Mediterranean Spotted Fever (Boutonneuse Fever) 

Updated: Jul 23, 2021
Author: D Matthew Shoemaker, DO, FIDSA; Chief Editor: Michael Stuart Bronze, MD 

Overview

Background

Mediterranean spotted fever (MSF), also known as boutonneuse fever (BF), is caused by Rickettsia conorii subspecies conorii (R conorii).  R conorii is an organism that is endemic in the Mediterranean region. It was first described in Tunisia in 1910; Tunisia was a French protectorate at the time MSF was first described clinically. The illness derives its name from the French word boutonneux which translates as spotty or pimpled.

R conorii is transmitted by the dog tick Rhipicephalus sanguineus. The illness causes a characteristic diffuse maculopapular rash and frequently a distinct black eschar, tache noire (black spot), at the site of the tick bite. More than 95% will have a diffuse maculopapular rash and approximately 70% of patients will have a single eschar.[31]

R. conorii is also found in southern Europe, Africa, and India.[32]  Depending on where the infection is acquired, and which subspecies is the causative agent, then it may go by a different name:

  • Marseilles fever ( Rickettsia conorii subspecies conorii)
  • Kenya tick typhus ( Rickettsia conorii subspecies conorii)
  • South African tick bite fever ( Rickettsia conorii subspecies conorii)
  • Astrakhan fever ( Rickettsia conorii subspecies caspia)
  • Israeli tick typhus ( Rickettsia conorii subspecies israelensis)
  • Indian tick typhus ( Rickettsia conorii subspecies indica)

The major clinical features of MSF are as follows:

  • Fever
  • Exanthem (maculopapular rash)
  • Eschar (tache noire) at site of tick bite

The exanthem is typically maculopapular and involves the entire body including the palms and soles. The exanthem may be papulovesicular in some patients; this form is more common in adults in Africa. It may be challenging to differential this form from viral exanthems, particularly chickenpox. 

In a minority of patients, isolated lymphadenopathy is the only symptom. R conorii infection should be considered in patients with isolated lymphadenopathy who live in or have traveled to an endemic area, even when other more specific features are not present. In this setting care should be taken to examine the area distal to the lymphadenopathy for an inoculation eschar which if present can help to support the diagnosis.

Although MSF is usually a mild disease, severe complications including neurologic involvement does occur in 6-10% of cases. Neurologic manifestations can result in a delayed diagnosis and appropriate therapy for MSF due to workup and empiric therapy for bacterial meningitis. Complications of MSF are more common in patients with underlying disease or in elderly persons (the so-called malignant form of MSF). Mild forms of the disease are usually observed in children.

Treatment relies on early and appropriate antibiotic therapy. Prevention is important. Patients should be educated about avoiding tick bites and minimizing contact with dogs in areas that are endemic with MSF. 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. This necrosis is what results in the eschar (tach noire) at site of tick bite. 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.

MSF 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 MSF is typically 5 to 7 days but can be longer (reportedly, upto 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 0.3 to 2.0 µm.  They are found within the cytoplasm and occasionally the nucleus of eukaryotic cells. A member of this genus, R conorii, is the organism responsible for MSF.

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.

Ticks are the only confirmed reservoir for R conorii. It has been postulated, but never proven, that dogs are a reservoir for R conorii. 

Additionally, 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

MSF is uncommon in the United States. About 50 imported cases of MSF have been reported and confirmed by the US Centers for Disease Control and Prevention (CDC).[7]  A rickettsial illness similar to MSF with an eschar is found in the southeastern United States. The causative organism is Rickettsia parkeri and the vector is the Gulf Coast tick (Amblyomma maculatum). Rocky Mountain spotted fever, is also found in the United States. Rocky Mountain spotted fever (RMSF) is caused by Rickettsia rickettsii, for which the ixodid tick is the vector. RMSF is typically more severe than MSF. RMSF does not cause an eschar.

International statistics

MSF is known to be prevalent in southern Europe, Israel, Africa, and central Asia, including India. The frequency of travel-associated MSF has increased worldwide because of increased travel to endemic areas, including ecotourism. However, the true incidence of MSF is unknown. In many endemic areas, mild infection is common, underdiagnosed, and underreported.

In the Mediterranean region, the incidence of MSF 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 MSF, 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]  A seroprevalence study of kenneled dogs in southern Italy revealed an R conorii seroprevalence of 72%.[33]

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 MSF (eg, disease acquired via infected dogs or as a holiday souvenir) are described. MSF 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 MSF 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, MSF was characterized as a benign rickettsiosis.  However, severe sequala have been reported and include Guillain-Barré syndrome, polyneuropathy, altered mental status, hepatomegaly, acute renal failure, thrombocytopenia, hypoxemia, hemophagocytic lymphohistiocytosis, and death have been reported.[15, 21, 34, 35, 36, 37] Factors associated with more severe disease include older age, alcoholism, immune compromise, and glucose-6-phosphatase dehydrogenase (G6PD) deficiency.

Such complications notwithstanding, MSF 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) MSF developing in patients who are immunocompromised, elderly, or both.[16]

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

 

Presentation

History

The incubation period for Mediterranean spotted fever (MSF), also known as boutonneuse fever (BF), is approximately 5 to 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 MSF in its early stages, the diagnosis is commonly made on the basis of clinical findings.[17] The clinical diagnosis is supported when a history of travel to an endemic area is coupled with the following triad:

  • Fever
  • Exanthem (maculopapular rash)
  • Eschar (tache noire) at site of tick bite

More specifically, patients commonly report the following:

  • Fever of 39 to 41°C
  • Nonpruritic skin rash, mainly on the lower legs, occurring 2 to 6 days after the fever appeared
  • Myalgia, arthralgia, or both

MSF 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 region). About 88% of MSF 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 MSF cases. Spotless fever and cases appearing in the winter also may be due to Rickettsia infection. Therefore, a high degree of clinical suspicion is required so as not to miss the diagnosis.

Physical Examination

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

  • High fever
  • Maculopapular rash
  • Eschar (tache noire) at site of tick bite
  • Stupor
  • Pulmonary infiltrates
  • Bradycardia
  • Coma
  • Jaundice
  • Gastrointestinal 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 MSF 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 to 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 MSF
  • Arthromyalgia (16 to 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
 

DDx

Diagnostic Considerations

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

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

  • Thrombocytopenia (< 100 X 10 9/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
  • Pulmonary infiltrates
  • Bradycardia
  • Coma
  • Jaundice
  • Gastrointestinal bleeding
  • Arthralgic and myalgic arthritis
  • Hepatomegaly and splenomegaly
  • Orchitis
  • Conjunctival hyperemia
  • Meningism [18]
  • Local lymphadenopathy

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

  • Hepatitis
  • Aseptic acute arthritis
  • Small-vessel vasculitis
  • Sepsis

Differentials

 

Workup

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.[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.

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

Doxycycline is considered first-line antibiotic of choice for MSF. Clinical response is typically observed after 2-4 days of first-line therapy, as noted by the decrease in fever and the slow resolution of the maculopapular rash. Patients already in good health are usually discharged home to complete a total of 7 days of antibiotic therapy.

A recent randomized clinical trial demonstrated that clarithromycin is an acceptable alternative to doxycycline for MSF.[26]  Based on this, it is extrapolated that azithromycin would be a suitable alternative, especially in pregnant women and young children for whom doxycycline is contraindicated.

Single-dose azithromycin can be used for prophylaxis of MSF following a tick bite in an endemic area.[25]

Chloramphenicol is an acceptable alternative but adverse drug reactions, particular blood dyscrasias and gray baby syndrome in pregnancy, and lack of commercial availability in the United States limit its use.

Fluoroquinolones may have a deleterious effect as demonstrated in an analysis of risk factors for malignant MSF.[27]

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

Pharmacologic Therapy

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

The preferred drug is doxycycline (100 mg PO q12hr).

Other effective treatments include the following:

  • Chloramphenicol (50-60 mg/kg/day PO in 4 divided doses)
  • Azithromycin (500 mg PO once daily) or clarithromycin (500 mg PO q12h)
    • These have been shown to be efficacious in children and can be used as alternatives to doxycycline in adults, including pregnant women. [25]
    • 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]
  • Chloramphenicol (50-60 mg/kg/day PO in 4 divided doses)
  • Children with malignant MSF, 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 MSF, 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.
  • Pregnant women should receive azithromycin or clarithromycin.
    • Josamycin, a newer macrolide antibiotic which is not currently commercially available in the United States, seems to be effective against malignant MSF (when available).
    • Some have suggested that it may be the drug of choice for malignant MSF 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 for tick borne infections and appears to be safe.
  • Fluoroquinolones may have a deleterious effect as demonstrated in an analysis of risk factors for malignant MSF. [27]

Prevention

To prevent infection by rickettsiae, precautions should be taken to avoid exposure to ticks.

Protective clothing should be worn, preferably impregnated with permethrin or another pyrethroid. Topical repellents such as DEET or permethrin can be used on any exposed skin. Topical repellents have a short duration of effect and frequent application is therefore recommended. During travel, daily self-checks and removal of any ticks found should be performed.

Additionally, care should be taken to avoid close contact with ticks’ animal vectors (eg, dogs, goats, and sheep) when in endemic areas.

There is no vaccine for MSF.

 

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.