Boutonneuse Fever Workup
- Author: Jason F Okulicz, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD more...
Boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), is diagnosed primarily on the basis of clinical symptoms and epidemiologic data, along with laboratory evidence of recent exposure to rickettsial organisms. Both culture techniques and serologic tests are used to confirm the diagnosis. Currently, indirect immunofluorescence (IIF) is the most commonly used confirmatory test.
A magnetic resonance study can demonstrate multifocal white matter disturbances if the central nervous system is involved.
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.
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 may be considered the reference standard for diagnosis; however, it is rarely performed during the acute phase of the disease, and it cannot be performed retrospectively unless samples were appropriately collected and stored (at −70°C).
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 IIF, 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.
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.
IIF 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 BF with a single serum dilution. It can be of use in laboratories that lack more sophisticated equipment (such as that needed for IIF).
Polymerase chain reaction (PCR) is not routinely used or universally available. Ergas et al reported early diagnosis using nested PCR. 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.
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.
Popivanova NI, Murdjeva MA, Baltadzhiev IG, Haydushka IA. Dynamics in serum cytokine responses during acute and convalescent stages of Mediterranean spotted fever. Folia Med (Plovdiv). 2011 Apr-Jun. 53(2):36-43. [Medline].
Valbuena G, Walker DH. Expression of CX3CL1 (fractalkine) in mice with endothelial-target rickettsial infection of the spotted-fever group. Virchows Arch. 2005 Jan. 446(1):21-7. [Medline].
Rydkina E, Sahni A, Baggs RB, Silverman DJ, Sahni SK. Infection of human endothelial cells with spotted Fever group rickettsiae stimulates cyclooxygenase 2 expression and release of vasoactive prostaglandins. Infect Immun. 2006 Sep. 74(9):5067-74. [Medline]. [Full Text].
de Sousa R, Ismail N, Nobrega SD, França A, Amaro M, Anes M, et al. Intralesional expression of mRNA of interferon- gamma , tumor necrosis factor- alpha , interleukin-10, nitric oxide synthase, indoleamine-2,3-dioxygenase, and RANTES is a major immune effector in Mediterranean spotted fever rickettsiosis. J Infect Dis. 2007 Sep 1. 196(5):770-81. [Medline].
Damås JK, Davì G, Jensenius M, Santilli F, Otterdal K, Ueland T, et al. Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever. J Infect. 2009 Jan. 58(1):68-75. [Medline].
Brouqui P, Parola P, Fournier PE, Raoult D. Spotted fever rickettsioses in southern and eastern Europe. FEMS Immunol Med Microbiol. 2007 Feb. 49(1):2-12. [Medline].
Palau LA, Pankey GA. Mediterranean Spotted Fever in Travelers from the United States. J Travel Med. 1997 Dec 1. 4(4):179-182. [Medline].
Jufresa J, Alegre J, Suriñach JM, Aleman C, Recio J, Juste C, et al. [Study of 86 cases of Mediterranean boutonneuse fever hospitalized at a university hospital]. An Med Interna. 1997 Jul. 14(7):328-31. [Medline].
Segura-Porta F, Diestre-Ortin G, Ortuño-Romero A, Sanfeliu-Sala I, Font-Creus B, Muñoz-Espin T, et al. Prevalence of antibodies to spotted fever group rickettsiae in human beings and dogs from and endemic area of mediterranean spotted fever in Catalonia, Spain. Eur J Epidemiol. 1998 Jun. 14(4):395-8. [Medline].
de Sousa R, Nóbrega SD, Bacellar F, Torgal J. Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 hospitalized patients. Ann N Y Acad Sci. 2003 Jun. 990:285-94. [Medline].
Cascio A, Iaria C. Epidemiology and clinical features of Mediterranean spotted fever in Italy. Parassitologia. 2006 Jun. 48(1-2):131-3. [Medline].
Mert A, Ozaras R, Tabak F, Bilir M, Ozturk R. Mediterranean spotted fever: a review of fifteen cases. J Dermatol. 2006 Feb. 33(2):103-7. [Medline].
Tijsse-Klasen E, Jameson LJ, Fonville M, Leach S, Sprong H, Medlock JM. First detection of spotted fever group rickettsiae in Ixodes ricinus and Dermacentor reticulatus ticks in the UK. Epidemiol Infect. 2011 Apr. 139(4):524-9. [Medline].
Popivanova N, Hristova D, Hadjipetrova E. Guillain-Barré polyneuropathy associated with mediterranean spotted fever: case report. Clin Infect Dis. 1998 Dec. 27(6):1549. [Medline].
Aliaga L, Sánchez-Blázquez P, Rodríguez-Granger J, Sampedro A, Orozco M, Pastor J. Mediterranean spotted fever with encephalitis. J Med Microbiol. 2009 Apr. 58:521-5. [Medline].
Ezpeleta D, Muñoz-Blanco JL, Tabernero C, Giménez-Roldán S. [Neurological complications of Mediterranean boutonneuse fever. Presentation of a case of acute encephalomeningomyelitis and review of the literature]. Neurologia. 1999 Jan. 14(1):38-42. [Medline].
Leone S, De Marco M, Ghirga P, Nicastri E, Lazzari R, Narciso P. Retinopathy in Rickettsia conorii infection: case report in an immunocompetent host. Infection. 2008 Aug. 36(4):384-6. [Medline].
Tsiachris D, Deutsch M, Vassilopoulos D, Zafiropoulou R, Archimandritis AJ. Sensorineural hearing loss complicating severe rickettsial diseases: report of two cases. J Infect. 2008 Jan. 56(1):74-6. [Medline].
Demeester R, Claus M, Hildebrand M, Vlieghe E, Bottieau E. Diversity of life-threatening complications due to Mediterranean spotted fever in returning travelers. J Travel Med. 2010 Mar-Apr. 17(2):100-4. [Medline].
Broadhurst LE, Kelly DJ, Chan CT, Smoak BL, Brundage JF, McClain JB, et al. Laboratory evaluation of a dot-blot enzyme immunoassay for serologic confirmation of illness due to Rickettsia conorii. Am J Trop Med Hyg. 1998 Jun. 58(6):786-9. [Medline].
Ergas D, Sthoeger ZM, Keysary A, Strenger C, Leitner M, Zimhony O. Early diagnosis of severe Mediterranean spotted fever cases by nested-PCR detecting spotted fever Rickettsiae 17-kD common antigen gene. Scand J Infect Dis. 2008. 40(11-12):965-7. [Medline].
Giulieri S, Jaton K, Cometta A, Trellu LT, Greub G. Development of a duplex real-time PCR for the detection of Rickettsia spp. and typhus group rickettsia in clinical samples. FEMS Immunol Med Microbiol. 2012 Feb. 64(1):92-7. [Medline].
Dzelalija B, Petrovec M, Avsic-Zupanc T, Strugar J, Milic TA. Randomized trial of azithromycin in the prophylaxis of Mediterranean spotted fever. Acta Med Croatica. 2002. 56(2):45-7. [Medline].
Anton E, Muñoz T, Travería FJ, Navarro G, Font B, Sanfeliu I, et al. Randomized Trial of Clarithromycin for Mediterranean Spotted Fever. Antimicrob Agents Chemother. 2015 Dec 28. 60 (3):1642-5. [Medline].
Botelho-Nevers E, Rovery C, Richet H, Raoult D. Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect. J Antimicrob Chemother. 2011 Aug. 66(8):1821-30. [Medline].
Antón E, Font B, Muñoz T, Sanfeliu I, Segura F. Clinical and laboratory characteristics of 144 patients with mediterranean spotted fever. Eur J Clin Microbiol Infect Dis. 2003 Feb. 22(2):126-8. [Medline].
Bentov Y, Sheiner E, Kenigsberg S, Mazor M. Mediterranean spotted fever during pregnancy: case presentation and literature review. Eur J Obstet Gynecol Reprod Biol. 2003 Apr 25. 107(2):214-6. [Medline].
Cohen J, Lasri Y, Landau Z. Mediterranean spotted fever in pregnancy. Scand J Infect Dis. 1999. 31(2):202-3. [Medline].