AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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

The major clinical features 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 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. 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 BF is usually 4-15 days, but it can be longer (reportedly 5-28 d in German travelers).

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.

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.

Frequency

United States

The disease is unrecognized in most cases. About 50 imported cases of BF have been reported and confirmed by the US Centers for Disease Control and Prevention (CDC).

International

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

• In the Mediterranean region, the incidence of BF 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.
• In the Valles Occidental in Spain, a population without a previous history of BF, antibodies against R conorii were detected in 4.6-13.5% (mean, 8%) of humans and in 26.1% of dogs.
• 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.
• In the Mediterranean coast of Turkey, immunoglobulin G (IgG) antibodies against R conorii were detected in 13.3% of the healthy population.
• 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) BF are described.

Mortality/Morbidity

Mortality is generally estimated to be less than 5%.

• In one series, 2.5% of patients died from the malignant form.
• In another series, 33% of 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 BF.
• Death from malignant (severe) BF has been associated with delay in diagnosis (>5 d) and treatment (>10 d).

Race

BF affects all races.

Sex

The male-to-female ratio is 1.7:1.

Age

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

About 88% of cases are diagnosed between June and September (reproduction cycle of Rhipicephalus species).

• 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 complain of 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 BF:
• • Fever 39-40°C is noted in 97.2-100% of patients.
  • Erythematous papules, mainly on the lower limbs, are observed in 96.1-100% of patients.
  • Purpura can be diagnosed 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 BF 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

Causes

The organism responsible for BF 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Kawasaki disease
Aseptic acute arthritis
Small-vessel vasculitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Suspicious rashes, including poxlike vesicles, may be caused by this organism.
• • Confirm the diagnosis by using culture techniques instead of serologic tests.
  • Serologic confirmation of BF 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 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

• 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.
• 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 BF 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.

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

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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

Consultations

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

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antibiotics are the mainstay of therapy for rickettsial diseases.

Drug Category: Antibiotics

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

Drug Name	Chloramphenicol (Chloromycetin)
Description	Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.
Adult Dose	50-100 mg/kg/d PO/IV divided q6h for 10 d; not to exceed 4 g/d
Pediatric Dose	50-75 mg/kg/d PO/IV divided q6h
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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)

Drug Name	Ciprofloxacin (Cipro)
Description	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.
Adult Dose	250-500 mg PO bid for 7-14 d
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity
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)
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Name	Rifampin (Rifadin, Rimactane, Rifadin IV)
Description	Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Adult Dose	600 mg PO/IV qd
Pediatric Dose	10-20 mg/kg PO/IV; not to exceed 600 mg/d
Contraindications	Documented hypersensitivity
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)
Pregnancy	C - Safety for use during pregnancy has not been established.
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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 BF, 5% of patients presented with malignant BF.
• One-dose azithromycin can be used for prophylaxis of BF.

Deterrence/Prevention

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

Complications

• Complications can occur mainly in patients who are immunocompromised or elderly and who present with the malignant form of BF. In Spain, complications are observed in about 22% of BF 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 BF
  • 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 is very good in mild cases.
• The main concern is malignant BF cases occurring in patients who are immunocompromised and/or elderly.

Patient Education

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• BF 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 BF, 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 BF, 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 BF 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 BF (when available). Consider this the drug of choice in malignant BF in pregnancy.
  • 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

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Mert A, Ozaras R, Tabak F, et al. Mediterranean spotted fever: a review of fifteen cases. J Dermatol. Feb 2006;33(2):103-7. [Medline].
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• Rydkina E, Sahni A, Baggs RB, et al. 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].
• 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].
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• Vitale G, Mansueto S, Gambino G, et al. The acute phase response in Sicilian patients with boutonneuse feveradmitted to hospitals in Palermo, 1992-1997. J Infect. Jan 2001;42(1):33-9. [Medline].

Article Last Updated: Jan 23, 2007