Boutonneuse Fever 

Updated: Mar 11, 2016
Author: Jason F Okulicz, MD, FACP, FIDSA; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), is transmitted by the dog tick Rhipicephalus sanguineus. The tick bite causes a characteristic rash and a distinct mark—namely, a tache noire (black spot) at the site of the bite.

The etiologic agent for BF is Rickettsia conorii, an organism that is endemic in the Mediterranean basin and is also associated with Marseilles fever, Kenya tick typhus, South African tick bite fever, Indian tick typhus, and Israeli tick typhus. Persons with Israeli spotted fever seldom, if ever, develop the tache noire at the site of the tick bite. BF and African tick bite fever are separate illnesses that occur in the same geographic area. Unlike BF, African tick bite fever causes local adenopathy and multiple eschars.

The major clinical features of BF are as follows:

  • Fever

  • Exanthem (rash)

  • Tache noire

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. R conorii infection should be considered in patients with lymphadenopathy who live in or have traveled to an endemic area, even when other more specific features are not present.

Although BF is usually a mild disease, severe complications with neurologic involvement can occur in about 6-10% of cases, often resulting from delayed diagnosis of BF and the common practice of prescribing beta-lactam antibiotics as empiric therapy. Complications of BF are more common in patients with underlying disease or in elderly persons (the so-called malignant form of BF). Mild forms of the disease are usually observed in children.

Treatment relies on antibiotic therapy. Prevention is important. Patients should be educated about avoiding tick bites and minimizing contact with dogs in areas that are endemic for BF. For patient education resources, see the First Aid and Injuries Center, as well as Ticks.

Pathophysiology

Once introduced through a tick bite, R conorii invades and proliferates in the endothelial cells of small vessels, causing endothelial injury and tissue necrosis, as illustrated by the tache noire at the bite site. Activation of the acute-phase response with changes in the coagulation state follows. Thrombosis is not an important pathogenic mechanism in this infection, but deep venous thrombosis can occur late in the course of illness.

BF patients have an alteration in cell-mediated immunity, together with a reduction in CD4 cells and a considerable alteration in the cytokine profile.[1] The incubation time of BF is usually 4-15 days but can be longer (reportedly, 5-28 days in German travelers).

Fractalkine (CX3CL1) is a chemokine expressed mainly by endothelial cells. Its peak of expression on day 3 of infection reportedly coincides with the time of infiltration of macrophages into infected tissues and precedes the peak of rickettsial content in tissues.[2]

Induction of the endothelial cyclooxygenase (COX)-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]

The course of the illness may be divided into stages as follows:

  • The first day of fever is recognized as the first day of the disease

  • The acute stage extends from day 2 to day 14

  • Week 3 (days 15-21) is the borderline period between the acute stage and the convalescent stage

  • The convalescent stage starts after day 21

Etiology

Rickettsiae are obligate, intracellular gram-negative coccobacilli that measure 1 ´ 0.3 µm and are found within the cytoplasm and occasionally the nucleus of eukaryotic cells. A member of this genus, R conorii, is the organism responsible for BF.

R sanguineus (the brown dog tick) is the most common vector for R conorii. 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 ticks are infected with R conorii.

In addition, the following 6 species or subspecies within the spotted fever group in the genus Rickettsia have been described as emerging pathogens[6] :

  • Rickettsia slovaca

  • Rickettsia sibirica subsp mongolitimonae

  • Rickettsia massiliae

  • R conorii subsp israelensis

  • R conorii subsp caspia

  • Rickettsia aeschlimannii

Epidemiology

United States statistics

BF is uncommon in the United States. About 50 imported cases of BF have been reported and confirmed by the US Centers for Disease Control and Prevention (CDC).[7] A disease similar to BF, Rocky Mountain spotted fever, is found in the United States. Rocky Mountain spotted fever is caused by Rickettsia rickettsii, for which the ixodid tick is the vector.

International statistics

BF is known to be prevalent in southern Europe, Africa, and central Asia, including India. The frequency of travel-associated BF has increased worldwide because of increased travel to endemic areas, including ecotourism. However, 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 to be about 50 cases per 100,000 inhabitants per year. In the Leon province of Spain, antibodies to R conorii were discovered in 1% of humans and in 14% of dogs.[8] In the Valles Occidental in Spain, a population without a previous history of BF, antibodies to R conorii were detected in 4.6-13.5% (mean, 8%) of humans and in 26.1% of dogs.[9]

In southern Portugal, 7.6% of the population have antibodies to R conorii; nationally as many as 20,000 cases are estimated to occur each year, but only about 5% are reported.[10] In Sicily, almost 400 cases are reported every year (mainly from June to September).[11] In Croatia, 51.6% of a studied population with a recent history of a tick bite had antibodies to R conorii. On the Mediterranean coast of Turkey, immunoglobulin G (IgG) antibodies against R conorii were detected in 13.3% of the healthy population.[12]

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 BF (eg, disease acquired via infected dogs or as a holiday souvenir) are described. BF and other rickettsial infections are reported from Korea.[13] In the United Kingdom, spotted fever group rickettsial species were detected in 9.7% of Ixodes ricinus ticks and 27% of Dermacentor reticularis ticks.[14]

Age-, sex-, and race-related demographics

People of all ages are susceptible to R conorii infection. In published reports, most BF patients present at the mean age of about 50 years if a cohort of adult patients is examined. The male-to-female ratio for BF is 1.7:1. This condition affects people of all races.

Prognosis

Traditionally, BF was characterized as a benign rickettsiosis; however, Guillain-Barré syndrome, polyneuropathy, altered mental status, hepatomegaly, acute renal failure, thrombocytopenia, hypoxemia, and death have been reported.[15] Factors associated with more severe disease include older age, alcoholism, immune compromise, and glucose-6-phosphatase dehydrogenase (G6PD) deficiency.

Such complications notwithstanding, BF is still a benign condition in most cases, carrying a low mortality (in the range of 2-5%). The prognosis is especially good in cases of mild disease; the main concern is malignant (severe) BF developing in patients who are immunocompromised, elderly, or both.[16]

In one series, 2.5% of BF patients died of the malignant form. In another series, 33% of BF patients with underlying disease (eg, chronic liver disease, alcoholism, diabetes mellitus, G6PD deficiency, end-stage renal disease, or cardiac disease) died of malignant BF. Death from malignant BF has been associated with delays in diagnosis (>5 days) and treatment (>10 days).

 

Presentation

History

The incubation period for boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), is approximately 5-7 days after the infecting tick bite, which is typically painless and often goes unnoticed. About 37% of patients give a history of a tick bite; about 89% report having had contact with a dog; and some give a history of travel to an endemic area.

Because there is no test that can reliably confirm BF in its early stages, the diagnosis is commonly made on the basis of clinical findings.[17] The clinical diagnosis is obvious when a history of travel to an endemic area is coupled with the following triad:

  • Fever

  • Rash (exanthem)

  • Tache noire

More specifically, patients commonly report the following:

  • Fever of 39-41°C

  • Nonpruritic skin rash, mainly on the lower legs, occurring 2-6 days after the fever appeared

  • Headache

  • Myalgia, arthralgia, or both

BF cases are on the increase all over the world and should be considered in all febrile patients returning from abroad, especially from endemic areas (eg, the Mediterranean basin). About 88% of BF cases are diagnosed between June and September (as a reflection of the reproduction cycle of Rhipicephalus); however, physicians should be aware that climate changes are leading to increases in the number of off-season BF cases. Spotless fever and cases appearing in the winter also may be due to Rickettsia infection; suspicion is required.

Physical Examination

Findings that may be observed in a patient with BF include the following:

  • High fever

  • Maculopapular rash

  • Tache noire (eschar)

  • Stupor

  • Pneumonia

  • Bradycardia

  • Coma

  • Jaundice

  • Gastrointestinal (GI) bleeding

  • Arthralgic and myalgic arthritis

  • Hepatomegaly and splenomegaly

  • Orchitis

  • Conjunctival hyperemia

  • Meningism[18]

  • Meningitis

  • Local lymphadenopathy

  • Retinopathy,[19] sensorineural hearing loss,[20] and other neurologic manifestations (rare)

The presence of malignant BF is indicated when 2 or more specific clinical symptoms occur in conjunction with 2 or more specific laboratory test results (see DDx).

Complications

Complications of BF tend to occur mainly in patients who are immunocompromised or elderly and who present with the malignant form of the disease. In Spain, complications are observed in about 22% of BF cases. Generally, however, the complication rate is estimated to be in the range of 1-20%.

The following complications have been reported[21] :

  • Renal failure - This is mainly due to renal vasculitis, acute tubular necrosis, or perivascular interstitial glomerulonephritis

  • Respiratory failure

  • GI bleeding

  • Stroke

  • Deep venous thrombosis (DVT) - This is observed in about 9% of patients during the late acute phase and the early convalescent phase of BF

  • Arthromyalgia (16-76% of patients) and arthritis (rare)

  • Pulmonary complications (very rare)

  • Meningoencephalitic involvement - This may occur during the acute phase (lymphocytic coma or meningitis)

  • Myelitis - This tends to occur early in the convalescent phase as acute-onset paraplegia involving the lumbosacral spinal cord (very rare)

  • Septic shock

  • Multiorgan failure

  • Hepatosplenomegaly

  • Autoimmune anemia

  • Cryoglobulinemia

 

DDx

Diagnostic Considerations

The malignant form of boutonneuse fever (BF) is diagnosed on the basis of specific combinations of laboratory findings and clinical symptoms.

Laboratory findings indicative of malignant BF when combined with clinical symptoms (see below), are as follows (≥2 required):

  • Thrombocytopenia (< 100 X 109/L)

  • Renal failure (creatinine level >150 mmol/L)

  • Hyponatremia (< 130 mmol/L)

  • Hypocalcemia (< 2.1 mmol/L)

  • Hypoxemia (arterial oxygen pressure < 80 mm Hg)

Clinical symptoms indicative of malignant BF when combined with laboratory findings (see above), are as follows (≥2 required):

  • Purpuric rash

  • Stupor

  • Pneumonia

  • Bradycardia

  • Coma

  • Jaundice

  • Gastrointestinal bleeding

  • Arthralgic and myalgic arthritis

  • Hepatomegaly and splenomegaly

  • Orchitis

  • Conjunctival hyperemia

  • Meningism[18]

  • Meningitis

  • Local lymphadenopathy

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Hepatitis

  • Meningitis

  • Aseptic acute arthritis

  • Small-vessel vasculitis

  • Sepsis

Differentials

  • Chickenpox

  • Cowpox Infection, Human

  • Drug Eruptions

  • Fever of Unknown Origin

  • Kawasaki Disease

  • Lyme Disease

  • Malaria

  • Measles

  • Q Fever

  • Rocky Mountain Spotted Fever

  • Roseola Infantum

  • Scarlet Fever

  • Schnitzler Syndrome

  • Typhus

  • Viral Infections of the Mouth

  • West Nile Encephalitis

 

Workup

Approach Considerations

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.

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 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.[22]

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.[23] 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.[24]

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.

 

Treatment

Approach Considerations

The course of boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), can be shortened with appropriate treatment (ie, antibiotics). The illness sometimes takes a malignant form—for instance, in people who are elderly and especially in those who are immunocompromised. In a study of 142 patients hospitalized with BF, 5% of patients presented with malignant BF.

Tetracyclines, along with chloramphenicol and quinolones, may be considered first-line antibiotics for BF. After 2-4 days of first-line therapy, the fever decreases and the rash usually disappears. Patients already in good health are usually discharged after 7-8 days of treatment. Single-dose azithromycin can be used for prophylaxis of BF.

Because the differential diagnosis for BF includes many rare diseases, consultations with a dermatologist and an infectious disease specialist should be considered.

Pharmacologic Therapy

Patients with the benign form of BF are usually treated with antibiotics for 7 days; those with the malignant form of BF are usually treated with antibiotics for 2 weeks.

The preferred drug is doxycycline (100 mg PO q12hr). Other effective treatments include the following:

  • Ciprofloxacin (200 mg IV q12hr or 750 mg PO q12hr)

  • Levofloxacin (500 mg PO once daily)

  • Chloramphenicol (50-60 mg/kg/day PO in 4 divided doses)

  • Macrolides such as azithromycin (500 mg PO once daily) and clarithromycin (500 mg PO q12h) - These have been shown to be efficacious in children[25] and can be used as alternatives to doxycycline in adults, including pregnant women. A small randomized trial in children and adults showed a similar time to resolution of fever and other symptoms among those treated with clarithromycin versus doxycycline (or doxycycline plus josamycin in children).[26]

For children with malignant BF, tetracyclines (especially doxycycline) should be considered first; these are the most effective drugs for this potentially life-threatening disease. A single short (≤1 week) course of doxycycline should not result in cosmetically significant staining of teeth. In malignant BF, there is a narrow window of time during which effective antibiotic therapy delivered in an extremely efficient way can substantially reduce the risk of an unfavorable outcome.

In pregnant women, erythromycin should be administered; however, it is not as effective as the tetracyclines are.

In an analysis of risk factors for malignant BF, researchers noted that fluoroquinolones may have a deleterious effect.[27]

Josamycin, a newer macrolide antibiotic, seems to be effective against malignant BF (when available). Some have suggested that it may be the drug of choice for malignant BF in pregnant women.[28, 29, 30]

Rifampin, though designated by the US Food and Drug Administration (FDA) as a category C drug in pregnancy and tuberculosis, has also been used extensively in this setting and appears to be safe.

Prevention

To prevent infection by rickettsiae, precautions should be taken to avoid exposure to ticks, in particular by refraining from close contact with ticks’ animal vectors (eg, dogs, goats, and sheep) when in endemic areas.

Protective clothing should be worn, preferably impregnated with permethrin or another pyrethroid. Topical repellents can be used on any exposed skin; however, these agents have a short duration of effect (~1-2 hours per application), and frequent application is therefore recommended. During travel, daily self-checks and removal of any ticks found should be performed.

At present, there is no vaccine for BF.

 

Medication

Medication Summary

The goals of pharmacotherapy for boutonneuse fever (BF), also known as Mediterranean spotted fever (MSF), are to reduce morbidity, to prevent complications, and to eradicate the infection. Antibiotics are the mainstay of therapy for this disease, as for other rickettsial diseases. Patients with BF typically improve within 24 hours after initiation of therapy; a delay in response should cast doubt on the diagnosis.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Tetracyclines, along with chloramphenicol and quinolones, may be considered first-line agents for this condition. Patients presenting with the benign form of BF usually receive antibiotics for 7 days, whereas those presenting with malignant BF are treated for 2 weeks. Clarithromycin and azithromycin have been used to treat children with BF.

Doxycycline (Vibramycin, Adoxa, Doryx, Monodox)

Doxycycline is a tetracycline with a broad spectrum of activity. It inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Ciprofloxacin (Cipro, Cipro XR)

Ciprofloxacin is a fluoroquinolone that is active against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms but has no activity against anaerobes (eg, Bacteroides fragilis). It inhibits bacterial DNA synthesis and consequently growth. Treatment should be continued for at least 2 days (typically, 7-14 days) after signs and symptoms have disappeared.

Levofloxacin (Levaquin)

Levofloxacin is a second-generation quinolone that acts by interfering with DNA gyrase in bacterial cells. It is bactericidal and is highly active against gram-negative and gram-positive organisms, including Pseudomonas aeruginosa.

Chloramphenicol

Chloramphenicol binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.

Azithromycin (Zithromax, Zmax)

Azithromycin acts by binding to 50S ribosomal subunits of susceptible microorganisms and blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Nucleic acid synthesis is not affected.

In vitro incubation techniques demonstrate that azithromycin concentrates in phagocytes and fibroblasts. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Plasma concentrations of azithromycin are very low, but tissue concentrations are much higher, giving this agent value in treating intracellular organisms. Azithromycin has a long tissue half-life.

Azithromycin is used to treat mild-to-moderate microbial infections, including uncomplicated skin and skin structure infections caused by S aureus, Streptococcus pyogenes, or Streptococcus agalactiae.

Clarithromycin (Biaxin, Biaxin XL)

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

Rifampin (Rifadin)

Rifampin inhibits DNA-dependent bacterial (but not mammalian) RNA polymerase. Cross-resistance may occur.

Erythromycin (Ery-Tab, PCE, Erythrocin)

Erythromycin is a macrolide used for penicillin-allergic individuals. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl transfer ribonucleic acid (t-RNA) from ribosomes, causing RNA-dependent protein synthesis to arrest. Erythromycin is administered for the treatment of staphylococcal and streptococcal infections.