Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis — United States | MMWR
MMWR Recommendations and Reports
Vol. 65, No. RR-2
May 13, 2016
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Summary
Tickborne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of low-cost, effective antibacterial therapy. Recognition early in the clinical course is critical because this is the period when antibacterial therapy is most effective. Early signs and symptoms of these illnesses are nonspecific or mimic other illnesses, which can make diagnosis challenging. Previously undescribed tickborne rickettsial diseases continue to be recognized, and since 2004, three additional agents have been described as causes of human disease in the United States: Rickettsia parkeri, Ehrlichia muris-like agent, and Rickettsia species 364D. This report updates the 2006 CDC recommendations on the diagnosis and management of tickborne rickettsial diseases in the United States and includes information on the practical aspects of epidemiology, clinical assessment, treatment, laboratory diagnosis, and prevention of tickborne rickettsial diseases. The CDC Rickettsial Zoonoses Branch, in consultation with external clinical and academic specialists and public health professionals, developed this report to assist health care providers and public health professionals to 1) recognize key epidemiologic features and clinical manifestations of tickborne rickettsial diseases, 2) recognize that doxycycline is the treatment of choice for suspected tickborne rickettsial diseases in adults and children, 3) understand that early empiric antibacterial therapy can prevent severe disease and death, 4) request the appropriate confirmatory diagnostic tests and understand their usefulness and limitations, and 5) report probable and confirmed cases of tickborne rickettsial diseases to public health authorities.
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Introduction
Ticks (Acari: Ixodidae and Argasidae) transmit multiple and diverse pathogens (including bacteria, protozoa, and viruses), which cause a wide range of human and animal diseases, including rickettsial diseases, caused by bacteria in the order Rickettsiales. Vertebrate animals play an integral role in the life cycle of tick species, whereas humans are incidental hosts. Awareness, diagnosis, and control of tickborne rickettsial diseases are most effectively addressed by considering the intersecting components of human, animal, and environmental health that collectively form the foundation of One Health (1), an approach that integrates expertise from multiple disciplines and facilitates understanding of these complex zoonoses.
Tickborne rickettsial diseases in humans often share similar clinical features yet are epidemiologically and etiologically distinct. In the United States, these diseases include 1) Rocky Mountain spotted fever (RMSF) caused by Rickettsia rickettsii; 2) other spotted fever group (SFG) rickettsioses, caused by Rickettsia parkeri and Rickettsia species 364D; 3) Ehrlichia chaffeensis ehrlichiosis, also called human monocytic ehrlichiosis; 4) other ehrlichioses, caused by Ehrlichia ewingii and Ehrlichia muris-like (EML) agent; and 5) anaplasmosis, caused by Anaplasma phagocytophilum (2), also called human granulocytic anaplasmosis. Rickettsial pathogens transmitted by arthropods other than ticks, including fleas (Rickettsia typhi), lice (Rickettsia prowazekii), and mites (Rickettsia akari) are not included in this report. Imported tickborne rickettsial infections that might be diagnosed in returning international travelers are summarized; however, tickborne and nontickborne rickettsial illnesses typically encountered outside the United States are not addressed in detail in this report.
The reported incidence of tickborne rickettsial diseases in the United States has increased during the past decade (3–5). Tickborne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of effective antibacterial therapy. Early signs and symptoms of tickborne rickettsial illnesses are nonspecific, and most cases of RMSF are misdiagnosed at the patient’s first visit for medical care, even in areas where awareness of RMSF is high (6,7). To increase the likelihood of an early, accurate diagnosis, health care providers should be familiar with risk factors, signs, and symptoms consistent with tickborne rickettsial diseases.
This report provides practical information to help health care providers and public health professionals to
recognize the epidemiology and clinical manifestations of tickborne rickettsial diseases;
obtain an appropriate clinical history for suspected tickborne rickettsial diseases;
recognize potential severe manifestations of tickborne rickettsial diseases;
make treatment decisions on the basis of epidemiologic and clinical evidence;
recognize that early and empiric treatment with doxycycline can prevent severe morbidity or death;
recognize doxycycline as the treatment of choice for adults and children of all ages with suspected rickettsial disease;
make treatment decisions for patients with certain conditions, such as a doxycycline allergy or pregnancy;
recognize when to consider coinfection with other tickborne pathogens;
determine appropriate confirmatory diagnostic tests for tickborne rickettsial diseases;
understand the availability, limitations, and usefulness of confirmatory diagnostic tests;
recognize unusual transmission routes, such as transfusion- or transplantation-associated transmission;
recognize selected rickettsial diseases among returning travelers;
advise patients regarding how to avoid tick bites; and
report probable and confirmed cases to appropriate public health authorities to assist with surveillance, control measures, and public health education efforts.
Additional information concerning the tickborne rickettsial diseases described in this report is available from medical and veterinary specialists, various medical and veterinary societies, state and local health authorities, and CDC. The information and recommendations in this report are meant to serve as a source of general guidance for health care providers and public health professionals; however, individual clinical circumstances should always be considered. This report is not intended to be a substitute for professional medical advice for individual patients, and persons should seek advice from their health care providers if they have concerns about tickborne rickettsial diseases.
Methods
This report updates the 2006 CDC recommendations for the diagnosis and management of tickborne rickettsial diseases in the United States (8). Updated recommendations are needed to address the changing epidemiology of tickborne rickettsial diseases, provide current information about new and emerging tickborne rickettsial pathogens, and highlight advances in recommended diagnostic tests and updated treatment information.
The CDC Rickettsial Zoonoses Branch reviewed the 2006 report and determined which subject-matter areas required updates or revisions. Internal and external subject-matter experts in tickborne rickettsial diseases, representing a range of professional experiences and viewpoints, were identified by the CDC Rickettsial Zoonoses Branch to contribute to the revision. Contributors represented various areas of expertise within the field of tickborne rickettsioses and included practicing physicians specializing in internal medicine, family medicine, infectious diseases, and pathology; veterinarians with expertise in state, national, and international public health; epidemiologists; tick ecologists; microbiologists; and experts in rickettsial laboratory diagnostics. The peer-reviewed literature, published guidelines, and public health data were reviewed, with particular attention to new material available since preparation of the previous report. The scientific literature was searched through February 2016 using the MEDLINE database of the National Library of Medicine. The terms searched were Rickettsia, Rickettsia infections, R. rickettsii, RMSF,Ehrlichia, ehrlichiosis, E. chaffeensis, anaplasmosis, Anaplasma, and A. phagocytophilum. Text word searches were performed on multiple additional terms tailored to specific questions, which included epidemiology, treatment, diagnosis, and prevention. Titles of articles and abstracts extracted by the search were reviewed, and if considered potentially relevant, the full text of the article was retrieved. Reference lists of included articles were reviewed, and additional relevant citations were provided by contributors. In certain instances, textbook references were used to support statements considered general knowledge in the field. Articles selected were in English or had available translations. Peer-reviewed publications and published guidelines were used to support recommendations when possible. Abstracts without a corresponding full-length publication, dissertations, or other non–peer-reviewed literature were not used to support recommendations. When possible, data were obtained from studies that determined the presence of tickborne rickettsial infection using confirmatory diagnostic methods. Additional criteria were applied on a per-question basis. For some questions, an insufficient number of studies was identified to support the development of a recommendation. In these instances, the report indicates that the evidence was insufficient for a recommendation, and when possible, general guidance is provided based on the available evidence and expert opinion of the CDC Rickettsial Zoonoses Branch. All contributors had the opportunity to review and provide input on multiple drafts of the report, including the final version. Future updates to this report will be dictated by new data in the field of tickborne rickettsial diseases.
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Epidemiology
Overview
Tickborne rickettsial pathogens are maintained in natural cycles involving domestic or wild vertebrates and primarily hard-bodied ticks (Acari: Ixodidae). The epidemiology of each tickborne rickettsial disease reflects the geographic distribution and seasonal activities of the tick vectors and vertebrate hosts involved in the transmission of these pathogens, as well as the human behaviors that place persons at risk for tick exposure, tick attachment, and subsequent infection ( Box 1). SFG rickettsiosis, ehrlichiosis, and anaplasmosis are nationally notifiable in the United States. Cases have been reported in each month of the year, although most cases are reported during April–September, coincident with peak levels of tick host-seeking activity (3–5,9–14). The distribution of tickborne rickettsial diseases varies geographically in the United States and approximates the primary tick vector distributions, making it important for health care providers to be familiar with the regions where tickborne rickettsial diseases are common. Travelers within the United States might be exposed to different tick vectors during travel, which can result in illness after they return home. Travelers outside of the United States might also be exposed to different tick vectors and rickettsial pathogens in other countries, which can result in illness after they return to the United States (see Travel Outside of the United States). Health care, public health, and veterinary professionals should be aware of changing vector distributions, emerging and newly identified human tickborne rickettsial pathogens, and increasing travel among persons and pets within and outside of the United States.
Spotted Fever Group Rickettsiae
SFG rickettsiae are related closely by various genetic and antigenic characteristics and include R. rickettsii (the cause of RMSF), R. parkeri, and Rickettsia species 364D, as well as many otherRickettsia species of unknown pathogenicity. RMSF is the rickettsiosis in the United States that is associated with the highest rates of severe and fatal outcomes. During 2008–2012, passive surveillance indicated that the estimated average annual incidence of SFG rickettsiosis was 8.9 cases per million persons in the United States (4). The passive surveillance category in the United States for SFG rickettsiosis might not differentiate between RMSF and other SFG rickettsioses because of the limitations of submitted diagnostic evidence. Reported annual incidence of SFG rickettsiosis has increased substantially during the past 2 decades. The highest incidence occurs in persons aged 60–69 years, and the highest case-fatality rate is among children aged <10 years, although illness occurs in all age groups (4). Incidence varies considerably by geographic area ( Figure 1). During 2008–2012, 63% of reported SFG rickettsiosis cases originated from five states: Arkansas, Missouri, North Carolina, Oklahoma, and Tennessee (4). However, SFG rickettsiosis cases have been reported from each of the contiguous 48 states and the District of Columbia (4,9,12,14).
A notable regional increase in the reported incidence of SFG rickettsiosis occurred in Arizona during 2003–2013. Over this period, approximately 300 cases of RMSF and 20 deaths were reported from American Indian reservations in Arizona compared with three RMSF cases reported in the state during the previous decade (15). Since identification of the first case of locally transmitted RMSF in 2003 (16), RMSF has been found to be endemic in several American Indian communities in Arizona. On the three most affected reservations, the average annual incidence rate for 2009–2012 was approximately 1,360 cases per million persons (17). The 7%–10% case-fatality rate in these communities, which is the highest of any region in the United States, has been associated predominantly with delayed recognition and treatment (4,18).
Rickettsia rickettsii
In the United States, the tick species that is most frequently associated with transmission of R. rickettsii is the American dog tick, Dermacentor variabilis ( Figure 2). This tick is found primarily in the eastern, central, and Pacific coastal United States ( Figure 3). The Rocky Mountain wood tick, Dermacentor andersoni ( Figure 4), is associated with transmission in the western United States (Figure 5). More recently, the brown dog tick, Rhipicephalus sanguineus ( Figure 6), which is located throughout the United States ( Figure 7), has been recognized as an important vector in parts of Arizona (16) and along the U.S.-Mexico border. Several tick species of the genus Amblyomma are vectors of R. rickettsii from Mexico to Argentina, including A. cajennense, A. aureolatum, A. imitator, and A. sculptum (19–22). Although the geographic ranges of A. imitator and A. mixtum (a species closely related to A. cajennense) extend into Texas, the role of Amblyomma ticks in transmission of R. rickettsii in the United States has not been established.
D. variabilis ticks often are encountered in wooded, shrubby, and grassy areas and tend to congregate along walkways and trails. These ticks also can be found in residential areas and city parks. Larval and nymphal stages of most Dermacentor spp. ticks in the United States usually do not bite humans. Although adult D. variabilis and D. andersoni ticks bite humans, the principal hosts tend to be deer, dogs, and livestock. Adult Dermacentor ticks are active from spring through autumn, with maximum activity during late spring through early summer.
The brown dog tick, Rh. sanguineus, has been a recognized vector of R. rickettsii in Mexico since the 1940s (23); however, Rhipicephalus-transmitted R. rickettsii in the United States was not identified until 2003, when it was confirmed in a child on tribal lands in Arizona (16). Canids, especially domestic dogs, are the preferred hosts for the brown dog tick at all life stages. Humans are incidental hosts, bitten as a result of contact with tick-infested dogs or tick-infested environments. All active stages (larvae, nymphs, and adults) of Rh. sanguineus will bite humans and can transmitR. rickettsii. Heavily parasitized dogs ( Figure 8), as well as sizable infestations of brown dog ticks in and around homes, have been found in affected communities in Arizona (16,17,24). Free-roaming dogs can spread infected ticks among households within a neighborhood, resulting in community-level clusters of infection. Children aged <10 years represent more than half of reported cases in this region and are theorized to have higher rates of exposure to Rh. sanguineus ticks because of increased interaction with dogs and their habitats (16,25). On Arizona tribal lands, the warm climate and proximity of ticks to domiciles provide a suitable environment for Rh. sanguineus to remain active year-round (26). The majority of human cases of RMSF in Arizona occur during July–October after seasonal monsoon rains; however, cases have been reported every month of the year (25).
Similar epidemiologic characteristics and transmission dynamics have been reported in parts of Mexico (27–30). A high incidence of RMSF occurs in several northern Mexican states, including Baja California and Sonora, which border the United States. Persons infected with R. rickettsii in Mexico have sought health care across the U.S. border; health care providers should be aware of the risk for RMSF in persons traveling from areas where the disease incidence is high. Rh. sanguineus is found worldwide but is reported to transmit R. rickettsii in the southwestern United States, Mexico, and possibly some RMSF-endemic areas of South America (16,29–32). This species might contribute to the enzootic cycle more commonly than has been recognized (33,34).
Rickettsia parkeri
The first confirmed case of human R. parkeri infection was reported in 2004 (35). During 2004–2015, at least 40 patients with R. parkeri rickettsiosis were identified from 10 states (35–41) (CDC, unpublished data, 2015). The median age of patients from case reports was 53 years (range: 23–83 years) (38); R. parkeri rickettsiosis has not been documented in children, and no fatal cases have been reported. R. parkeri is transmitted by the Gulf Coast tick, Amblyomma maculatum ( Figure 9). The geographic range of A. maculatum extends across the southern United States from Texas to South Carolina and as far north as Kansas, Maryland, Oklahoma, and Virginia ( Figure 10). The Gulf Coast tick is typically found in prairie grassland and coastal upland habitats (42). R. parkeririckettsiosis cases have been documented during April–October, with most cases occurring during July–September.
Rickettsia Species 364D
The first confirmed case of human disease associated with Rickettsia species 364D was described in 2010 from California and likely was transmitted by the Pacific Coast tick, Dermacentor occidentalis (43). Fewer than 10 cases of Rickettsia species 364D infection, all from California, have been reported in the literature (43,44). Cases have been documented in children and adults (44). The Pacific Coast tick is found in the coastal ranges of Oregon and California and in the states of Baja California and Sinaloa in Mexico. Principal hosts of adult ticks are horses, cattle, and black-tailed deer, whereas immature ticks feed on rodents and rabbits. The prevalence and distribution of Rickettsia species 364D in D. occidentalis ticks suggests that these infections in humans might be more common in California than currently recognized (45,46). Reported cases of Rickettsia species 364D rickettsiosis have occurred during July–September (43,44).
Ehrlichiae
In the United States, three Ehrlichia species are known to cause symptomatic human infection. E. chaffeensis, the cause of human monocytic ehrlichiosis, was described first in 1987 and is the most common agent of human ehrlichiosis (47). E. ewingii was reported as a human pathogen in 1999 after being detected in peripheral blood leukocytes of four patients with illness during 1996–1998 (48). EML agent ehrlichiosis, first described in 2011, is the most recently recognized form of human ehrlichiosis in the United States and was detected originally in the blood of four patients from Minnesota and Wisconsin in 2009 (49).
During 2008–2012, the average annual incidence of ehrlichiosis was 3.2 cases per million persons, which is more than twice the estimated incidence during 2000–2007 (5). Cases have been reported from an increasing number of counties (5) ( Figure 11). Incidence generally increases with age, with the highest age-specific incidences occurring among persons aged 60–69 years (5,13,50). Case-fatality rates are highest among children aged <10 years and adults aged ≥70 years, and an increased risk for death has been documented among persons who are immunosuppressed (5,13). In areas where ehrlichiosis is endemic, the actual disease incidence is likely underrepresented in estimates that are based on passive surveillance (51–53).
Ehrlichia chaffeensis
E. chaffeensis is transmitted to humans by the lone star tick, Amblyomma americanum ( Figure 12). The lone star tick is among the most commonly encountered ticks in the southeastern United States, with a range that extends into areas of the Midwest and New England states ( Figure 13). Ehrlichiosis cases have been reported throughout the range of the lone star tick; states with the highest reported incidence rates include Arkansas, Delaware, Missouri, Oklahoma, Tennessee, and Virginia (5). The white-tailed deer is a major host of all stages of lone star ticks and is thought to be an important natural reservoir for E. chaffeensis (54). Consequently, the lone star tick is found most commonly in woodland habitats that have white-tailed deer populations. The lone star tick feeds on a wide range of hosts, including humans, and has been implicated as the most common tick to bite humans in the southern United States (55,56). Although all stages of this tick feed on humans, only adult and nymphal ticks are known to be responsible for transmission of E. chaffeensis to humans. Most cases of E. chaffeensis ehrlichiosis occur during May–August.
Ehrlichia ewingii
E. ewingii ehrlichiosis became a notifiable disease in 2008. During 2008–2012, cases were primarily reported from Missouri; however, cases also were reported from 10 other states within the distribution of the principal vector, the lone star tick, A. americanum (5,57) (Figure 13). Although E. ewingii ehrlichiosis initially was reported predominantly among persons who were immunosuppressed, passive surveillance data from 2008–2012 indicated that the majority of persons (74%) with reported E. ewingii infection did not report immunosuppression (5). No fatal cases of E. ewingii ehrlichiosis have been reported. The ecologic features of E. ewingii are not completely known; however, dogs, goats, and deer have been infected naturally and experimentally (58–60).
Ehrlichia muris-Like Agent
In 2011, a new species of Ehrlichia referred to as the EML agent was described as a human pathogen after detection in the blood from four patients (three from Wisconsin and one from Minnesota) by using molecular testing techniques (49). The EML agent subsequently was identified in blood specimens from 69 symptomatic patients who lived in or were exposed to ticks in Minnesota or Wisconsin during 2007‒2013 (61). The blacklegged tick, Ixodes scapularis ( Figure 14), is an efficient vector for the EML agent in experimental studies (62,63), and DNA from the EML agent has been detected from I. scapularis collected in Minnesota and Wisconsin but has not been detected in I. scapularis from other states (64,65).
Anaplasma phagocytophilum
A. phagocytophilum causes human anaplasmosis, which is also known as human granulocytic anaplasmosis (formerly known as human granulocytic ehrlichiosis). Passive surveillance from 2008–2012 indicates that the average annual incidence of anaplasmosis was 6.3 cases per million persons (3). Incidence is highest in the northeastern and upper Midwestern states, and the geographic range of anaplasmosis appears to be expanding (3,66) ( Figure 15). In Wisconsin, anaplasmosis has been identified as an important cause of nonspecific febrile illness during the tick season (67). Age-specific incidence of anaplasmosis is highest among those aged ≥60 years (3). The reported case-fatality rate during 2008–2012 was 0.3% and was higher among persons aged ≥70 years and those with immunosuppression (3).
I. scapularis (Figure 14) is the vector for A. phagocytophilum in the northeastern and Midwestern United States (68) ( Figure 16), whereas the western blacklegged tick, Ixodes pacificus ( Figure 17), is the principal vector along the West Coast ( Figure 18). The bites of nymphal and adult ticks can transmit A. phagocytophilum to humans. The relative roles of particular animal species as reservoirs of A. phagocytophilum strains that cause human illness are not fully understood and likely vary geographically; however, mice, squirrels, woodrats, and other wild rodents are thought to be important in the enzootic cycle. Most anaplasmosis cases occur during June–November. The seasonality of anaplasmosis is bimodal, with the first peak during June–July and a smaller peak during October, which corresponds to the emergence of the adult stage of I. scapularis (13).
The blacklegged tick also transmits nonrickettsial pathogens in certain geographic areas, including Borrelia burgdorferi (the cause of Lyme disease), Babesia microti (the primary cause of human babesiosis in the United States), Borrelia miyamotoi, (a cause of tickborne relapsing fever), and deer tick virus (Powassan virus, lineage II; a cause of tickborne encephalitis). The preponderance of cases of human anaplasmosis occur in the same states that report high incidences of Lyme disease and human babesiosis. Simultaneous infections with A. phagocytophilum and B. burgdorferi or B. microti have been described (69–73), and discerning such a mixed infection is important because it might affect antimicrobial choice (see Coinfections of Anaplasma with Other Tickborne Pathogens).
Epidemiologic Clues from the Clinical History
Obtaining a thorough clinical history that includes questions about recent 1) tick exposure, 2) recreational or occupational exposure to tick-infested habitats, 3) travel to areas where tickborne rickettsial diseases are endemic, and 4) occurrence of similar illness in family members, coworkers, or pet dogs can provide critical information to make a presumptive diagnosis of tickborne rickettsial disease. However, the absence of one or more of these factors does not exclude a diagnosis of tickborne rickettsial disease. Health care providers should be familiar with the epidemiologic clues that support the diagnosis of tickborne rickettsial disease but recognize that classic epidemiologic features are not reported in many instances ( Box 2).
History of Tick Bite or Exposure
A detailed history should be taken to elicit information about known tick bites or activities that might be associated with exposure to ticks. Although the recognition of a tick bite is helpful, unrecognized tick bites are common in patients who are later confirmed to have a tickborne rickettsial disease. A history of a tick bite within 14 days of illness onset is reported in only 55%–60% of RMSF cases (9,12,25) and 68% of ehrlichiosis cases (10). Therefore, absence of a recognized tick bite should never dissuade health care providers from considering tickborne rickettsial disease in the appropriate clinical context. In fact, the absence of classic features, such as a reported tick bite, has been associated with delays in RMSF diagnosis and increased risk for death (9,18,74,75). The location of the tick bite might be obscure, and the bite is typically painless. Bites from immature stages of ticks (e.g., nymphs, which are 1–2 mm, or the size of a pinhead) ( Figure 19) might be even less apparent. Some patients who do not report tick exposure might describe other pruritic, erythematous, or ulcerated cutaneous lesions that they refer to as mosquito, spider, chigger, or bug bites, all of which might be indistinguishable from a recent tick bite.
A thorough recreational and occupational history can help reveal potential exposures to tick habitats. In areas endemic for ticks, activities as commonplace as playing in a backyard, visiting a neighborhood park, gardening, or walking dogs are potential sources of tick exposure. Many types of environments serve as tick habitats, depending on the specific tick vector species. Areas with high uncut grass, weeds, and low brush might pose a high risk for certain vector species; however, these tick species also seek hosts in well-maintained grass lawns around suburban homes (76). Moreover, certain species can withstand drier conditions and might be found in vegetation-free areas or forest floors covered with only leaf litter or pine needles. Additional areas that might be inhabited by ticks include vegetation bordering roads, trails, yards, or fields; urban and suburban recreational parks; golf courses; and debris piles or refuse around homes (24,77–80). Activities that commonly result in contact with potential tick habitats include recreational pursuits (e.g., camping, hiking, fishing, hunting, gardening, and golfing) and occupational activities (e.g., forestry work, farming, landscaping, and military exercises). Although peak tick season is an important consideration, health care providers should remain aware that tickborne rickettsial illnesses have been reported in every month of the year, including winter (3–5,25,81). Climate differences and seasonal weather patterns can influence the duration and peak of tick season in a given geographic region and a given year.
Queries about contact with pets, especially dogs, and a history of tick attachment or recent tick removal from pets might be useful in assessing potential human tick exposure. Pet dogs with attached ticks can serve as useful indicators of peridomestic tick infestation (17,82,83). Tick-infested dogs can transfer ticks directly to humans during interactions and serve as transport hosts, carrying ticks in and around dwellings where the ticks can then transfer to the human occupants (84) (see Similar Illness in Household Members, Coworkers, or Pets).
Recent Travel to Areas Known To Be Endemic for Tickborne Rickettsial Diseases
Health care providers practicing in areas where the incidence of tickborne rickettsial disease is historically low might be less likely to distinguish these diseases from other clinically similar and more commonly encountered infectious and noninfectious syndromes. Tickborne rickettsial diseases typically are sporadic, and identifying these infections requires a high index of clinical suspicion, especially in environments in which the infections have not been recognized previously as occurring frequently. Knowledge of the epidemiology of tickborne rickettsial diseases, including the regions of the United States with a high incidence, is important. The distribution of tickborne rickettsial diseases is influenced by the geographic range of the tick vector, which can change over time. Distribution maps of tick vectors and disease incidence can serve as guides; however, the distribution borders are not fixed in space or over time, and the ranges for many tick species might be expanding.
Travel history within and outside of the United States can provide an important clue in considering the diagnosis of a tickborne rickettsial disease. Travel from an area where tickborne rickettsial diseases are endemic within 2 weeks of the onset of a clinically compatible illness could support a presumptive diagnosis of tickborne illness, especially if travel activities that might result in tick exposure are reported. Tickborne rickettsial diseases occur worldwide, and the imported diseases might have epidemiologic, seasonal, and clinical features that differ from those in the United States. Selected additional tickborne rickettsial diseases that might be considered in returning international travelers are presented (see Travel Outside of the United States and Appendix A).
Similar Illness in Household Members, Coworkers, or Pets
Clustering of certain tickborne rickettsial diseases is a well-recognized epidemiologic occurrence, particularly after common exposures to natural foci of infected ticks. Temporally and geographically related clusters of illness have occurred among family members (including their pet dogs), coworkers, or persons frequenting a particular common area. Described clusters include ehrlichiosis among residents of a golfing community (80), ehrlichiosis and RMSF among soldiers on field maneuvers (85,86), and RMSF among family members (87–89). Infections with R. rickettsiiand Ehrlichia species have been observed concurrently in humans and their pet dogs (48,83,90). Recognition of a dog’s death from RMSF has even prompted recognition and appropriate treatment of RMSF in the sick owner (90). Health care providers should ask ill patients about similar illnesses among family members, coworkers, community residents, and pet dogs.
Dogs are frequently exposed to ticks and are susceptible to infections with many of the same tickborne rickettsial pathogens as humans, including R. rickettsii, E. chaffeensis, E. ewingii, and A. phagocytophilum (82). Evidence of current or past rickettsial infection in dogs might be useful in determining the presence of human risk for tickborne rickettsial diseases in a given geographic area (82). Tickborne rickettsial infection in dogs can range from inapparent to severe. RMSF in dogs manifests with fever, lethargy, decreased appetite, tremors, scleral injection, maculopapular rash on ears and exposed skin, and petechial lesions on mucous membranes (91–93). A veterinarian should be consulted when tickborne rickettsial disease is suspected in dogs or other animals (see Protecting Pets from Tick Bites). Documentation of a tickborne rickettsial disease in a dog should prompt veterinary professionals to warn pet owners about the risk for acquiring human tickborne disease. Cases of RMSF in dogs preceding illness in their owners (83) illustrate the value of communication between veterinarians and human health care providers when zoonotic diseases are suspected and emphasize the importance of a One Health approach to address zoonotic diseases.
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Clinical Signs and Symptoms and Pathophysiology of Disease
Tickborne rickettsial diseases commonly have nonspecific clinical signs and symptoms early in the course of disease. Although the clinical presentations of tickborne rickettsial disease overlap, the frequency of certain associated signs and symptoms (e.g., rash and other cutaneous findings), typical laboratory findings, and case-fatality rates differ by pathogen ( Table 1). Familiarity with the clinical signs and symptoms and pathophysiology of tickborne rickettsial diseases, including RMSF and other SFG rickettsioses ( Box 3), ehrlichioses ( Box 4), and anaplasmosis ( Box 5) will assist health care providers in developing a differential diagnosis, prescribing appropriate antibacterial treatment, and ordering appropriate confirmatory diagnostic tests.
Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses
Rocky Mountain Spotted Fever
Pathophysiology
R. rickettsii is an obligate intracellular pathogen that primarily infects vascular endothelial cells, and, less commonly, underlying smooth muscle cells of small and medium vessels ( Figure 20). Infection with R. rickettsii leads to systemic vasculitis that manifests externally as characteristic petechial skin lesions. If disease progresses untreated, it can result in end-organ damage associated with severe morbidity and death. Pathogen-mediated injury to the vascular endothelium results in increased capillary permeability, microhemorrhage, and platelet consumption (94). Late-stage manifestations, such as noncardiogenic pulmonary edema (acute respiratory distress syndrome [ARDS]) and cerebral edema, are consequences of microvascular leakage. Hyponatremia occurs as a result of appropriate secretion of antidiuretic hormone in response to hypovolemia (95).
Signs and Symptoms
Symptoms of RMSF typically appear 3–12 days after the bite of an infected tick or between the fourth and eighth day after discovery of an attached tick (96). The incubation period is generally shorter (5 days or less) in patients who develop severe disease (97). Initial symptoms include sudden onset of fever, headache, chills, malaise, and myalgia. Other early symptoms might include nausea or vomiting, abdominal pain, anorexia, and photophobia. A rash typically appears 2–4 days after the onset of fever; however, most patients initially seek health care before appearance of a rash (25,74,98). The classic triad of fever, rash, and reported tick bite is present in only a minority of patients during initial presentation to health care (6,25); therefore, health care providers should not wait for development of this triad before considering a diagnosis of RMSF.
The RMSF rash classically begins as small (1–5 mm in diameter), blanching, pink macules on the ankles, wrists, or forearms that subsequently spread to the palms, soles, arms, legs, and trunk, usually sparing the face. Over the next several days of illness, the rash typically becomes maculopapular, sometimes with central petechiae ( Figures 21 and 22). The classic spotted or generalized petechial rash, including involvement of the palms and soles, usually appears by day 5 or 6 and is indicative of advanced disease. Absence of rash should not preclude consideration of RMSF; <50% of patients have a rash in the first 3 days of illness, and a smaller percentage of patients never develop a rash (6,25). The rash might be atypical, localized, faint, or evanescent (99). In some persons, skin pigmentation might make the rash difficult to recognize. The rash might resemble those of other infectious and noninfectious etiologies (see Differential Diagnosis of Fever and Rash). Children aged <15 years more frequently have a rash than older patients and develop the rash earlier in the course of illness (6–8). Lack of rash or late-onset rash in RMSF has been associated with delays in diagnosis and increased mortality (6,18,74). Unlike some SFG rickettsioses, an inoculation eschar is rarely present with RMSF (100,101). Other clinical features that have been observed in association with RMSF include abdominal pain that mimics acute appendicitis (102), cholecystitis (103), or gastroenteritis; diarrhea; conjunctival suffusion; periorbital and peripheral edema (more common in children); calf pain; acute transient hearing loss; hepatomegaly; and splenomegaly (6,104).
Severe, late-stage manifestations of RMSF include meningoencephalitis, acute renal failure, ARDS, cutaneous necrosis, shock, arrhythmia, and seizure. Features of late illness might be confused with other diseases or syndromes. For example, RMSF-associated cutaneous necrosis and gangrene might be difficult to distinguish clinically from purpura fulminans associated with meningococcemia (105). RMSF-associated neurologic manifestations, renal failure, and thrombocytopenia have led to confusion with the diagnosis of thrombotic thrombocytopenic purpura (TTP) (106–108). RMSF-associated vasculitis has been confused with idiopathic, acute vasculitides, such as Kawasaki disease in pediatric patients. RMSF might also mimic bacterial or viral meningoencephalitis (109). Focal neurologic deficits, including cranial or peripheral motor nerve paralysis, or sudden transient hearing loss can occur (110–112).
Clinical Course
Clinical suspicion for RMSF should be maintained in cases of nonspecific febrile illness and sepsis of unclear etiology, particularly during spring and summer months. Delay in diagnosis and treatment is the most important factor associated with increased likelihood of death, and early empiric therapy is the best way to prevent RMSF progression. Without treatment, RMSF progresses rapidly. Patients treated after the fifth day of illness are more likely to die than those treated earlier in the course of illness (9,18,74,75). The frequency of hospital admission, intensive care unit admission, and death increases with time from symptom onset to initiation of appropriate antibacterial treatment (18) ( Table 2). Delays in diagnosis and initiation of antirickettsial therapy have been associated with seeking health care early in the course of the illness (7,74), late-onset or absence of rash (6,18), and nonspecific or atypical early manifestations, such as gastrointestinal symptoms (18,98) or absence of headache (75). Epidemiologic factors associated with increased risk for death include disease that occurs early or late in the typical tick season (74) and the lack of a report of a tick bite (9,75,98). Although knowledge of the epidemiology might help guide diagnosis, the absence of epidemiologic clues can be misleading.
RMSF is the most frequently fatal rickettsial illness in the United States; the case-fatality rate in the preantibiotic era was approximately 25% (113–115). Present-day case-fatality rates, estimated at 5%–10% overall, depend in part on the timing of initiation of appropriate treatment; case-fatality rates of 40%–50% among patients treated on days 8 or 9 of illness have been described recently (18) (Table 2). Additional risk factors for fatal RMSF include age ≥40 years, age <10 years, and alcohol abuse (18,75,116,117). Glucose-6-phosphate dehydrogenase deficiency is a risk factor for fulminant RMSF, with death occurring in ≤5 days (118). Experimental and accumulated anecdotal clinical data suggest that treatment of patients with RMSF using a sulfonamide antimicrobial can result in increased disease severity and death (119,120).
Long-term neurologic sequelae of RMSF include cognitive impairment; paraparesis; hearing loss; blindness; peripheral neuropathy; bowel and bladder incontinence; cerebellar, vestibular, and motor dysfunction; and speech disorders (7,110,121–124). These complications are observed most frequently in persons recovering from severe, life-threatening disease, often after lengthy hospitalizations, and are most likely the result of R. rickettsii-induced vasculopathy. Cutaneous necrosis and gangrene ( Figure 23) might result in amputation of digits or limbs (105). Long-term or persistent disease caused by R. rickettsii has not been observed.
Laboratory Findings
The total white blood cell count is typically normal or slightly increased in patients with RMSF, and increased numbers of immature neutrophils often are observed. Thrombocytopenia, slight elevations in hepatic transaminases (aspartate transaminase and alanine transaminase), and hyponatremia might be present, particularly as the disease advances (25,77); however, laboratory values cannot be relied on to guide early treatment decisions because they are often within or slightly deviated from the reference range early in the course of illness (25). Indicators of diffuse tissue injury, such as elevated levels of creatine kinase or serum lactate dehydrogenase, might be present later in the course of illness. Disseminated intravascular coagulation (DIC) is rare. (125,126). When cerebrospinal fluid (CSF) is evaluated, a lymphocytic (or less commonly, neutrophilic) pleocytosis (usually <100 cells/µL) can be observed (122). CSF protein might be moderately elevated (100–200 mg/dL), and the glucose level is typically within normal range (