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Parassitologia 48: 131-133, 2006
Epidemiology and clinical features of Mediterranean Spotted
Fever in Italy
A. Cascio1, C. Iaria2
1Clinica
delle Malattie Infettive, Dipartimento di Patologia Umana, Università di Messina, Italy; 2AILMI (Associazione
Italiana per la Lotta contro le Malattie Infettive), Università di Messina, Italy.
Abstract. Mediterranean Spotted Fever is caused by Rickettsia conorii and is transmitted to humans by
Rhipicephalus sanguineus, the common dog tick. It is characterized by the symptomatologic triad: fever,
exanthema and "tache noire", the typical eschar at the site of the tick bite. In Italy the most affected region
is Sicily. The seasonal peak of the disease (from June through September) occurs during maximal activity
of immature stage ticks. Severe forms of the disease have been reported in 6% of patients, especially adults
with one of the following conditions: diabetes, cardiac disease, chronic alcoholism, glucose-6-phosphate
dehydrogenase deficiency, end stage kidney disease. The mortality rate may reach 2.5%. Oral or parenteral
administration of tetracyclines or chloramphenicol represent the standard treatment. Recent studies indicate that oral clarithromycin and azithromycin could constitute an acceptable alternative for the treatment
of the disease in children; furthermore, they could be recommended during pregnancy.
Key words: Spotted Fever, boutonneuse fever, Rickettsia, clarithromycin, azithromycin.
Mediterranean Spotted Fever (MSF) is a tick-borne disease caused by Rickettsia conorii. In the Mediterranean
area this organism is transmitted to humans by all
stages (nymphs, larvae and adults) of the brown dog
tick Rhipicephalus sanguineus (Parola and Raoult,
2001). Ticks are the only vector and the main host of R.
conorii being rickettsiae transmitted vertically and
transovarially from females via the eggs to larvae of the
next generation (Gilot et al., 1990; Parola and Raoult,
2001; Randolph, 1998; Santos et al., 2002).
Dogs can be infected by R. conorii, but clinical signs of
the disease have not been reported (Shaw et al., 2001).
Dogs, by acting as natural hosts for R. sanguineus, significantly increase contact between these species and
humans, thereby increasing the risk of transmission
(Mumcuoglu et al., 1993).
Interestingly, the number of cases of MSF in Italy and
elsewhere appears to have increased over the past 20
years (Cascio et al., 1998; Mansueto et al., 1986;
Walker and Fishbein, 1991). In Italy the most affected
region is Sicily where more than half of the Italian cases
are reported (Fig. 1). In Sicily an average of 6.7 cases
occurred out of 100,000 people in 2004, compared
with the national average of 0.9 cases per 100,000 people. The seasonal peak of the disease (from June
through September) occurs during maximal activity of
immature stage ticks (Cascio et al., 1998; Gilot et al.,
1990).
by an erythematosus halo that appear in the site of the
tick bite. The onset of fever is generally sudden, and in
typical cases the patients have fever >39°C. Usually
exanthema follows the fever within 2-3 days and it
rarely develops later than the 5th day. Exanthema is initially macular and sparse and generally it first appears
on the wrists and ankles spreading rapidly to the palms
and soles; it subsequently becomes maculopapular and
extends to the trunk and less frequently to the face,
often turning red-purple in color. In some patients only
a few lesions resembling mosquito bites can be present,
in others exanthema may be petechial or purpuric and
rarely papulovesicular (Cascio et al., 1998; Colomba et
al., 2006). The "tache noire" is present in about 70%
of cases. It is generally a single lesion; the most common localizations are the scalp, the neck, and the truncus (Cascio et al., 1998). In the scalp it is often surrounded by an area of alopecia. Lymph nodes draining
the skin site of the tick bite can be tender and slightly
painful on palpation.
Clinical features
The infecting tick bite is painless, and the tick is usually unnoticed, especially when smaller larvae or nymphs
are involved. When not engorged, at these stages ticks
are smaller than a pinhead. A history of tick bite is an
important finding but is often absent. MSF is characterized by a symptomatologic triad: fever, exanthema
and "tache noire" the typical black eschar surrounded
Fig. 1. Annual incidence of MSF cases (clinically ascertained) in Italy and Sicily (official reporting system, Italian
Ministry of Health).
132
SOIPA XXIV - Relazioni dei Simposi
Arthralgia and/or myalgia generally involve the joints
and the muscles of the lower limbs, but only rarely do
they restrict the mobility of the patients. Arthritis generally affects a single joint of the lower limb with moderate signs of inflammation (slight tenderness, erythema, and swelling and pain on motion). Arthralgia is
more severe in adults. Headache is rarely complained of
by children, while it is a typical symptom of the disease
in adults (Cascio and Titone, 1987).
Non-exanthematic forms can occur, and, in these cases,
the only signs of infection can be the presence of lymphadenopathy and/or tache noire and/or fever (Cascio et
al., 1998). Non-exanthematic forms may at least in part
explain the discrepancy between the high prevalence of
seropositivity and the prevalence of the disease documented in some studies (Walker and Fishbein, 1991).
In the western Hemisphere, Rocky Mountain Spotted
fever (RMSF), which is caused by R. rickettsii, can be a
severe disease, but MSF is generally milder. Historical
studies have shown that MSF can lead to 10-14 days of
Fever if not treated, and that it is rarely fatal in children
(Cascio and Titone, 1987). Severe forms of the disease
have been reported in 6% of patients, especially adults
with one of the following conditions: diabetes, cardiac
disease, chronic alcoholism, glucose-6-phosphate dehydrogenase deficiency, end stage kidney disease. The
mortality rate may reach 2.5%. Patients with malignant
forms have a petechial rash and neurological, renal, or
cardiac problems, especially elderly people (Amaro et
al., 2003; Anstey et al., 1997; de Sousa et al., 2003). In
an Italian series of 525 cases, complications (renal failure, myocarditis, pneumonia, encephalitis, anicteric
hepatitis, gastrointestinal bleeding, anaemia and
impaired glucose tolerance) were reported in 12.7% of
cases (Bellissima et al., 2001).
Israeli spotted fever caused by R. israeli is more severe
than MSF. It is characterized by more frequent purpuric
rash, thrombocytopenia, hyponatriemia and systemic
complications, such as pneumonia, nephritis,
encephalopathy, and occasional fatalities also in children; unlike MSF there is no "tache noire" (Anstey et
al., 1997). Initially, the distribution of Israeli spotted
fever rickettsia appeared to be restricted to Israel, but
more recently, the organism has also been isolated from
patients with MSF in Portugal (Bacellar et al., 1999; de
Sousa et al., 2005) and from R. sanguineus ticks collected in 1990 in western Sicily (Giammanco et al.,
2003; Giammanco et al., 2005).
In the last decade newly recognized tick-borne rickettsioses have been shown to be prevalent in Europe.
Lymphangitis-associated rickettsiosis is a new rickettsiosis caused by R. sibirica mongolotimonae. This
pathogen should be systematically considered in the differential diagnosis of atypical rickettsioses, especially
rashless fevers with lymphangitis and lymphadenopathy
(Fournier et al., 2000; Fournier et al., 2005). In 1997,
R. slovaca, transmitted by Dermacentor marginatus
tick was linked to the illness occurring especially in
children and women, during the autumn and winter
and characterized by an unusual crustaceous scalp reaction after receiving a tick bite and enlarged regional
lymph nodes. This clinical syndrome was denominated
TIBOLA (tick-borne lymphadenopathy) (Raoult et al.,
2002). In some Italian series, patients that could fit the
diagnosis of TIBOLA have been reported (Cascio et al.,
1998; Colomba et al., 2006). And in my personal experience I have seen a patient that could fit the diagnosis
of lymphangitis-associated rickettsiosis (unpublished
data). However, because of the scarce specificity of
standard serological methods further diagnostic tests in
patients with these clinical syndromes should be undertaken in the future.
Laboratory findings
The main laboratory findings are a slight increase of
transaminases and a slight thrombocytopenia. The
Weil-Felix test was the first assay used to diagnose MSF
and other rickettsioses. This test lacks sensitivity and
specificity. It could be used only as a first line of testing
in rudimentary hospital laboratories. Today, the most
commonly used serological test is the immunofluorescence antibody test (Anstey et al., 1997). Recently, a
sensitive and specific PCR test based on sequences of
the 17-kD protein gene (Leitner et al., 2002) and a
nested PCR assay based on specific primers derived
from the rickettsial outer membrane protein B gene of
R. conorii have been developed (Choi et al., 2005).
However, these procedures are restricted to specialized
laboratories.
Therapy
The main feature of MSF is a generalized vasculitis with
localization of R. conorii in the cytoplasm of endothelial cells (Anstey et al., 1997). Effective intracellular
concentrations of antimicrobials are therefore considered the "sine qua non" for a successful treatment for
this disease. Standard treatment for MSF was the oral
or parenteral administration of tetracyclines or chloramphenicol. However, both of these drugs can have
significant adverse effects in children. Recent studies
indicate that oral clarithromycin and azithromycin
could constitute an acceptable alternative for the treatment of the disease in children (Cascio et al., 2001;
Cascio et al., 2002); furthermore, they could be recommended during pregnancy. In case of neurological signs,
tetracyclines (minocycline or doxycycline) or chloramphenicol should be given at any age.
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