Mediterranean Spotted Fever (Boutonneuse Fever) Workup

Updated: Sep 15, 2021
  • Author: D Matthew Shoemaker, DO, FIDSA; Chief Editor: Michael Stuart Bronze, MD  more...
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Approach Considerations

Mediterranean spotted fever (MSF), also known as boutonneuse fever (BF), is diagnosed primarily on the basis of clinical symptoms and epidemiologic data, along with laboratory evidence of recent exposure to rickettsial organisms. Both serologic [indirect immunofluorescence antibody (IFA) and enzyme-linked immunosorbent assay (ELISA)] and polymerase chain reactions (PCR) tests are used to confirm the diagnosis. Currently serologic testing is the most commonly used diagnostic test for MSF. There are PCR assays available for SFG Rickettsia species. 

Magnetic resonance imaging can demonstrate multifocal white matter disturbances if the central nervous system is involved. These findings are not specific for MSF.

Characteristic histopathologic findings at the site of the primary lesion consist of epidermal ulceration, hyperplasia of the endothelium of the small dermal antinodes, and perivascular infiltrates in the dermis.


Laboratory Studies

Basic laboratory tests for BF include the following:

  • Complete blood count (CBC) with differential - Normochromic anemia; leukopenia and lymphopenia; thrombocytopenia (35% of patients)
  • Liver function tests - Increased liver enzymes (60.5-64.8% of patients)
  • Creatinine - Increased levels (29.7% of patients)
  • Urinalysis - Hematuria (35.9% of patients); proteinuria (56.4% of patients)
  • Fibrinogen - Increased levels during acute phase
  • Fibronectin - Decreased levels during acute phase

Culture of the organism via animal inoculation can be performed but is not commercially available and is only used in research settings. Routine microbiologic techniques are insufficient for isolating this organism.

Serologic testing is commonly employed for confirmation of the diagnosis, however, these tests are useful only after an acute infection because antibodies can be detected late (even >30 days after the onset of symptoms).

On serologic testing, the antibody titer in serum is increased only 2 weeks after the infection and reaches its peak level after 4 weeks. Afterward, the immunoglobulin M (IgM) level decreases and the immunoglobulin G (IgG) level remains high for several months. Titers of 1:64 or greater are diagnostic. [29]

With the Weil-Felix reaction (agglutination type), the result can become positive 40 days after the symptoms started, with OX19, OX2, and OXK strains of Proteus vulgaris antigens. This test is still used in clinical practice because of its convenience, but it has low sensitivity and specificity.

When R conorii is isolated by means of the centrifugation-shell vials technique, the result can become positive 14 days after inoculation. Results can be obtained within 2-3 days after receipt of the sample.

IFA of R conorii in circulating endothelial cells (CEC) isolated from whole blood can be performed by using immunomagnetic beads. This test is sensitive; 50% of results are positive. Results can be obtained in 3 hours. The initiation of the therapy has no influence on the results. This test can be used in all routine laboratories.

Enzyme-linked immunosorbent assay (ELISA) techniques were developed to detect antibodies to lipopolysaccharide (LPS) of R conorii. ELISA is a relatively simple and convenient way of serodiagnosing MSF with a single serum dilution. It can be of use in laboratories that lack more sophisticated equipment (such as that needed for IFA).

PCR is available for R rickettsia and SFG Rickettsia species. PCR can be used in the acute phase of illness and does not require additional testing.  The limitation of PCR is that its sensitivity can be negatively impacted by antibiotic therapy. Ergas et al reported early diagnosis using nested PCR. [30] Either PCR or Western blot studies can be used to differentiate R conorii from Rickettsia africae. Species isolation should be considered in patients with unusual presentations, including severe disease, and those traveling from areas with poorly defined rickettsial activity. [31]

Direct immunofluorescence of cutaneous biopsy specimens is diagnostic only during the acute phase of the disease. It reveals endothelial hyperplasia, intraluminal thrombosis, and lymphocytic perivascular infiltrate. This test is specific and sensitive if performed before the initiation of antimicrobial therapy and before the 10th day of the disease. It is not widely available, because it is time-consuming and requires an experienced pathologist with a well-equipped laboratory. Results can be obtained within 2-3 days after sample receipt.