Appendices for Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis — United States

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Appendix A

Selected Tickborne Rickettsioses Outside of the United States

Tickborne rickettsial diseases are found worldwide. This appendix highlights some of the more common tickborne rickettsial pathogens typically transmitted outside the United States and known to cause disease in humans.
Disease Geographic distribution of human cases Pathogen Signs and symptoms
African tick bite fever Sub-Saharan Africa, Caribbean (French West Indies), and Oceania Rickettsia africae Fever, headache, myalgia, eschar (sometimes multiple), regional lymphadenopathy, rash (maculopapular or vesicular); typically mild illness with benign course
Mediterranean spotted fever (also known as boutonneuse fever) Europe (Mediterranean basin), Middle East, Indian subcontinent, and Africa Rickettsia conorii Fever, headache, myalgia, eschar (usually singular), and rash (maculopapular or petechial, sometimes involving palms and soles); typically moderately severe illness, can be severe or fatal
Queensland tick typhus Eastern Australia, including Tasmania Rickettsia australis Fever, headache, myalgia, eschar, regional lymphadenopathy, and rash (maculopapular or vesicular); typically mild illness, can be severe or fatal
Flinders Island spotted fever Australia and southeast Asia Rickettsia honei Fever, headache, myalgia, eschar (in a minority of patients), and rash; typically mild illness
Japanese spotted fever Japan and South Korea Rickettsia japonica Fever, headache, eschar, and rash; can be severe or fatal
Siberian tick typhus (also known as North Asian tick typhus) North Asia Rickettsia sibirica Fever, eschar, regional lymphadenopathy, and rash (maculopapular); typically mild illness
Lymphangitis associated rickettsiosis* Southern Europe and Africa Rickettsia sibirica mongolitimonae Fever, eschar (single or multiple), regional lymphadenitis, lymphangitis, and rash (maculopapular); typically mild illness, can have severe complications
Tickborne lymphadenopathy (also known as Dermacentor-borne necrosis and lymphadenopathy or scalp eschar and neck lymphadenopathy after tick bite) Europe Rickettsia slovaca and Rickettsia raoultii Eschar (typically on the scalp), painful regional lymphadenopathy, alopecia surrounding eschar, low fever (<50%), rash (rare), and asthenia; typically mild illness with benign course
Rickettsia massiliae spotted fever* Europe and South America Rickettsia massiliae Fever, eschar, and rash; typically mild to moderately severe illness

*Few human cases are described in the peer-reviewed literature, and the clinical picture and geographic distribution might be incomplete.

Appendix B

Diagnostic Assays for Tickborne Rickettsial Diseases
Stage of illness Specimen Optimal specimen characteristics Pathogen Assay Test advantages and limitations
Acute (active signs and symptoms of disease) Whole blood
  • EDTA-anticoagulated blood
  • Preferred volume of 3–5 mL
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 PCR
  • Test is most sensitive during the first week of illness and before or within 48 hours of beginning therapy with doxycycline.
  • Sensitivity diminishes within 1 week after the collection date.
  • Anaplasma and Ehrlichia spp.
 Blood smear
  • A blood smear can provide a rapid presumptive diagnosis.
  • Sensitivity is low.
  • An experienced microscopist is required.
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 Culture
  • Culture is the microbiological reference standard.
  • Confirmation of diagnosis might require ≥10 days, and propagation requires BSL-3 facilities.
  • Test is most sensitive during the first week of illness and before beginning therapy with doxycycline.
  • Availability is restricted to reference centers or research laboratories.
Serum Preferred volume of 3–5 mL
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 PCR
  • Molecular assessment of serum is generally less sensitive than evaluation of whole blood.
  • Serum can be used if whole blood is not available.
IFA
  • Antibodies are often absent during the first week of illness.
  • Antibodies are usually specific to the genus rather than the species of pathogen.
  • Confirmation requires a fourfold or greater increase in titer between acute and convalescent serum specimens (see below for convalescent serum).
Eschar Swab of unroofed eschar SFG rickettsiae PCR
  • Swab is less invasive than skin biopsy.
  • Assessment of swab might be less sensitive than evaluation of eschar biopsy and does not allow for culture or IHC.
Fresh tissue Punch biopsy specimens (≥4 mm) of eschar or rash SFG rickettsiae PCR
  • Eschars contain abundant numbers of SFG rickettsiae relative to blood; when present, they represent the best clinical sample for a specific diagnosis.
  • Test is most sensitive during the first week of illness and before or within 48 hours of beginning therapy with doxycycline.
Culture
  • Isolation is more effective from tissue than from blood for SFG rickettsiae.
  • Collect specimen before beginning therapy with doxycycline.
  • Availability is restricted to reference centers or research laboratories.
Autopsy specimens might include representative samples of all major organs
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 PCR Test is most sensitive during the first week of illness and before or within 48 hours of beginning therapy with doxycycline.
Culture
  • Isolation is more effective from tissue than from blood for SFG rickettsiae.
  • Isolation is most effective from spleen, lymph node, liver, or bone marrow for Anaplasma and Ehrlichia spp.
  • Collect specimen before beginning therapy with doxycycline.
  • Availability is restricted to reference centers or research laboratories.
IHC Availability is restricted to reference centers or research laboratories.
Formalin-fixed tissue
  • Biopsy specimens might include skin, bone marrow, or lymph node
  • Autopsy specimens might include representative samples of all major organs
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 PCR Formalin fixation results in cross-linking and fragmentation of DNA, which might limit sensitivity of nucleic acid detection methods.
IHC Availability is restricted to reference centers or research laboratories.
Convalescent (2–4 weeks after resolution of illness) Serum Preferred volume of 3–5 mL
  • Anaplasma and Ehrlichia spp.
  • SFG rickettsiae
 IFA
  • Antibodies are usually specific to the genus rather than the species of pathogen.
  • Confirmation of acute infection requires a fourfold or greater increase in titer between acute and convalescent serum specimens.

Abbreviations: BSL-3 = biosafety level 3; DNA = deoxyribonucleic acid; EDTA = ethylenediaminetetraacetic acid; IFA = indirect immunofluorescence antibody; IHC = immunohistochemical stain; PCR = polymerase chain reaction; SFG = spotted fever group.

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