eMedicine Specialties > Dermatology > Bacterial Infections

Boutonneuse Fever

Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School

Updated: Jul 7, 2009

Introduction

Background

Boutonneuse fever (BF) is usually a mild rickettsial disease caused by Rickettsia conorii (endemic in the Mediterranean basin); however, severe complications with neurologic involvement can occur in about 6-10% of boutonneuse fever patients. Boutonneuse fever complications are more common in patients with underlying disease or in elderly persons (so-called malignant form of boutonneuse fever). Mild forms are usually observed in children. Also see Mediterranean Spotted Fever.

The major clinical features of boutonneuse fever are fever, exanthem, and tache noire (eschar, necrotic plaque). In some patients, the eruption is papulovesicular; this form is more common in adults in Africa. In other patients, the only symptom is an isolated lymphadenopathy. Consider R conorii infection in patients with lymphadenopathy who live in or have traveled to an endemic area even when other more specific features are not present.

Pathophysiology

The pathogen for boutonneuse fever is introduced through the bite of a tick. The organism, R conorii, invades and proliferates in the endothelial cells of small vessels, destroying them. Activation of the acute-phase response with changes in the coagulation state follows. Boutonneuse fever patients have an alteration in cell-mediated immunity together with a reduction in CD4 cells and a considerable alteration in the cytokine profile. The incubation time of boutonneuse fever is usually 4-15 days, but it can be longer (reportedly 5-28 d in German travelers).

In recent years, 6 more species or subspecies within the spotted fever group within the genus Rickettsia have been described as emerging pathogens. They include Rickettsia slovaca, Rickettsia sibirica mongolitimonae, Rickettsia massiliae, Rickettsia conorii israelensis, Rickettsia conori caspia, and Rickettsia aeschlimannii.¹

Fractalkine (CX3CL1) is a chemokine expressed mainly by endothelial cells, which are the major cellular targets of rickettsiae. The peak of expression of CX3CL1 on day 3 of infection reportedly coincided with the time of infiltration of macrophages into infected tissues and preceded the peak of rickettsial content in tissues.²

Induction of the endothelial cyclooxygenase-2 system and the ensuing release of vasoactive prostaglandins) may contribute to the regulation of inflammatory responses and vascular permeability changes.³

Expression of type I cytokines may correlate with milder disease expression.^4,5

Frequency

United States

Boutonneuse fever is unrecognized in most cases. About 50 imported cases of boutonneuse fever have been reported and confirmed by the US Centers for Disease Control and Prevention (CDC).⁶

International

The true incidence of boutonneuse fever is unknown. In many endemic areas, mild infection is common, underdiagnosed, and underreported.

• In the Mediterranean region, the incidence of boutonneuse fever is estimated at 50 cases per 100,000 inhabitants per year.
• In Croatia, 51.6% of a studied population with a recent history of a tick bite had antibodies to R conorii.
• In the Leon province of Spain, antibodies to R conorii were discovered in 1% of humans and in 14% of dogs.⁷
• In the Valles Occidental in Spain, a population without a previous history of boutonneuse fever, antibodies against R conorii were detected in 4.6-13.5% (mean, 8%) of humans and in 26.1% of dogs.⁸
• In southern Portugal, 7.6% of the population have antibodies to R conorii, and nationally as many as 20,000 cases are estimated to occur each year, but only about 5% are reported.⁹
• In the Mediterranean coast of Turkey, immunoglobulin G (IgG) antibodies against R conorii were detected in 13.3% of the healthy population.¹⁰
• In Zambia, the seroprevalence of antibodies against R conorii is estimated to be 16.7% in the human population and higher in cattle-breeding areas.
• In Germany, Norway, and the Netherlands, sporadic cases of so-called imported (eg, via infected dogs, as a holiday souvenir) boutonneuse fever are described.
• On the Italian island of Sicily, almost 400 cases are reported every year (mainly from June to September).¹¹
• Boutonneuse fever and other rickettsial infections are reported from Korea.¹²

Mortality/Morbidity

Mortality is generally estimated to be less than 5%.

• In one series, 2.5% of boutonneuse fever patients died from the malignant form.
• In another series, 33% of boutonneuse fever patients with underlying disease (eg, chronic liver disease, alcoholism, diabetes mellitus, glucose-6-phosphate dehydrogenase deficiency end stage kidney disease, cardiac disease) died because of malignant boutonneuse fever.
• Death from malignant (severe) boutonneuse fever has been associated with delay in diagnosis (>5 d) and treatment (>10 d).

Race

Boutonneuse fever affects all races.

Sex

The male-to-female ratio for boutonneuse fever is 1.7:1.

Age

People of all ages are susceptible to infection. In published reports, most boutonneuse fever patients present at the mean age of about 50 years if a cohort of adult patients is examined.

Clinical

History

No test reliably confirms boutonneuse fever in its early stages and diagnosis is often made based on clinical findings.¹³

About 88% of boutonneuse fever cases are diagnosed between June and September (reproduction cycle of Rhipicephalus species); however, because of climate changes, physicians should be aware of increasing off-season boutonneuse fever cases. 

• About 37% of patients give a history of a tick bite.
• About 89% of patients had contact with a dog.
• Some patients give a history of travel to an endemic area.
• Patients report the following:
  • Fever of 39-41°C
  • Nonpruritic skin rash mainly on the lower legs, occurring 2-6 days after fever appeared
  • Headache
  • Myalgia, arthralgia, or both

Physical

• The following triad of symptoms are most characteristic for boutonneuse fever:
  • Fever 39-40°C is noted in 93-100% of patients.
  • Erythematous papules, mainly on the lower limbs, are observed in 94.5-100% of patients.
  • Purpura is present in about 45% of patients.
  • Tache noire (eschar) at the site of the tick bite is discovered in 71.8% of patients.
• The malignant form of boutonneuse fever is diagnosed when patients present with at least 2 laboratory findings and 2 clinical symptoms of the following criteria:
  • Laboratory findings
    • Thrombocytopenia less than 100 G/L
    • Renal failure (creatinine level >150 mmol/L)
    • Hyponatremia (<130 mmol/L)
    • Hypocalcemia (<2.1 mmol/L)
    • Hypoxemia (arterial oxygen pressure <10.5 kPa)
  • Clinical symptoms
    • Purpuric rash
    • Stupor
    • Pneumonia
    • Bradycardia
    • Coma
    • Jaundice
    • Gastrointestinal bleeding
    • Arthralgic and myalgic arthritis
    • Hepatomegaly and splenomegaly
    • Orchitis
    • Conjunctival hyperemia
    • Meningism¹⁴
    • Meningitis
    • Local lymphadenopathy

Causes

The organism responsible for boutonneuse fever is the coccobacillus R conorii, an obligatory intracellular bacterium.

• Vectors of R conorii
  • Rhipicephalus sanguineus (brown dog tick) is the most common vector. In Cyprus, 3.8% of ticks are infected with R conorii. In Crimea (Ukraine), 8% of ticks are infected with R conorii.
  • In Cyprus, 8.16% of Hyalomma species are infected with R conorii.

Differential Diagnoses

Other Problems to Be Considered

Kawasaki disease¹⁵
Aseptic acute arthritis
Small-vessel vasculitis
Sepsis

Workup

Laboratory Studies

• Suspicious rashes, including poxlike vesicles, may be caused by this organism.
  • Confirm the diagnosis of boutonneuse fever by using culture techniques instead of serologic tests.
  • Serologic confirmation of boutonneuse fever by immunofluorescent antibody test is possible only late in the infection.
• Use culture of the organism as 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 (-70°C).
• Basic laboratory tests for boutonneuse fever include the following:
  • Normochromic anemia
  • Leukopenia and lymphopenia
  • Thrombocytopenia (35% of patients)
  • Increased liver enzymes (60.5-64.8% of patients)
  • Increased creatinine values (29.7% of patients)
  • Urinalysis (blood in 35.9% of patients, and proteins in 56.4% of patients; asymptomatic)
  • Fibrinogen level (increased during acute phase)
  • Fibronectin level (decreased during acute phase)

Imaging Studies

• In boutonneuse fever, a magnetic resonance study can demonstrate multifocal white matter disturbances if the central nervous system is involved.

Other Tests

• Serology is usually a confirmatory method; however, these tests are useful only after an acute infection because antibodies can be detected late (even after 30 d post onset of symptoms).
• On indirect immunofluorescence (IIF), the antibody titer in serum is increased only 2 weeks after the infection and at the peak level after 4 weeks. Afterward, the immunoglobulin M (IgM) level decreases and the IgG level remains high for several months. Titers of 1:64 or greater are diagnostic.¹⁶
• 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.
  • It is still used in clinical practice because of its convenience but has low sensitivity and specificity.
• Isolation of R conorii by the centrifugation-shell vials technique
  • The result can become positive 14 days after inoculation.
  • Results can be obtained within 2-3 days of sample receipt.
• IIF of R conorii in circulating endothelial cells (CEC) isolated from whole blood by using immunomagnetic beads can be performed.
  • 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 lipopolysaccharides (LPS) of R conorii.
  • ELISA is a relatively simple and convenient way to serodiagnose boutonneuse fever with a single serum dilution.
  • It can be of use in laboratories that lack more sophisticated equipment (as needed for IIF).
• Polymerase chain reaction (PCR) is not routinely used or universally available. Ergas et al reported early diagnosis using nested PCR.¹⁷

Procedures

• 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.
  • The test is specific and sensitive if performed before the initiation of antimicrobial therapy and before the 10th day of the disease.
  • The test 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 of sample receipt.

Staging

• The first day of fever is recognized as the first day of the disease.
• The acute stage is from the second to 14th day of the illness.
• The convalescent stage starts from the 21st day.
• The third week is the borderline period between the acute stage and the convalescent stage.

Treatment

Medical Care

• Patients with the benign form of boutonneuse fever are usually treated with antibiotics for 7 days.
• Patients with the malignant form of boutonneuse fever are usually treated with antibiotics for 2 weeks.
• Tetracyclines with chloramphenicol and quinolones may be considered first-line antibiotics for boutonneuse fever.

Consultations

The differential diagnosis for boutonneuse fever includes many rare diseases. Consider consultations with a dermatologist and an infectious disease specialist.

Medication

Antibiotics are the mainstay of therapy for rickettsial diseases.

Antibiotics

Tetracyclines together with chloramphenicol and quinolones may be considered first-line antibiotics. Patients presenting with the benign form of boutonneuse fever are usually on antibiotics for 7 d and those with the malignant form for 2 wk.

Clarithromycin or azithromycin have been used to treat children with boutonneuse fever.¹⁸

Doxycycline (Bio-Tab, Doryx, Vibramycin, Doxy, Vibra-Tabs)

Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

200 mg PO/IV immediately and 100 mg hs, followed by 100 mg bid for 3 d; alternatively, 100-200 mg PO bid for 14 d

Pediatric

<8 years: Not recommended
>8 years: 2-5 mg/kg/d PO/IV qd or divided bid; not to exceed 200 mg/d

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines may decrease effects of oral contraceptives by reducing the enterohepatic circulation of estrogens, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider drug serum level determinations in prolonged therapy; tetracycline use during tooth development (last one half of pregnancy through age 8 y) can cause permanent discoloration of teeth; Fanconilike syndrome may occur with outdated tetracyclines

Chloramphenicol (Chloromycetin)

Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Dosing

Adult

50-100 mg/kg/d PO/IV divided q6h for 10 d; not to exceed 4 g/d

Pediatric

50-75 mg/kg/d PO/IV divided q6h

Interactions

Concurrently with barbiturates, chloramphenicol serum levels may decrease while barbiturate levels may increase causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum chloramphenicol levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use only for indicated infections or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (eg, aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (Gray syndrome)

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, Staphylococcus epidermidis, and most gram-negative organisms, but no activity against anaerobes. Inhibits bacterial DNA synthesis and consequently growth. Continue treatment for at least 2 d (7-14 d typical) after signs and symptoms have disappeared.

Dosing

Adult

250-500 mg PO bid for 7-14 d

Pediatric

<18 years: Not recommended
>18 years: Administer as in adults

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Rifampin (Rifadin, Rimactane, Rifadin IV)

Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.

Dosing

Adult

600 mg PO/IV qd

Pediatric

10-20 mg/kg PO/IV; not to exceed 600 mg/d

Interactions

Induces microsomal enzymes, which may decrease effects of acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, oral contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue 1 or both agents if alterations in LFTs occur)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur

Antibiotic, Macrolide

Clarithromycin (Crixan, Biaxin, Klaricid)

Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.

Dosing

Adult

250 mg PO bid for 7-14 d

Pediatric

7.5 mg/kg PO bid; not to exceed 500 mg PO bid

Interactions

Toxicity increases with coadministration of fluconazole and pimozide; effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, carbamazepine, ergot alkaloids, triazolam, and HMG-CoA reductase inhibitors
Plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increases in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents; decreases metabolism of repaglinide, thus increasing serum levels and effects

Contraindications

Documented hypersensitivity; coadministration of pimozide

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; give half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Azithromycin (Zithromax, Zmax)

Used to treat uncomplicated skin and skin structure infections caused by Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae.
Acts by binding to 50S ribosomal subunit of susceptible microorganisms and blocks dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.
Concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Treats mild-to-moderate microbial infections.
Plasma concentrations are very low, but tissue concentrations are much higher, giving it value in treating intracellular organisms. Has a long tissue half-life.

Dosing

Adult

Day 1: 500 mg PO
Days 2-5: 250 mg PO qd

Pediatric

Not established

Interactions

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Contraindications

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result from prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function or prolonged QT intervals

Follow-up

Further Inpatient Care

• The fever decreases and the rash usually disappears after 2-4 days of first-line therapy.
• Patients, being already in good health, are usually discharged after 7-8 days of treatment.
• In one study presenting 142 patients hospitalized with boutonneuse fever, 5% of patients presented with malignant boutonneuse fever.
• One-dose azithromycin can be used for prophylaxis of boutonneuse fever.

Deterrence/Prevention

• No vaccine exists for boutonneuse fever.
• Advise patients to pay attention to and not get in close contact with dogs, goats, and sheep when in endemic areas.

Complications

• Complications with boutonneuse fever can occur mainly in patients who are immunocompromised or elderly and who present with the malignant form of boutonneuse fever. In Spain, complications are observed in about 22% of boutonneuse fever cases.
  • Renal failure - Mainly due to renal vasculitis, acute tubular necrosis, or perivascular interstitial glomerulonephritis
  • Respiratory failure
  • Gastrointestinal bleeding
  • Stroke
  • Deep venous thrombosis (DVT) - Observed in about 9% of patients during the late acute and early convalescent phase of boutonneuse fever
  • Arthromyalgia (16-76% of patients) and arthritis (rare)
  • Pulmonary complications (very rare)
  • Meningoencephalitic involvement - During the acute phase (lymphocytic coma, meningitis)
  • Myelitis - Early during convalescence, as acute-onset paraplegia involving the lumbosacral spinal cord (very rare)

Prognosis

• The prognosis for boutonneuse fever is very good in mild cases.
• The main concern is malignant boutonneuse fever cases occurring in patients who are immunocompromised and/or elderly.¹⁹

Patient Education

• For excellent patient education resources, visit eMedicine's Bites and Stings Center. Also, see eMedicine's patient education article Ticks.

Miscellaneous

Medicolegal Pitfalls

• Boutonneuse fever cases are on the increase all over the world and should be considered in febrile patients returning from abroad, especially from endemic areas (eg, Mediterranean basin).
• Antibodies develop late in the course of the disease and serologic confirmation can be useful only in the retrospective analysis.
• Spotless fever and cases appearing in the winter also may be due to Rickettsia species infection; suspicion is required.
• The clinical diagnosis is obvious when a history of travel to an endemic area and the triad of fever, rash, and tache noire exists.
• History of a contact with a dog can be of considerable help.
• Prompt diagnosis depends mainly on clinical suspicion.

Special Concerns

• Regarding children with the malignant form of boutonneuse fever, tetracyclines should be considered (especially doxycycline). They are the most effective drugs for this disease (potentially life threatening). Recognize that a single short course (up to 1 wk) of doxycycline should not result in cosmetically significant staining of teeth. For patients with malignant boutonneuse fever, a narrow window of time exists during which effective antibiotic therapy in an extremely efficient way reduces the risk of any unfavorable outcome.
• The course of boutonneuse fever may be malignant in people who are elderly and especially in those who are immunocompromised.
• In pregnant women, erythromycin should be administered; however, it is not as effective as tetracyclines.
  • Josamycin, a new macrolide antibiotic, seems to be effective against malignant boutonneuse fever (when available). Consider this the drug of choice in malignant boutonneuse fever in pregnancy.^20,21,22
  • Rifampin, though it belongs to Food and Drug Administration (FDA) category class C in pregnancy and tuberculosis, has also been used extensively and appears to be safe.
  • Recent studies indicate that oral clarithromycin and azithromycin could be regarded as an alternative treatment in children and in pregnant women.

References

1. Brouqui P, Parola P, Fournier PE, Raoult D. Spotted fever rickettsioses in southern and eastern Europe. FEMS Immunol Med Microbiol. Feb 2007;49(1):2-12. [Medline].

2. Valbuena G, Walker DH. Expression of CX3CL1 (fractalkine) in mice with endothelial-target rickettsial infection of the spotted-fever group. Virchows Arch. Jan 2005;446(1):21-7. [Medline].

3. 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. Sep 2006;74(9):5067-74. [Medline].

4. de Sousa R, Ismail N, Nobrega SD, 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. Sep 1 2007;196(5):770-81. [Medline].

5. Damas JK, Davì G, Jensenius M, et al. Relative chemokine and adhesion molecule expression in Mediterranean spotted fever and African tick bite fever. J Infect. Jan 2009;58(1):68-75. [Medline].

6. Palau LA, Pankey GA. Mediterranean Spotted Fever in Travelers from the United States. J Travel Med. Dec 1 1997;4(4):179-182. [Medline].

7. Jufresa J, Alegre J, Surinach JM, et al. [Study of 86 cases of Mediterranean boutonneuse fever hospitalized at a university hospital]. An Med Interna. Jul 1997;14(7):328-31. [Medline].

8. Segura-Porta F, Diestre-Ortin G, Ortuno-Romero A, 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. Jun 1998;14(4):395-8. [Medline].

9. de Sousa R, Nobrega SD, Bacellar F, Torgal J. Mediterranean spotted fever in Portugal: risk factors for fatal outcome in 105 hospitalized patients. Ann N Y Acad Sci. Jun 2003;990:285-94. [Medline].

10. Mert A, Ozaras R, Tabak F, Bilir M, Ozturk R. Mediterranean spotted fever: a review of fifteen cases. J Dermatol. Feb 2006;33(2):103-7. [Medline].

11. Cascio A, Iaria C. Epidemiology and clinical features of Mediterranean spotted fever in Italy. Parassitologia. Jun 2006;48(1-2):131-3. [Medline].

12. Choi YJ, Jang WJ, Ryu JS, et al. Spotted fever group and typhus group rickettsioses in humans, South Korea. Emerg Infect Dis. Feb 2005;11(2):237-44. [Medline].

13. Chipp E, Digby S. Rickettsia: an unusual cause of sepsis in the emergency department. Emerg Med J. Nov 2006;23(11):e60. [Medline].

14. Ezpeleta D, Munoz-Blanco JL, Tabernero C, Gimenez-Roldan S. [Neurological complications of Mediterranean boutonneuse fever. Presentation of a case of acute encephalomeningomyelitis and review of the literature]. Neurologia. Jan 1999;14(1):38-42. [Medline].

15. Jenkins DR, Rees JC, Pollitt C, Cant A, Craft AW. Mediterranean spotted fever mimicking Kawasaki disease. BMJ. Mar 1 1997;314(7081):655-6. [Medline].

16. Broadhurst LE, Kelly DJ, Chan CT, et al. Laboratory evaluation of a dot-blot enzyme immunoassay for serologic confirmation of illness due to Rickettsia conorii. Am J Trop Med Hyg. Jun 1998;58(6):786-9. [Medline].

17. Ergas D, Zev Sthoeger M, 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].

18. 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].

19. Aliaga L, Sanchez-Blazquez P, Rodriguez-Granger J, Sampedro A, Orozco M, Pastor J. Mediterranean spotted fever with encephalitis. J Med Microbiol. Apr 2009;58:521-5. [Medline].

20. Anton E, Font B, Munoz T, Sanfeliu I, Segura F. Clinical and laboratory characteristics of 144 patients with mediterranean spotted fever. Eur J Clin Microbiol Infect Dis. Feb 2003;22(2):126-8. [Medline].

21. Bentov Y, Sheiner E, Kenigsberg S, Mazor M. Mediterranean spotted fever during pregnancy: case presentation and literature review. Eur J Obstet Gynecol Reprod Biol. Apr 25 2003;107(2):214-6. [Medline].

22. Cohen J, Lasri Y, Landau Z. Mediterranean spotted fever in pregnancy. Scand J Infect Dis. 1999;31(2):202-3. [Medline].

23. Buscemi S, D'Orio L, Sgroi C. [Clinical characteristics and therapeutic perspectives of boutonneuse fever. Assessment of a caseload of 39 patients]. Ann Ital Med Int. Jan-Mar 1997;12(1):11-4. [Medline].

24. Caroleo S, Longo C, Pirritano D, et al. A case of acute quadriplegia complicating Mediterranean spotted fever. Clin Neurol Neurosurg. Jun 2007;109(5):463-5. [Medline].

25. Cascio A, Dones P, Romano A, Titone L. Clinical and laboratory findings of boutonneuse fever in Sicilian children. Eur J Pediatr. Jun 1998;157(6):482-6. [Medline].

26. Corazza M, Bertelli G, Altieri E, Strumia R. Mediterranean spotted fever: a case report. J Eur Acad Dermatol Venereol. Nov 1999;13(3):229-30. [Medline].

27. Dignat-George F, Tissot-Dupont H, Grau GE, Camoin-Jau L, Raoult D, Sampol J. Differences in levels of soluble E-selectin and VCAM-1 in malignant versus non malignant Mediterranean spotted fever. Thromb Haemost. Dec 1999;82(6):1610-3. [Medline].

28. Elghetany MT, Walker DH. Hemostatic changes in Rocky Mountain spotted fever and Mediterranean spotted fever. Am J Clin Pathol. Aug 1999;112(2):159-68. [Medline].

29. La Scola B, Raoult D. Diagnosis of Mediterranean spotted fever by cultivation of Rickettsia conorii from blood and skin samples using the centrifugation-shell vial technique and by detection of R. conorii in circulating endothelial cells: a 6-year follow-up. J Clin Microbiol. Nov 1996;34(11):2722-7. [Medline].

30. Mansueto S, Vitale G, Mocciaro C, et al. Modifications of general parameters of immune activation in the sera of Sicilian patients with Boutonneuse fever. Clin Exp Immunol. Mar 1998;111(3):555-8. [Medline].

31. Milano S, D'Agostino P, Di Bella G, et al. Interleukin-12 in human boutonneuse fever caused by Rickettsia conorii. Scand J Immunol. Jul 2000;52(1):91-5. [Medline].

32. Psaroulaki A, Loukaidis F, Hadjichristodoulou C, Tselentis Y. Detection and identification of the aetiological agent of Mediterranean spotted fever (MSF) in two genera of ticks in Cyprus. Trans R Soc Trop Med Hyg. Nov-Dec 1999;93(6):597-8. [Medline].

33. Vitale G, Mansueto S, Gambino G, et al. The acute phase response in Sicilian patients with boutonneuse fever admitted to hospitals in Palermo, 1992-1997. J Infect. Jan 2001;42(1):33-9. [Medline].

Keywords

boutonneuse fever, BF, Mediterranean spotted fever, MSF, Carducci fever, Carducci's fever, tick typhus, South African tick typhus, Indian tick typhus, tick bite fever, rickettsial disease, Rickettsia conorii, R conorii

Contributor Information and Disclosures

Author

Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Robin Travers, MD, Assistant Professor of Medicine (Dermatology), Dartmouth University School of Medicine; Staff Dermatologist, New England Baptist Hospital; Private Practice, SkinCare Physicians
Robin Travers, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Informatics Association, Massachusetts Medical Society, Medical Dermatology Society, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Paul Krusinski, MD, Director of Dermatology, Professor, Department of Internal Medicine, Fletcher Allen Health Care, University of Vermont
Paul Krusinski, MD is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Glen H Crawford, MD, Assistant Clinical Professor, Department of Dermatology, University of Pennsylvania School of Medicine; Chief, Division of Dermatology, The Pennsylvania Hospital
Glen H Crawford, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Phi Beta Kappa, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)