Geography plays an important role in the epidemiology of ehrlichiosis and anaplasmosis infections. During 2000–2007, the Ozark Mountains and the Eastern Seaboard regions reported high incidence rates of E. chaffeensis
infection. Similarly, the Northern Midwest and the Northern Atlantic Seaboard regions reported high incidence rates of A. phagocytophilum
infection. These spatial trends are consistent with the epizoology of these pathogens, which are transmitted by distinct tick species with defined geographic ranges and host preferences.16
National surveillance for these diseases is important for several reasons: assessment of the overall burden of tick-borne disease as an important public health problem, detection of the emergence of novel related pathogens in unexpected areas, and monitoring for changes in human disease risk with the possible expansion of tick populations.
The annual incidence of reported ehrlichiosis and anaplasmosis increased during 2000–2007. The reported incidence of other tick-borne diseases, including Rocky Mountain spotted fever (RMSF) and Lyme disease, also increased during the same period, leading to speculation about possible ecologic or climatic changes resulting in expanding vector or reservoir ranges.14,29,30
However, numerous other factors likely influenced these observations. These factors include novel diagnostic assays, revised case definitions, increased physician awareness and reporting, and improved state and local surveillance for tick-borne diseases.30
Specifically, case definition changes in 2000 and 2001 and the publication of national guidelines for the diagnosis of tick-borne rickettsial diseases in 2006 may have broadly increased awareness and case recognition.16,24,25
During the study period, PCR of whole blood became more widely available as a sensitive and specific tool to aid the early diagnosis of ehrlichiosis and anaplasmosis (Holzbauer S and others, International Conference on Emerging Infectious Diseases, 2010). These changes may have improved reporting of cases through national surveillance systems.
Ehrlichiosis and anaplasmosis contribute substantially to the overall burden of tick-borne rickettsial diseases in the United States. The combined reported incidence rate for ehrlichiosis, anaplasmosis, and UUOA during 2000–2007 was more than 7.2 per million PY, which is similar to the reported incidence of RMSF in recent years.29
The hospitalization rate was high among reported cases of ehrlichiosis (49%) and anaplasmosis (36%) and was disproportionately greater among the elderly. During 2000–2007 the reported number of fatal outcomes associated with ehrlichiosis and anaplasmosis (n = 43) was similar to that reported for RMSF (n = 35), which has traditionally been considered a disease with a high potential for fatal outcome.29
Past studies have suggested that infections with E. chaffeensis
are fatal 3% of the time, and fatal outcomes for infections with A. phagocytophilum
are less frequently reported.12,13
Risk factors for severe or fatal outcome include immune compromise and older age: several accounts of ehrlichiosis and anaplasmosis among prior organ allograft recipients have been reported.31–36
In the current surveillance report, 9 patients reported by CRF had a history of organ transplant, and 239 reported other conditions associated with immune compromise, including cancer, diabetes, and arthritis.
Although not specifically captured as a risk factor in the current surveillance system, at least two anaplasmosis infections transmitted through blood transfusion have been reported, suggesting that blood product recipients are a group at potential risk for infection.37,38
Finally, delayed administration of doxycycline treatment is a significant risk factor for severe and fatal outcome in tick-borne rickettsial diseases.39
Although antibiotic administration information was not obtained as part of this study, we expect severe or fatal outcomes among patients for whom doxycycline treatment was initiated early in the course of illness to be rare.
The reported incidence of UUOA was 0.45 cases per million PY, and most cases reported under UUOA were cases of ehrlichiosis or anaplasmosis where the causative species was not differentiated. During the current surveillance period, 70% of UUOA cases were reported from Wisconsin, a state where A. phagocytophilum
is endemic but E. chaffeensis
and E. ewingii
are rarely confirmed. Furthermore, the overall use of the UUOA reporting category in much of the country increased during the studied period. A likely explanation for this increase in use of the category UUOA is physician difficulty in ordering and interpreting appropriate tests to diagnose A. phagocytophilum
. In 2001, the name human granulocytic ehrlichiosis shifted to human anaplamosis when the organism Ehrlichia phagocytophila
was renamed Anaplasma phagocytophilum
We believe this name change led to confusion among healthcare providers about which diagnostic test to request in a given geographic area.
In areas where ehrlichiosis and anaplasmosis are endemic, discerning the etiologic agent requires testing for both. In these geographic areas, cases are ideally reported under UUOA when only a single test is ordered, although the stringency with which this recommendation has been applied during the current study period is not clear. In geographic areas where one agent predominates, lack of testing for the less common agent should not necessarily require a report of UUOA. Further confusing this issue, however, is the fact that a new Ehrlichia agent was identified in Wisconsin and Minnesota in 2009 (McFadden JW, International Conference on Emerging Infectious Disease 2010). The new agent appears similar to E. muris and may cross-react with assays for E. chaffeensis (CDC, unpublished data). The impact of this new agent on national surveillance programs is unknown, and recommended diagnostic testing strategies beyond a differential PCR have not yet been established.
Another factor complicating surveillance for these organisms is cross-reactivity among E. chaffeensis
, E. ewingii
, and A. phagocytophilum
on serologic assays, making it difficult to interpret the results from inappropriate testing. Wisconsin used the UUOA category to report these poorly defined cases during 2000–2007 (Johnson D, Wisconsin Department of Health, unpublished data). Using an E. chaffeensis
serologic test to diagnose the cause of illness in a patient residing in an A. phagocytophilum
-endemic area increases the chance of false-negative results. Serologic cross-reactivity to E. chaffeensis
can occur in up to half of A. phagocytophilum
Thus, consistent use of incorrect tests at the provider level will result in a substantial number of missed diagnoses and underestimate the true burden of disease.
Acquisition of appropriate documentation to confirm cases in accordance with the surveillance case definitions remains problematic for rickettsial diseases. Because of its availability and reliability, IFA is considered the gold standard for testing. However, its usefulness is limited unless paired serum samples are tested and an increase in titer (seroconversion) is documented. Patient convalescent-phase samples are not often obtained, yielding at best a probable case definition. In the current study, 2,234 reported ehrlichiosis, anaplasmosis, and UUOA cases (57%) were diagnosed as probable cases using only a single positive serum test result. Because antibodies may remain elevated for months or even years after infection, probable cases represent a group of patients for whom a definitive diagnosis of ehrlichiosis or anaplasmosis is less assured because past exposures can be identified as current cases. Further complicating the validity of a single serum sample is the fact that most cases may lack detectable antibody in the first 7–10 days of illness.41
Given the continued reliance of physicians in the United States on single serum samples for diagnosis (in this case, most reported cases were diagnosed by using a single serum sample), the true number of ehrlichiosis and anaplasmosis reports is significantly underestimated.
In this report, hospitalized and fatal cases are more likely to be reported as confirmed than less severe cases. We believe cases without a prompt convalescence offer more opportunity and motivation for acquiring diagnostic evidence. Case status lies on the causal pathway between severity of disease and clinical course. Although the variable is designed to capture the strength of supporting laboratory evidence, case status also captures the severity of disease.
Reported incidence rates for ehrlichiosis and anaplasmosis generally increased with age during the study period (). Although this finding may reflect the true relationship between age and incidence, this increase may also be the result of an artifact of surveillance. The increasing seropositivity with age may be due to diagnosis of other nonspecific febrile illnesses as tick-borne rickettsial disease among older patients relative to younger patients.42–44
Conversely, the impact of immune status on the clinical course of illness indicates the importance of host factors, and age may also play an important role in the clinical course.
In this report, almost all cases reporting race and ethnicity were white and non-Hispanic (). However, a representative cross-sectional study found no association between race and ethnicity with E. chaffeensis
Because the surveillance case definitions require supporting laboratory evidence, these results may be confounded by access to and use of diagnostic services.24,45,46
Similarly, missing data and misclassification of race and ethnicity in these surveillance data may significantly bias the results.47
Because these results relied on passive surveillance methods, the rate estimates presented here represent a minimum incidence. Similarly, these reports relied on patients, physicians, laboratories, State Public Health Departments, and the CDC for accurate reporting, and misclassification and missing data can lead to information bias of an unknown magnitude.
These results summarize the surveillance data reported using the CSTE case definitions during 2000–2007. New case definitions were implemented in 2008 for E. chaffeensis
, A. phagocytophilum
, and E. ewingii
that explicitly name the etiologic agent should help minimize the confusion from prior taxonomic changes.25
However, surveillance trends may change again in response to these new case criteria. For future iterations of case definitions, specifying stricter requirements on the timing of acute-phase and convalescent-phase serologic analysis for laboratory confirmation of a case would help improve the quality of data obtained. We anticipate continually evolving case definitions will be needed to better define our understanding, recognition, and the reporting of these emerging tick-borne diseases.