and females. Understanding age trends in infection may help target prevention efforts and assist physicians in accurate and timely diagnoses.

Although HME and HGA infection have a similarly wide range of clinical presentations,47 there appears to be some variation in the overall clinical severity of HME and HGA in this report. Patients with HME showed the highest case-fatality rate among the reported cases of ehrlichiosis and anaplasmosis (3% for HME, compared with 0.4% for HGA). Similarly, reports of life-threatening complications were highest among HME patients (17%, compared with 7% for HGA). Statistical analysis showed that rates of hospitalization, severe complications, and case-fatality were significantly greater among HME patients compared with HGA patients. Thus, HME appears to be more clinically severe than HGA, which is consistent with findings from previous studies.22 The case-fatality rate for OE cases was 1%, and life threatening complications were reported in 12%, suggesting that a large proportion of these cases may be unidentified HME. Our results also show that 33–54% of all ehrlichiosis and anaplasmosis patients were hospitalized due to severe and potentially fatal complications, primarily meningitis/encephalitis, renal failure, and ARDS. Because 6–13% of patients are reported to have an underlying immunosuppressive condition, and HME and HGA may be significantly more severe in these patients, physicians should strongly consider treating such patients with a clinically compatible illness and possible tick exposure.

These data are subject to several important limitations. First, although these surveillance systems provide our only insight into the national burden of disease, they likely substantially under-represent the true number of cases due to poor recognition and reporting. Another important limitation is that it is difficult to assess the accuracy of the diagnosis for cases reported to these systems. Supporting laboratory data were not available for NETSS cases, and although requested, were provided for only 60% of cases reported through CRFs. Thus, this report may include cases that were inaccurately classified as ehrlichiosis or anaplasmosis, which may bias the results. Laboratory confirmation of ehrlichiosis and anaplasmosis is difficult due to the need to obtain paired serum samples, often necessitating physician involvement after the patient has recovered. Failure to obtain second serum samples and infrequent PCR testing has been documented elsewhere,48 and presents a serious obstacle for accurate diagnosis of ehrlichiosis and anaplasmosis. Serologic testing by IFA is potentially non-specific, and serologic cross-reactivity is well known to occur between E. ewingii and E. chaffeensis, and between A. phagocytophilum and E. chaffeensis.49–51 In addition, both E. ewingii and A. phagocytophilum infect granulocytes, and species identification cannot be distinguished by blood-smear inspection only. In this report, more specific investigative tools (e.g., PCR, blood culture, or IHC) were used infrequently for diagnosis confirmation. Since the majority of cases reported here were categorized as probable cases and involved only a single serum sample, there is a considerable potential for incorrect diagnosis. In addition, the diagnostic difficulties for E. ewingii (cross-reactivity with E. chaffeensis and morulae presence in granulocytes) may have resulted in the misclassification of some of these cases as HGA or HME, especially in states such as Missouri and Arkansas where the disease has been previously reported. Thus, it should be emphasized to state health departments and physicians that confirmatory laboratory results, combined with the demographic and clinical information provided on the CRF, are crucial for understanding the epidemiology of HME and HGA within the United States and for accurate monitoring of these diseases.

Because of the relative ease of reporting to NETSS for a variety of notifiable diseases, there may be an expectation that NETSS provides more consistent reporting than CRFs by state health departments; yet, it appears that for some states, CRF reporting of HME and HGA outnumbers NETSS reporting, and, overall, OE cases were reported in higher numbers by CRFs than NETSS. However, because these two surveillance systems are separate and do not permit cross-referencing, it is not possible to assess how many cases are reported to both NETSS and CRF. Thus, the variations in ehrlichiosis and anaplasmosis noted between NETSS and CRF are likely due to inconsistencies within state reporting systems.

There are additional limitations to the passive surveillance systems that our results highlight. For example, the travel history of a patient may be more important than state of residence in terms of assessing risk for tick-borne diseases, but this information cannot be accurately assessed through the current surveillance systems. Furthermore, HME was reported in some northern states where the tick vector is not known to be present, and there are substantial differences in HGA case reporting between some neighboring states where incidence is known to be high. These discrepancies suggest that incorrect case classification and inconsistencies between state reporting systems may influence our ability to accurately describe the epidemiology of these diseases.

Human ehrlichiosis and anaplasmosis are likely under-recognized and underreported in the United States because of the non-specific nature of their clinical signs. Although rates of reporting appear to be increasing, the number of cases reported to state and national authorities probably represent only a small percentage of the actual number of cases. Active prospective epidemiologic studies of HME in Missouri and North Carolina showed an average annual incidence of 30 per million population, 20 times higher than reported to NETSS or CRF.22,46 Such underreporting and inadequate diagnosis of ehrlichiosis and anaplasmosis are significant limitations of the current passive surveillance system. Active prospective surveillance for HME and HGA may be warranted to better understand the magnitude of underreporting at the national level. Nonetheless, the two established national reporting systems provide data that will progressively strengthen our understanding and awareness of these newly recognized zoonotic infections. For example, cases reported by CRF provide important information that contributes to our understanding of health outcomes for immunosuppressed patients and of life-threatening complications, death, and laboratory diagnosis. Thus, submission of CRFs is encouraged as a means of supplementing our currently limited understanding of ehrlichiosis and anaplasmosis. In addition, it is important that state health departments in disease-endemic areas reinforce to physicians the need to accurately diagnose and report cases.

This report shows that advanced age and residence in specific geographic regions in the United States are risk factors for ehrlichiosis and anaplasmosis, especially during the summer months when tick exposure is likely. This report justifies the use of empirical therapy with doxycycline for all patients who are suspected of having HME or HGA because of the potential for serious or even fatal outcome if these diseases are left untreated, especially in patients with immunosuppressive conditions. It is important to continue to examine and describe the variations in clinical signs and epidemiologic trends between ehrlichiosis, anaplasmosis, and other tick-borne illnesses to help physicians differentiate, diagnose, and treat these diseases.

Received November 23, 2004. Accepted for publication April 1, 2005.

Acknowledgments: We thank Aaron Curns for technical assistance with the case report form data, Travis Wheeling for data collection assistance with the case report forms, Claudia Chesley for helpful manuscript comments, and the staff who reported cases from the participating states.

* Address correspondence to Dr. Linda J. Demma, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-44, Atlanta, GA 30333. E-mail: lqd1{at}cdc.gov Back

Authors’ addresses: Linda J. Demma, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-44, Atlanta, GA 30333, Telephone: 404-639-2375, Fax: 404-639-2778, E-mail: lqd1{at}cdc.gov. Robert C. Holman, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop A-39, Atlanta, GA 30333. Jennifer H. McQuiston, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-44, Atlanta, GA 30333, Telephone: 404-639-0041, Fax: 404-639-2778, E-mail: fzh7{at}cdc.gov. John W. Krebs, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., Mail-stop G-44, Atlanta, GA 30333, Telephone: 404-639-1079, Fax: 404-639-2778, E-mail: jok2{at}cdc.gov. David L. Swerdlow, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road, Mailstop G-44, Atlanta, GA 30333, Telephone: 404-639-1329, Fax: 404-639-4436, E-mail: dls3{at}cdc.gov.


REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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