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Physician Diagnosis

Because the laboratory tests that detect TBRD are often not positive in the first week of illness, physicians must base early patient treatment decisions on the signs and symptoms, as well as the patient’s history. The physician may also look at specific blood tests to help determine the likelihood of TBRD. Clues such as a low platelet count (thrombocytopenia), low serum sodium levels (hyponatremia), abnormal white blood cell counts (elevated or decreased), or elevated liver enzyme levels are often helpful predictors. Treatment should never be delayed while waiting for confirmation of TBRD infection by laboratory results.

Laboratory Detection

 IFA reaction of a positive human serum to Rickettsia rickettsii

IFA reaction of a positive human serum to Rickettsia rickettsii (the agent of RMSF), 400X

Serologic assays are the most frequently used methods for confirming cases of TBRD. The indirect immunofluorescence assay (IFA) (see figure) is generally considered the reference standard in TBRD serology. Other assays include ELISA or EIA, latex agglutination, and dot immunoassays.

Serologic tests can be used to detect either IgG or IgM antibodies. Blood samples taken early (acute) and late (convalescent) in the disease are the preferred specimens for evaluation. Most patients demonstrate increased IgM titers by the end of the first week of illness, but IgM assays may be falsely elevated due to other bacterial infections. IgG antibodies are considered more accurate for the TBRD, but detectable levels of IgG antibody generally do not appear until 7-10 days after the onset of illness. It is important to consider the amount of time it takes for antibodies to appear when ordering laboratory tests, especially because most patients visit their physician relatively early in the course of the illness, before diagnostic antibody levels may be present. The value of testing two sequential serum or plasma samples together to show a rising antibody level is very important in confirming acute infection with TBRD. Because antibody titers may persist in some individuals for years after the original exposure, only demonstration of recent changes in titers between paired specimens can be considered reliable confirmation of an acute infection.

The most rapid and specific diagnostic assays for TBRD rely on molecular methods like PCR which can detect DNA present in a whole blood or tissue sample. PCR on whole blood specimens taken early during illness have been shown to be a very effective tool to diagnose ehrlichiosis and anaplasmosis infections. However, whole blood is not as effective of a specimen for RMSF, and a skin biopsy from a rash site is preferred for RMSF PCR testing. Immunostaining procedures can also be performed on formalin-fixed tissue samples. Ideally, whole blood or skin biopsy specimens used for diagnosis should be taken before or within the first 48 hours after doxycycline treatment is started; after antibiotic therapy has been started, it becomes more difficult to detect the organisms by these methods. A specific diagnosis can also be confirmed by isolation of R. rickettsii from clinical samples like whole blood and biopsies. Isolation may require several weeks, but isolates are very important for investigating differences in the pathogenic properties and antimicrobial resistance of rickettsiae which cause disease in different parts of the United States. CDC accepts specimens for TBRD testing from state health department public health laboratories. For questions regarding specimen submission, please contact your state health department laboratory.

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