Description of Eschar-Associated Rickettsial Diseases Using Passive Surveillance Data — United States, 2010–2016

Rickettsial eschars are necrotic lesions that occur at the site of tick or mite bites and represent locations of primary inoculation of spotted fever group Rickettsia and Orientia species. In the United States, eschars are hallmarks of less severe spotted fever diseases, including those caused by endemic agents such as Rickettsia parkeri (1) and Rickettsia species 364D (2), as well as several imported agents, including Rickettsia africae, Rickettsia conorii, and Orientia tsutsugamushi. Eschars generally do not occur with Rocky Mountain spotted fever (RMSF), a potentially deadly disease caused by Rickettsia rickettsii and have not been associated with Ehrlichia or Anaplasma species. The presence of eschars can help differentiate less severe spotted fever rickettsioses from RMSF and clarify the potential contributions of each within surveillance data. The lone star tick (Amblyomma americanum), the Gulf Coast tick (Amblyomma maculatum), and the Pacific Coast tick (Dermacentor occidentalis) are the three most common species of tick vectors that spread escharassociated pathogens in the United States (1–4). Lone star and Gulf Coast ticks are vectors of R. parkeri, and Pacific Coast ticks are vectors of Rickettsia species 364D. In commonly available serologic assays, spotted fever group Rickettsia antigens cross-react, which presents a challenge when differentiating RMSF from other spotted fever rickettsioses. Incidence of spotted fever rickettsiosis continues to rise, with few cases providing species-specific laboratory evidence; therefore, the proportion of spotted fever rickettsioses caused by R. rickettsii remains unclear (5). This analysis serves as the first summary of eschar-associated rickettsial disease surveillance data in the United States. During 2010–2016, the presence or absence of eschars was reported in <20% of tickborne rickettsial disease (TBRD) cases. Eschar-associated illnesses represented a small percentage (1.1%) of TBRD cases. Among the 484 reported eschar-associated cases, 97 (20%) were classified as ehrlichiosis or anaplasmosis. Further research is needed to determine whether eschars associated with ehrlichiosis or anaplasmosis reflect a reporting error, a new finding, or the result of coinfection with another eschar-associated rickettsial pathogen. Notifiable rickettsial diseases are reported to CDC through the National Notifiable Diseases Surveillance System, which also collects basic demographic information. Supplementary information is recorded through submission of TBRD supplemental case report forms, or extractions from state surveillance systems, and includes clinical details, diagnostic criteria, and patient outcomes. Since 2010, the CDC supplemental case report form* has requested information on eschars. For this report, supplementary surveillance data collected by state and local health departments for illness with onset during 2010–2016 that were received and entered by CDC as of November 13, 2018, were summarized. TBRDs are not reportable conditions in Alaska and Hawaii, so no data from these states were included in this report. Case classifications were made according to the Council of State and Territorial Epidemiologists definitions (6,7). Confirmed cases were clinically compatible and had confirmatory diagnostic evidence obtained by seroconversion (fourfold change) in anti-Ehrlichia, -Anaplasma, or -Rickettsia immunoglobulin (Ig)G antibody titers by indirect immunofluorescence antibody assay or tested positive by polymerase chain reaction (PCR), immunohistochemistry, or culture. Probable cases were clinically compatible and included supportive laboratory evidence from serologic assays (including IgGor IgM-positive antibodies reactive to Ehrlichia, Anaplasma, or Rickettsia species using immunofluorescence antibody assay or other serologic methods) or reported the presence of morulae (intracellular inclusion bodies in leukocytes) (7). Data were analyzed using SAS software (version 9.4; SAS Institute). A rickettsial eschar begins as a small, painless papule that appears within a few days after the bite of an infected vector. The papule grows, becomes vesicular or pustular, and ulcerates forming a brown-to-black crust surrounded by a red annular halo (Figure 1). During 2010–2016, a total of 44,099 cases of TBRD with supplemental case report forms were reported to CDC, including 484 (1.1%) reported as eschar-associated TBRD; however, most case reports (35,749, 81.1%) were missing information on eschars altogether. Among reported escharassociated cases, 387 (80.0%) were classified as spotted fever rickettsioses, 64 (13.2%) as Ehrlichia chaffeensis ehrlichiosis, 30 (6.2%) as Anaplasma phagocytophilum anaplasmosis, one (0.2%) as Ehrlichia ewingii ehrlichiosis, and two (0.4%) as undetermined ehrlichiosis/anaplasmosis. Notation of suspected spotted fever species is not required but was listed for 16 (4.1%) cases,

Rickettsial eschars are necrotic lesions that occur at the site of tick or mite bites and represent locations of primary inoculation of spotted fever group Rickettsia and Orientia species. In the United States, eschars are hallmarks of less severe spotted fever diseases, including those caused by endemic agents such as Rickettsia parkeri (1) and Rickettsia species 364D (2), as well as several imported agents, including Rickettsia africae, Rickettsia conorii, and Orientia tsutsugamushi. Eschars generally do not occur with Rocky Mountain spotted fever (RMSF), a potentially deadly disease caused by Rickettsia rickettsii and have not been associated with Ehrlichia or Anaplasma species. The presence of eschars can help differentiate less severe spotted fever rickettsioses from RMSF and clarify the potential contributions of each within surveillance data. The lone star tick (Amblyomma americanum), the Gulf Coast tick (Amblyomma maculatum), and the Pacific Coast tick (Dermacentor occidentalis) are the three most common species of tick vectors that spread escharassociated pathogens in the United States (1)(2)(3)(4). Lone star and Gulf Coast ticks are vectors of R. parkeri, and Pacific Coast ticks are vectors of Rickettsia species 364D. In commonly available serologic assays, spotted fever group Rickettsia antigens cross-react, which presents a challenge when differentiating RMSF from other spotted fever rickettsioses. Incidence of spotted fever rickettsiosis continues to rise, with few cases providing species-specific laboratory evidence; therefore, the proportion of spotted fever rickettsioses caused by R. rickettsii remains unclear (5). This analysis serves as the first summary of eschar-associated rickettsial disease surveillance data in the United States. During 2010-2016, the presence or absence of eschars was reported in <20% of tickborne rickettsial disease (TBRD) cases. Eschar-associated illnesses represented a small percentage (1.1%) of TBRD cases. Among the 484 reported eschar-associated cases, 97 (20%) were classified as ehrlichiosis or anaplasmosis. Further research is needed to determine whether eschars associated with ehrlichiosis or anaplasmosis reflect a reporting error, a new finding, or the result of coinfection with another eschar-associated rickettsial pathogen.
Notifiable rickettsial diseases are reported to CDC through the National Notifiable Diseases Surveillance System, which also collects basic demographic information. Supplementary information is recorded through submission of TBRD supplemental case report forms, or extractions from state surveillance systems, and includes clinical details, diagnostic criteria, and patient outcomes. Since 2010, the CDC supplemental case report form* has requested information on eschars.
For this report, supplementary surveillance data collected by state and local health departments for illness with onset during 2010-2016 that were received and entered by CDC as of November 13, 2018, were summarized. TBRDs are not reportable conditions in Alaska and Hawaii, so no data from these states were included in this report. Case classifications were made according to the Council of State and Territorial Epidemiologists definitions (6,7). Confirmed cases were clinically compatible and had confirmatory diagnostic evidence obtained by seroconversion (fourfold change) in anti-Ehrlichia, -Anaplasma, or -Rickettsia immunoglobulin (Ig)G antibody titers by indirect immunofluorescence antibody assay or tested positive by polymerase chain reaction (PCR), immunohistochemistry, or culture. Probable cases were clinically compatible and included supportive laboratory evidence from serologic assays (including IgG-or IgM-positive antibodies reactive to Ehrlichia, Anaplasma, or Rickettsia species using immunofluorescence antibody assay or other serologic methods) or reported the presence of morulae (intracellular inclusion bodies in leukocytes) (7). Data were analyzed using SAS software (version 9.4; SAS Institute).
A rickettsial eschar begins as a small, painless papule that appears within a few days after the bite of an infected vector. The papule grows, becomes vesicular or pustular, and ulcerates forming a brown-to-black crust surrounded by a red annular halo ( Figure 1). During 2010-2016, a total of 44,099 cases of TBRD with supplemental case report forms were reported to CDC, including 484 (1.1%) reported as eschar-associated TBRD; however, most case reports (35,749, 81.1%) were missing information on eschars altogether. Among reported escharassociated cases, 387 (80.0%) were classified as spotted fever rickettsioses, 64 (13.2%) as Ehrlichia chaffeensis ehrlichiosis, 30 (6.2%) as Anaplasma phagocytophilum anaplasmosis, one (0.2%) as Ehrlichia ewingii ehrlichiosis, and two (0.4%) as undetermined ehrlichiosis/anaplasmosis. Notation of suspected spotted fever species is not required but was listed for 16 (4.1%) cases, * The TBRD case report form used for this review can be found at https://www. cdc.gov/ticks/pdf/2010_TBRD_case_report.pdf; however, a case definition change for spotted fever rickettsiosis will go into effect January 1, 2020, and a new case report form is forthcoming.
No eschar-associated cases were associated with R. rickettsii.

Discussion
The presence of an eschar can aid in the clinical and epidemiologic differentiation of less severe spotted fever rickettsioses (e.g., Pacific Coast tick fever [Rickettsia species 364D] and R. parkeri rickettsiosis) from the more severe RMSF (8). Complete reporting of eschars might help to explain the proportions of spotted fever rickettsioses that are caused by less pathogenic spotted fever group Rickettsia and those caused by R. rickettsii. In addition, rickettsial eschars serve as an important clinical specimen; rickettsial DNA can be extracted from eschar lesions obtained by punch biopsies, by removing a portion of the eschar scab, or by swabbing the ulcerated area (9). PCR testing of eschar swabs and scabs provides confirmatory testing without a more invasive biopsy, although the pathogen cannot be cultured and immunohistochemistry cannot be performed on eschar swabs or scabs. To assist agencies that request rickettsial disease testing, CDC provides instructions for collection and submission of eschar swab and skin biopsy specimens. † Demographic characteristics of patients with escharassociated TBRD were similar to those of patients for whom eschars were not reported. Eschar-associated cases reported during this period were less likely to be confirmed, and less severe (as indicated by lower hospitalization and case-fatality rates), than were cases for which eschars were not reported, consistent with previously published studies (1)(2)(3)8). Gulf Coast and lone star ticks transmit several eschar-causing pathogens (including R. parkeri) and are prevalent in the southern United States, where most eschar-associated cases were reported (1,3,10). Although incomplete data on travel history limits the ability to draw conclusions regarding the geographic distribution of eschar-associated illnesses, the predominance of reported cases in areas with compatible vectors is consistent with expected distributions of escharassociated illnesses, including R. parkeri rickettsiosis. Among the 22 cases reported from areas without these tick vectors, six were imported cases of either African tick bite fever (R. africae) or Mediterranean spotted fever (R. conorii) from Africa, but seven patients reported no travel and were primarily reported as having cases of anaplasmosis. Further investigation is needed to understand the occurrence of locally acquired eschar-associated illnesses in areas without known competent vectors.

Summary
What is already known about this topic?
Eschars are a clinical sign used to differentiate less severe rickettsioses from potentially deadly Rocky Mountain spotted fever.
What is added by this report?
Eschars are infrequently reported in tickborne rickettsial disease (TBRD) surveillance data and represent an underutilized resource to aid in distinguishing the various spotted fever group Rickettsia. Although 1% of total TBRD case reports during 2010-2016 documented the presence of an eschar, 81% of cases lacked information on eschars altogether.
What are the implications for public health practice?
Systematic reporting of the presence or absence of eschars on the TBRD case report form can improve the quality of surveillance data and enhance understanding of the impact of spotted fever rickettsioses in the United States.
Although the presence and frequency of spotted fever rickettsiosis associated with eschars was not surprising, the number of reported ehrlichiosis and anaplasmosis cases associated with eschars was unexpected. Approximately 20% of TBRD cases reporting the presence of an eschar during 2010-2016 were associated with cases of ehrlichiosis and anaplasmosis. Eschars had not previously been reported with Anaplasma or Ehrlichia species infections. Eschar-associated ehrlichiosis or anaplasmosis might represent a newly described clinical finding; signal coinfection with a spotted fever group Rickettsia and Anaplasma or Ehrlichia species; or indicate a reporting error. Coinfections could result from concomitant transmission of two pathogens carried by the same tick or from the bite of two separate tick species. Several pathogens are known to cocirculate: lone star ticks are known to transmit E. chaffeensis, E. ewingii, R. parkeri, and Rickettsia amblyommatis; however, coinfection has not been documented in humans (3,10). Further clinical research is needed to understand the importance of these findings.
The findings in this report are subject to at least three limitations. First, reported data regarding eschars come from passive surveillance systems and might not be representative of the overall disease incidence. Second, eschar reporting as part of TBRD surveillance is a relatively new element, introduced in 2010; as such, eschars might not be well understood or reported. Finally, conclusions about the demographic and geographic profiles of eschar-associated illnesses might be limited by missing data.
More complete reporting of eschars in surveillance data will help track this clinical feature as a hallmark of rickettsial disease and help differentiate less severe rickettsial diseases from deadly RMSF. Correct identification and complete documentation of eschar-associated TBRD surveillance data can enhance understanding of the impact of spotted fever rickettsioses in the United States.