Table: Selected features of Rocky Mountain spotted fever,1 human monocytotropic ehrlichiosis, human granulocytotropic anaplasmosis2, and Ehrlichia ewingii infection -- United States3
| Agent (disease) |
Primary vector(s) |
Approximate distribution4 |
Incubation period(days) |
Common initial signs and symptoms |
Common laboratory abnormalities |
Rash |
Case-fatality rate |
| Rickettsia rickettsii (Rocky Mountain spotted fever) |
Dermacentor variabilis (American dog tick), Dermacentor andersoni (Rocky Mountain wood tick), and Rhipicephalus sanguineus (brown dog tick) in AZ5 |
Widespread in the United States, especially South Atlantic and South Central states |
2-14 |
Fever, nausea, vomiting, myalgia, anorexia, and headache |
Thrombocytopenia, mild hyponatremia, and mildly elevated hepatic transaminase levels |
Maculopapular rash approximately 2-4 days after fever onset in 50%-80% of adults (>90% in children); might involve palms and soles |
5%-10% |
| Ehrlichia chaffeensis (human monocytotropic ehrlichiosis) |
Amblyomma americanum (lone star tick) |
South and Mid-Atlantic, North/South Central United States, and isolated areas of New England |
5-14 |
Fever, headache, malaise, and myalgia |
Leukopenia, thromobocytopenia, and elevated serum transaminase levels |
Rash in <30% of adults and approximately 60% of children |
2%-3% |
| Anaplasma phagocytophilum (human granulocytotropic anaplasmosis) |
Ixodes scapularis and Ixodes pacificus (blacklegged tick) in the United States |
New England, North Central and Pacific states |
5-21 |
Fever, headache, malaise, myalgia, and vomiting |
Leukopenia, thrombocytopenia, elevated serum transaminase levels |
Rare |
<1% |
| Ehrlichia ewingii infection |
Amblyomma americanum (lone star tick) |
South Atlantic and South Central United States to isolated areas of New England |
5-14 |
Fever, headache, myalgia, nausea, and vomiting |
Leukopenia, thromobocytopenia, and elevated serum transaminase levels |
Rare |
No documented fatalities |
1 SOURCE: Walker DH, Raoult D. Rickettsia rickettsii and other spotted fever group rickettsiae (Rocky Mountain spotted fever and other spotted fevers). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:2287-95.
2 SOURCE: Walker DH, Dumler JS. Ehrlichia chaffeensis (human monocytotropic ehrlichiosis), Anaplasma phagocytophilum (human granulocytotropic anaplasmosis) and other ehrlichiae. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's principles and practice of infectious diseases. 6th ed. Philadelphia, PA: Churchill Livingstone; 2005:2310-8.
3 Treatment for each of these diseases is the same: adults, doxycycline 100 mg orally (PO) or intravenously (IV) twice daily; and children, doxycycline 2.2 mg/kg administered PO or IV twice daily.
4 Mountain: Montana, Idaho, Wyoming, Colorado, New Mexico, Arizona, Utah, Nevada. East South Central: Kentucky, Tennessee, Alabama, Mississippi. East North Central: Ohio, Indiana, Illinois, Michigan, Wisconsin. West South Central: Arkansas, Louisiana, Oklahoma, Texas. West North Central: Minnesota, Iowa, Missouri, North Dakota, South Dakota, Nebraska, Kansas. Pacific: Washington, Oregon, California. New England: Massachusetts, Connecticut, Rhode Island, New Hampshire. South Atlantic: Delaware, Maryland, Virginia, District of Columbia, West Virginia, North Carolina, South Carolina, Georgia, Florida. Mid-Atlantic: New York, New Jersey, Pennsylvania.
5 SOURCE: Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from an unexpected tick vector in Arizona. N Engl J Med 2005;353:587-94.
Table: Case definitions for Rocky Mountain spotted fever1, human monocytotropic ehrlichiosis (HME), human granulocytotropic anaplasmosis (HGA), and unspecified ehrlichiosis2
| Rocky Mountain spotted fever |
Ehrlichiosis and anaplasmosis |
| Clinical description |
Tickborne illness characterized by acute onset of fever and possible headache, malaise, myalgia, and nausea/vomiting or neurologic signs. A macular or maculopapular rash is reported in the majority of patients and is frequently observed on the palms and soles. |
Tickborne illness characterized by acute onset of fever, headache, myalgia, and possible malaise. Nausea, vomiting, or rash might be observed in certain cases. Clinical laboratory findings might include thrombocytopenia, leukopenia, and possibly elevated liver enzymes. Intracytoplasmic morulae might be visible in the leukocytes of certain patients. |
| |
HME |
HGA |
Unspecified ehrlichiosis |
| Laboratory criteria |
Serologic evidence of 4-fold change in serum antibody titer against Rickettsia rickettsii antigens between paired serum samples, as determined by IFA3 or ELISA4;
or
demonstration of R. rickettsii antigen in a clinical specimen by IHC5 methods;
or
detection of R. rickettsii DNA in a clinical specimen by PCR assay;
or
isolation of R. rickettsii from a clinical specimen in cell culture.
|
Demonstration of 4-fold change in antibody titer to Ehrlichia chaffeensis antigen by IFA in paired serum samples;
or
positive PCR6 assay and confirmation of E. chaffeensis DNA;
or
identification of morulae in leukocytes and a positive IFA titer to E. chaffeensis antigen;
or
immunostaining of E. chaffeensis antigen in a biopsy or autopsy sample;
or
culture of E. chaffeensis from a clinical specimen.
|
Demonstration of 4-fold change in antibody titer to Anaplasma phagocytophilum antigen by IFA in paired serum samples;
or
positive PCR assay and confirmation of A. phagocytophilum DNA;
or
identification of morulae in leukocytes, and a positive IFA titer to A. phagocytophilum antigen;
or
immunostaining of A. phagocytophilum antigen in a biopsy or autopsy sample;
or
culture of A. phagocytophilum from a clinical specimen.
|
Demonstration of 4-fold change in antibody titer to more than one Ehrlichia species in which a dominant reactivity cannot be established;
or
Identification of a species other than E. chaffeensis or A. phagocytophilum by PCR, immunostaining, or culture.
|
| Case classification |
Probable case: Identified in a person with a clinically compatible illness and serologic evidence of antibody reactive with R. rickettsii in a single serum sample at a titer considered indicative of current or previous infection (cutoff titers are determined by individual laboratories). |
Probable case: Identified in a person with a clinically compatible illness with either a single positive IFA titer (based on cutoff titers established by the laboratory performing the test) or the visualization of morulae in leukocytes. |
| |
Confirmed case: Identified in a person with a clinically compatible illness that is laboratory confirmed by a 4-fold change in serum antibody titer, as determined by IFA or ELISA or positive PCR or positive IHC, or isolation in culture. |
1 SOURCE: CDC. Rocky Mountain spotted fever (Rickettsia rickettsii): 2004 case definition. Atlanta, GA: US Department of Health and Human Services, CDC, Epidemiology Program Office, Division of Public Health Surveillance and Informatics; 2004.
2 SOURCE: CDC. Ehrlichiosis (HGE, HME, other or unspecified): 2000 case definition. Atlanta, GA: US Department of Health and Human Services. CDC, Epidemiology Program Office, Division of Public Health Surveillance and Informatics; 2000.
3 Indirect immunofluorescence antibody
4 Enzyme-linked immunosorbent assay
5 Immunohistochemical
6 Polymerase chain reaction
Epidemiology of Tickborne Rickettsial Diseases (TBRD)
The following is a summary of the salient epidemiologic features of TBRD:
- Occurrence is seasonal, with the majority of illness onset during warmer spring and summer months, but cases might develop throughout the year.
- Rocky Mountain spotted fever (RMSF) has been reported in all of the contiguous 48 states, except Vermont and Maine.
- RMSF and human monocytotropic (or monocytic) ehrlichiosis (HME) are most commonly reported in the southeastern and south central United States.
- Human granulocytotropic (or granulocytic) anaplasmosis (HGA) is reported most frequently in New England, the north central states, and in focal areas along the West Coast.
Pathogen Tropisms and Clinical Presentation
The following is a summary of salient features of pathogen tropisms:
- Rickettsia. rickettsii infects endothelial cells, causing vasculitis, which leads to rash and life-threatening damage to the brain, lungs, and other viscera.
- R. rickettsii is not evident in blood smears, and these bacteria and do not stain with the majority of conventional stains.
- Ehrlichia and Anaplasma species infect monocytes or granulocytes, respectively, and morulae might occasionally be observed on peripheral blood smears by using routine stains.
Clues from the Clinical History
The following is a summary of salient features of clues from the clinical history:
- A detailed history of recent recreational or occupational activities might reveal potential exposure to ticks.
- Exposure can occur in the patient's backyard or neighborhood.
- Familiarity with TBRD epidemiology will be helpful when querying patients regarding recent travel to endemic areas (domestic and international).
- Clustering of certain TBRD is well-recognized and has been reported among family members, coworkers, and other defined groups.
Clinical Assessment
The following is a summary of salient clinical assessment features:
- Early clinical presentations of HME, HGA, RMSF, and Ehrlichia ewingii infection include fever, headache, myalgia, and malaise and are difficult to distinguish from other infectious and noninfectious diseases.
- Patients with RMSF typically do not have a spotted or petechial rash when they initially seek medical care during the first 2 to 4 days of illness.
- A complete blood count (CBC), metabolic panel, and peripheral blood smear examination are helpful in developing both a differential diagnosis and treatment approach to TBRD.
- Cerebrospinal fluid (CSF) analysis might reveal neutrophilic or lymphocytic pleocytosis and elevated protein but might not reliably distinguish TBRD and meningococcal disease, necessitating empiric antibiotic therapy for both conditions when indicated.
- Leukopenia, thrombocytopenia, mild hyponatremia, and mildly elevated hepatic transaminase levels are common and particularly useful clinical features of TBRD, although the absence of these features does not exclude a diagnosis of TBRD.
- Infrequent features of TBRD include severe abdominal pain and meningoencephalitis.
- Rash is observed frequently in RMSF, occasionally in HME, and rarely in HGA or E. ewingii infection
Treatment and Management
The following is a summary of salient features of treatment and management:
- Clinical history, symptoms, and physical and laboratory findings should guide the clinician's approach to patient management and treatment.
- Not all patients with TBRD will require hospitalization.
- Clinicians may consider a wait and watch approach for 24 to 48 hours for patients early in the course of illness and who have nonsupporting history, nonspecific clinical signs, and normal laboratory findings.
- Doxycycline is the drug of choice for the treatment of presumptive or confirmed TBRD in both adults and children.
- Limited courses of tetracycline-class antibiotics (e.g., doxycycline) do not pose a substantial threat of tooth staining in children.
- Tetracyclines typically are contraindicated for use during pregnancy but might be warranted in life-threatening situations where clinical suspicion of TBRD is high.
- Delay in treatment can lead to severe disease and fatal outcome of TBRD.
- In evaluating for TBRD, when early invasive meningococcal infection cannot be ruled out, providing treatment for both conditions by adding an antimicrobial that has activity against N. meningitidis is appropriate.
- Prophylactic use of antibiotics after a tick bite is not recommended.
Considerations for Management of Patients with Severe Manifestations of TBRD
The following is a summary of salient features of severe manifestations:
- TBRD can be life-threatening.
- Severe manifestations of TBRD include prolonged fever, renal failure, myocarditis, meningoencephalitis, hypotension, acute respiratory distress syndrome, and multiple organ failure.
Confirmatory Diagnostic Tests
The following is a summary of salient features of diagnostic testing:
- Blood smear microscopy might reveal presence of morulae in infected leukocytes, which is highly suggestive of HGA or, less commonly, HME.
- Blood smears are not useful to diagnose RMSF.
- Examination of paired serum samples obtained 2 to 3 weeks apart that demonstrate a rise in antibody titer is the most appropriate approach to confirm TBRD.
- Patients usually do not have diagnostic serum antibody titers during the first week of illness; therefore, an inability to detect antibodies (IgG or IgM) in acute-phase serum does not exclude TBRD.
- Immunohistochemistry of a biopsied skin lesion or autopsy tissues is useful for RMSF diagnosis in patients for whom diagnostic titers of antibodies have not yet developed.
- Whole blood specimens might be useful for a polymerase chain reaction (PCR) confirmation of HME, HGA, and E. ewingii infection; however, a negative result does not rule out the diagnosis.
Surveillance and Reporting
The following is a summary of salient features of surveillance and reporting:
- RMSF, HME, HGA, and other ehrlichioses are reportable diseases in the United States.
- Physicians who identify a potential case of TBRD should notify the local health department, which can assist with obtaining diagnostic testing to confirm the diagnosis.
- Surveillance and reporting of TBRD are key components of public health education and disease prevention efforts.
Prevention
The following is a summary of salient features of prevention:
- Avoid tick bites, which is key to the prevention of TBRD.
- Limit exposure to tick habitats, including grassy and wooded areas.
- Inspect the body carefully for ticks after being in a tick habitat.
- Remove attached ticks immediately by grasping with tweezers close to skin and pulling gently with steady pressure.
Conclusion
TBRD continue to cause severe illness and death in otherwise healthy adults and children, despite the availability of low cost, effective antimicrobial therapy. The greatest challenge to clinicians is the difficult diagnostic dilemma posed by these infections early in their clinical course when antibiotic therapy is most effective.
Early clinical presentations of HME, HGA, RMSF, and E. ewingii infection include fever, headache, myalgia, and malaise and are difficult to distinguish from other infectious and noninfectious diseases. Rash is observed frequently in RMSF, occasionally in HME, and rarely in HGA. TBRD tend to occur seasonally, with the majority of cases occurring during the warmer spring and summer months. However, cases might develop year-round. A detailed history of recent recreational or occupational activities might reveal potential exposure to ticks, although the absence of a history of a recent tick bite should not dissuade clinicians from considering a diagnosis of TBRD.
TBRD can be life-threatening. Severe manifestations of TBRD include prolonged fever, renal failure, myocarditis, meningoencephalitis, hypotension, acute respiratory distress syndrome, and multiple organ failure. Patients usually do not have diagnostic serum antibody levels during the first week of illness; therefore, an inability to detect antibodies (IgG or IgM) in acute-phase serum does not exclude TBRD. Health-care providers should not delay treatment while waiting for a diagnosis; rather, they should empirically provide treatment if they suspect TBRD. Doxycycline is the drug of choice for the treatment of presumptive or confirmed TBRD in both adults and children.
Examination of paired serum samples obtained during acute illness and 2 to 3 weeks later that demonstrate a rise in antibody titer is the most appropriate approach to confirm TBRD. Physicians who identify a potential case of TBRD should notify the local health department, which can assist with obtaining diagnostic testing to confirm the diagnosis.
No licensed vaccines for TBRD are available. Avoiding tick bites and promptly removing attached ticks remain the best disease prevention strategies.
