What is Mediterranean Spotted Fever or Boutonneuse Fever?

Mediterranean Spotted Fever (MSF), also known as Boutonneuse Fever (BF), is a disease which is transmitted by Rhipicephalus Sanguineus, which is a dog tick. The tick bite causes a distinctive rash and a mark, which is known as tache noire (black spot) at the location of the bite.

The causative agent for Mediterranean Spotted Fever or Boutonneuse Fever is Rickettsia Conorii, which is an organism endemic in the Mediterranean basin. Rickettsia Conorii is also associated with Kenya tick typhus, Marseilles fever, South African tick bite fever, Israeli tick typhus and Indian tick typhus. Individuals suffering from Israeli spotted fever very rarely develop the tache noire at the site of the tick bite.

Antibiotics are the main line of treatment for treating Mediterranean Spotted Fever (MSF) or Boutonneuse Fever (BF).

R. conorii enters the body through a tick bite, where after it invades and multiplies in the endothelial cells of the small vessels, results in endothelial injury and necrosis of the tissue, which is evidenced by the tache noire at the site of the bite. The acute-phase response is activated followed by changes in the coagulation state. A person can also have deep venous thrombosis in the late stage of Mediterranean Spotted Fever or Boutonneuse Fever. There are changes in the cell-mediated immunity, with decrease in CD4 cells with lot of alterations in the cytokine profile. The incubation time of Mediterranean Spotted Fever or Boutonneuse Fever is commonly 4-15 days; however, it can be also longer. Fractalkine is a chemokine, which is secreted primarily by endothelial cells. The peak secretion on the day 3 of the infection is thought to coincide with infiltration of the macrophages into infected tissues and also occurs before the peak of the rickettsial content in the tissues.
The introduction of the endothelial cyclooxygenase system and the following release of the vasoactive prostaglandins can promote the regulation of inflammatory responses and changes in the vascular permeability. The course of the Mediterranean Spotted Fever or Boutonneuse Fever is divided into the following stages:

• The first day of Mediterranean Spotted Fever or Boutonneuse Fever is counted from the first day of the fever.
• From day 2, the acute stage starts and continues till day 14.
• Days 15-21 or the week 3 is the borderline stage between the acute period and the convalescent period.
• The convalescent stage begins after day 21.

• High fever.
• Non-pruritic, maculopapular skin rash which develops primarily on the lower legs and occurs about 2-6 days after the fever associated with Mediterranean Spotted.
• Fever or Boutonneuse Fever.
• Tache noire, which is a black spot, is present at the location of the tick bite.
• Headache.
• Myalgia or arthralgia.
• Loss of consciousness or changes in the mental function can be a symptom of Mediterranean Spotted Fever or Boutonneuse Fever.
• Bradycardia.
• Pneumonia.
• Coma.
• Jaundice.
• Gastrointestinal (GI) bleeding.
• Hepatomegaly.
• Splenomegaly.
• Conjunctival hyperemia.
• Orchitis.
• Meningitis.
• Meningism.
• Local lymphadenopathy.
• Retinopathy.
• Sensorineural hearing loss.

There is no specific test, which can diagnose Mediterranean Spotted Fever or Boutonneuse Fever in the early stages. The diagnosis is made based on the medical history and clinical findings, which comprise of a history of travel to an endemic area along with the triad of fever, rash and tache noire.

As the differential diagnosis for Mediterranean Spotted Fever or Boutonneuse Fever includes many rare diseases, therefore it is important that there are consultations with dermatologist and an infectious disease specialist to arrive at the correct diagnosis.

Complications of Mediterranean Spotted Fever or Boutonneuse Fever are more likely to occur in patients who are elderly or immunocompromised, elderly patients and patients who have a malignant form of the disease. The following complications have been reported of Mediterranean Spotted Fever or Boutonneuse Fever:

• Respiratory failure.
• Renal failure.
• Stroke.
• GI bleeding.
• Deep venous thrombosis (DVT).
• Pulmonary complications; these are very rare.
• Arthromyalgia.
• Meningoencephalitic involvement can occur in the acute phase of Mediterranean Spotted Fever or Boutonneuse Fever and can comprise of meningitis or lymphocytic coma.
• Myelitis can occur in the early convalescent stage and is very rare.
• Septic shock.
• Hepatosplenomegaly.
• Multi-organ failure.
• Autoimmune anemia.
• Cryoglobulinemia.

• Antibiotic therapy is the main line of treatment for Mediterranean Spotted Fever or Boutonneuse Fever. Prevention of this condition is very important. Patients should be made aware in how to avoid the tick bites and ways to reduce contact with dogs in areas, which are endemic for Mediterranean Spotted Fever or Boutonneuse Fever.
• Antibiotics help shortening the course of Mediterranean Spotted Fever or Boutonneuse Fever. This disease can also take on a malignant form, particularly in individuals who are elderly and who are immunocompromised.
• Some of the first-line antibiotics for Mediterranean Spotted Fever comprise of tetracycline, along with quinolones and chloramphenicol.
• After 2 to 4 days of starting the treatment for Mediterranean Spotted Fever or Boutonneuse Fever, there is a decrease in the fever and the rash often disappears.
• Patients who were already in good health can be discharged after a week of treatment.
• Patients who have malignant form of Mediterranean Spotted Fever or Boutonneuse Fever are given antibiotics for 2 weeks.
• A single-dose of azithromycin can be given for prophylaxis of Mediterranean Spotted Fever or Boutonneuse Fever.
• Other medicines, which are given in Mediterranean Spotted Fever or Boutonneuse Fever, include doxycycline, ciprofloxacin, levofloxacin, macrolides and clarithromycin.
• For malignant Mediterranean Spotted Fever, tetracyclines, particularly doxycycline should be the first line of treatment. Erythromycin is considered safe for administering in pregnant women; however, it is not as effective as the tetracyclines.
• There is a newer macrolide antibiotic, Josamycin, which seems to be effective against malignant Mediterranean Spotted Fever or Boutonneuse Fever. It is also thought to be the drug of choice for malignant Mediterranean Spotted Fever in pregnant women.
• Rifampin is also considered to be a safe drug for treating Mediterranean Spotted Fever or Boutonneuse Fever.
• The aim of treatment for Mediterranean Spotted Fever or Boutonneuse fever is to prevent complications, reduce the morbidity and to eradicate the infection. As mentioned before, antibiotics are the mainstay of treatment for this disease. There is an improvement seen in patients having MSF within 24 hours after the initiation of treatment. Any delay in the response should cast a doubt on the diagnosis.

In some cases polyneuropathy, Guillain-Barre syndrome, changes in the mental status, hepatomegaly, thrombocytopenia, acute renal failure, hypoxemia and even death have been reported. Despite all this, Mediterranean Spotted Fever or Boutonneuse Fever is a benign condition and carries a low mortality rate. The prognosis is good, particularly in mild disease.

There is concern if this condition occurs in individuals who are suffering from a more severe disease and have certain associated or risk factors, such as alcoholism, older age, immune compromise and deficiency of glucose-6-phosphatase dehydrogenase.

• At present, there is no vaccine for Mediterranean Spotted Fever or Boutonneuse Fever.
• To prevent this condition, precautions should be taken for avoiding exposure to the ticks; especially close contact with ticks’ animal vectors, such as dogs, sheep and goats in endemic regions.
• Individuals should wear protective clothing, preferably impregnated with permethrin or another pyrethroid.
• Topical repellents should be applied on the exposed skin and frequent application is recommended.
• When travelling, removal of any ticks and daily self-checks should be performed.

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Also Read:

• Familial Mediterranean Fever (FMF): Etiology, Risk Factors, Signs, Symptoms, Treatment