Boutonneuse Fever

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Boutonneuse fever is a disease caused by the rickettsia genus and is of the spotted fever group classification. This disease classically causes fever, rash, and flu-like symptoms. It is most commonly found in the Mediterranean region of Europe. It follows a similar, yet more benign clinical course compared to that of Rocky Mountain spotted fever. Treatment is largely the same for all rickettsial infections, which includes the first-line treatment of doxycycline. Interprofessional communication and teamwork are paramount to diagnose and treat this unique disease successfully.


  • Identify the etiology of Boutonneuse fever.
  • Review significant history and physical exam findings encountered during the evaluation of patients with Boutonneuse fever.
  • Outline the management options available for Boutonneuse fever.
  • Discuss interprofessional team strategies for improving care coordination and communication to advance treatment strategies for Boutonneuse fever and improve outcomes.


Boutonneuse fever (BF) is an illness first detailed in Tunisia, North Africa, nearly a century ago and was called “boutonneuse” (French for “spotty”) because of the pimpled or papular skin rash that followed the fever. Boutonneuse fever is a type of infectious disease caused by bacteria of the rickettsia genus, typically found in the Mediterranean region of Europe. Other common regions include sub-Saharan Africa, India, Greece, and select regions surrounding the Black Sea.

Rickettsia conorii (the causative organism) is an obligate intracellular bacterium that cannot reproduce outside of a host cell. It is a type of gram-negative bacteria (it does not retain the crystal violet stain during the Gram staining technique of bacterial identification).

Boutonneuse fever is transmitted by the bite of a dog tick (Rhipicephalus sanguineus) and is classified as a spotted fever; most people that get sick with a spotted fever will have a black eschar (a “tache noire” or black spot) at the site of the bite. The tick bite causes the zoonotic (non-human to human) bacteria to enter the blood and disseminate.

Boutonneuse fever typically has an incubation period of 5 to7 days following the tick bite. The tick bite is usually painless and may not be noticed if it occurs in an inconspicuous location. The diagnosis is commonly made based on a history of travel to an endemic location and clinical findings: fever, exanthem (rash), and the tache noire (black eschar). This disease that follows classically causes flu-like symptoms. It typically follows a similar, yet more benign clinical course compared to that of Rocky Mountain spotted fever but can occasionally cause more advanced signs and symptoms such as hepatomegaly, jaundice, meningitis, other neurologic complications, orchitis, retinopathy, gastrointestinal bleeding, and pneumonia. 

Treatment of BF is largely the same as for all rickettsial infections. Doxycycline is a tetracycline that remains useful in the management of obligately intracellular bacterial pathogens such as rickettsia. Patients with a more benign progression are treated with antibiotics for 7 days. Those with more progressive symptoms are usually treated for 14 days. Macrolides such as azithromycin are efficacious in children and pregnant women.[1][2][3]


This disease process is caused by Rickettsia conorii, which is a gram-negative, obligate intracellular bacteria that spreads in zoonotic fashion via the tick vector. Rickettsia conorii is transmitted exclusively by the brown dog tick Rhipicephalus sanguineus, and humans are considered an accidental host. However, more recent data suggests vertebrate vectors, namely domesticated dogs, may play a larger role in transmission than previously thought. Transmission occurs rapidly after the initial bite, and the bacteria cause systemic disease by attaching and entering into human vascular endothelial cells.[1][4][5]


Boutonneuse fever was first described in the literature in 1910 in Tunis. Numerous reports followed from the Mediterranean basin, and at present time, southern Europe is considered the main endemic region. Over time, new subspecies of Rickettsia conorii, such as Rickettsia conorii israelensis, have been discovered in various regions. These regions include sub-Saharan Africa, India, Greece, and areas around the Black Sea such as Turkey, Bulgaria, and Ukraine. These subspecies differ to an extent on a molecular-genetic level, yet all result in a similar clinical syndrome. Most cases occur in the summer months, thought to be due to increased tick prevalence and increased tick activity in the summer months. It is prevalent equally in all ages and genders.

Cases in the U.S. are very infrequent and usually occur from travelers returning from endemic regions. Seroprevalence in European countries ranges from 3.9% in Italy, 11.9% in Spain, to upwards of 23% in Serbian mountain areas. Prevalence is no different when comparing urban versus rural areas.

More severe manifestations of the disease can occur in select patient populations with certain risk factors. These include patients with advanced age, immunocompromised hosts, chronic alcoholics, glucose-6-phosphate dehydrogenase [G6PD] deficiencies, prior prescriptions of inappropriate antibiotics, and delay of treatments.[6][7]


There are currently 8 proposed subspecies of Rickettsia conorii. These subspecies all display similar virulence in humans by preferentially infecting human vascular endothelial cells. The subspecies all demonstrate two surface proteins. The proteins are named outer membrane proteins A and B and are serotypically unique for each of the subspecies variants. Invasion of the vascular endothelial cells results in disseminated inflammation and increased vascular permeability throughout the body.

The incubation period lasts around 6 days, followed by the rapid development of symptoms. Classic symptoms for BF include a fever, rash, flu-like symptoms, and eschar at the bite site. This eschar, known uniquely as "tache noire," is another classically associated finding of this disease. All of these symptoms are present to varying degrees, with fever (96% to 100%) and rash (87-96%) being the most common symptoms reported. This rash is classically spread to the palms and soles and is most commonly maculopapular, and less common vesicular (6% to 10%).

MSF typically follows a less severe course compared to Rocky Mountain spotted fever (RMSF). The disease course is typically mild and self-limiting. The case-fatality rate (CFR) of BF is less than 5% versus RMSF at 55 to 10%. It does appear that certain subspecies of Rickettsia conorii are more severe, with a CFR of the R. conorii israelensis in one study approaching 29% compared to 9% for the Malish strain.[7][8]

History and Physical

Patients will present with symptoms beginning after an average incubation period 6 to 10 days following the tick bite. Symptoms include fever, flu-like symptoms, and rash. Lymphadenopathy is rare. "Tache noire" is the term for the eschar that classicly develops with this disease. Uncommonly, multiple eschars are present. Rash typically spreads 2 to 4 days after onset of fever. It is a maculopapular rash that spreads from the palms and soles and spares the face.

Less common is the presence of a vesicular-like rash. In endemic regions, high clinical suspicion must be maintained for patients presenting with undifferentiated rash, fever, or flu-like symptoms. Travel history may also be a key component in making this diagnosis.[9]


Diagnosis can usually be made based on clinical findings and epidemiological clues. Confirmation of the suspected clinical diagnosis can be made in four ways. Some lab findings can include: a relative left shift, leukopenia, thrombocytopenia, elevated aspartate aminotransferase levels, elevated LDH levels, and hyponatremia. Worsening synthetic liver function, thrombocytopenia, and diffuse epidermal purpura are ominous signs of disseminated and severe disease. These laboratory studies are largely non-contributory to the diagnosis of BF, as their prevalence varies significantly in the reported literature, and diagnosis can be made based on clinical evaluation alone, followed by confirmatory testing.

Confirmatory testing is done in four basic ways: serology, polymerase chain reaction, immunologic detection, and isolation of the causative organism. Serologic testing is the mainstay of diagnosis at present. There are several tests available, including Enzyme-linked immunosorbent assay (ELISA) and Western blot immunoassay. They may detect IgM and IgG antibodies 10 to 14 days after symptoms. Thus, the use of these modalities in acute clinical management is limited, especially at the initial onset of symptoms. Serologic testing also has significant cross-reactivity between various subspecies, reducing specificity. Species-specific diagnosis is routinely achieved by PCR followed by culture.[9]

Treatment / Management

The initiation of treatment for patients who are symptomatic with concerns for BF is paramount. Early detection and prompt treatment may shorten the disease course and reduce potential complications. Treatment is not to be delayed waiting for confirmatory lab testing. The current treatment of choice for all rickettsial infections is doxycycline. This includes pediatric and pregnant patients. Standard adult dosing is 100 mg twice daily for 7 to 10 days. This is routinely done on an outpatient basis if given within five days of symptom onset, and the disease is mild. Pediatric dosing is 2.2 mg/kg twice daily for children under 45 kg. Doxycycline was previously avoided in the pediatric and pregnant population due to possible side effects of dental staining in children and the risk of teratogenicity on the developing fetus. Recent studies have shown relative safety using doxycycline in these populations, especially with a short treatment duration being used for BF and other rickettsial infections. 

Contraindications to using doxycycline include severe allergic reaction and history of hepatotoxicity with prior use. In these cases, azithromycin is recommended for use in mild cases for pregnant and pediatric patients as a second-line agent. For more severe cases or pregnant females, chloramphenicol use is indicated. Dosing of azithromycin is 500 mg daily for 7 to 10 days, and 10 mg/kg in pediatrics, with a maximum dose of 500 mg. Chloramphenicol dosing is 50 mg/kg daily, divided into four doses. Azithromycin can be used if a pregnant woman is unable to take doxycycline or chloramphenicol. Fluoroquinolones have been used in the past, but are associated with worse overall outcomes, and their use is no longer recommended.[3][10][11][12]

Differential Diagnosis

A broad differential diagnosis exists for BF. Febrile illness presenting with an associated rash is a concern for several viral exanthems and bacterial syndromes including, but not limited to: varicella-zoster virus, rubella, rubeola, fifths disease, infectious mononucleosis, scarlet fever, toxic shock syndrome, and various other rickettsial infections. Also included in the differential are connective tissue disorders, such as lupus and dermatomyositis. Diseases presenting with fever and eschar, including cutaneous anthrax, and oriental infections are included. Other non-rickettsial protozoal infections, such as malaria, should also be considered.[13]


Prognosis has improved significantly since the advent of early detection due to awareness of the disease in endemic regions, and initiation of early antibiotic therapy. Fatality rates have fallen from nearly 20% in 1949 to less than 5% at present. Treatment should not be delayed awaiting confirmation of diagnosis from serologic testing or culture. It is well documented that recognition and treatment early on in the clinical course are crucial to improved outcomes. 


Generally, most outcomes follow a benign clinical course. However, more serious disease manifestations can occur more frequently in certain at-risk populations. These include myocarditis, atrial fibrillation, retinopathy, retinal vasculitis, cerebral infarct, meningoencephalitis, sensorineural hearing loss, acute quadriplegia secondary to an axonal polyneuropathy, splenic rupture, and the presence of hemophagocytic syndrome.[7]

Deterrence and Patient Education

Prevention of BF is key to preventing the total number of cases and deaths worldwide. This starts with education on disease causation and recommendations for improved hygienic practices. Routine tick checks for persons living in and traveling through endemic regions will aid in prevention. Awareness of common symptoms and the need for prompt evaluation by a medical professional is crucial, as earlier treatment results in improved outcomes.

Enhancing Healthcare Team Outcomes

An interdisciplinary approach from physicians, pharmacists, nurses, and community outreach programs advocating for informative, open-ended communication is necessary for successful management of BF. Currently, no vaccine exists, and prophylaxis is not recommended. Thus, educating the community of regions affected by BF, in a consistent and effective manner, is key to the prevention and recognition of disease.

Article Details

Article Author

Kevin MacConnachie

Article Editor:

Kevin Tishkowski


7/9/2021 12:13:00 AM

PubMed Link:

Boutonneuse Fever



Adem PV, Emerging and re-emerging rickettsial infections. Seminars in diagnostic pathology. 2019 May;     [PubMed PMID: 31101391]


Satjanadumrong J,Robinson MT,Hughes T,Blacksell SD, Distribution and Ecological Drivers of Spotted Fever Group Rickettsia in Asia. EcoHealth. 2019 Dec;     [PubMed PMID: 30993545]


Snowden J,King KC, Rickettsial Infection 2020 Jan;     [PubMed PMID: 28613765]


Laušević D,Ilić T,Nenadović K,Bacić D,Obrenović S, Seroprevalences of Rickettsia conorii, Ehrlichia canis and Coxiella burnetii in Dogs from Montenegro. Acta parasitologica. 2019 Dec;     [PubMed PMID: 31286358]


Herrador Z,Fernandez-Martinez A,Gomez-Barroso D,León I,Vieira C,Muro A,Benito A, Mediterranean spotted fever in Spain, 1997-2014: Epidemiological situation based on hospitalization records. PloS one. 2017;     [PubMed PMID: 28355307]


Lledó L,González R,Gegúndez MI,Beltrán M,Saz JV, Epidemiological study of rickettsial infections in patients with hypertransaminemia in Madrid (Spain). International journal of environmental research and public health. 2009 Oct;     [PubMed PMID: 20054452]


Alexandre N,Santos AS,Bacellar F,Boinas FJ,Núncio MS,de Sousa R, Detection of Rickettsia conorii strains in Portuguese dogs (Canis familiaris). Ticks and tick-borne diseases. 2011 Jun;     [PubMed PMID: 21771547]


Sousa Rd,França A,Dória Nòbrega S,Belo A,Amaro M,Abreu T,Poças J,Proença P,Vaz J,Torgal J,Bacellar F,Ismail N,Walker DH, Host- and microbe-related risk factors for and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients. The Journal of infectious diseases. 2008 Aug 15;     [PubMed PMID: 18582199]


Matzner O, Pest control. The Israel Medical Association journal : IMAJ. 2002 Aug;     [PubMed PMID: 12183884]


Biggs HM,Behravesh CB,Bradley KK,Dahlgren FS,Drexler NA,Dumler JS,Folk SM,Kato CY,Lash RR,Levin ML,Massung RF,Nadelman RB,Nicholson WL,Paddock CD,Pritt BS,Traeger MS, Diagnosis and Management of Tickborne Rickettsial Diseases: Rocky Mountain Spotted Fever and Other Spotted Fever Group Rickettsioses, Ehrlichioses, and Anaplasmosis - United States. MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports. 2016 May 13;     [PubMed PMID: 27172113]


Botelho-Nevers E,Rovery C,Richet H,Raoult D, Analysis of risk factors for malignant Mediterranean spotted fever indicates that fluoroquinolone treatment has a deleterious effect. The Journal of antimicrobial chemotherapy. 2011 Aug;     [PubMed PMID: 21642652]


Raoult D, Antibiotic treatment of rickettsiosis, recent advances and current concepts. European journal of epidemiology. 1991 May;     [PubMed PMID: 1884779]


Boyd AS, Rickettsialpox. Dermatologic clinics. 1997 Apr;     [PubMed PMID: 9098640]