Boutonneuse Fever

Etiology

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]

Epidemiology

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]

Pathophysiology

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]

Evaluation

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](B2)

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

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. 

Complications

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]