A 63-year-old woman was admitted to a district general hospital in May 2005. She had been referred by a general practitioner with a 3-day history of headache, photophobia, vomiting, and an extensive skin rash. She had returned from a holiday in the Algarve region of Portugal 5 days previously. She had taken many countryside walks but did not give any history of insect/animal bites. Her medical history was unremarkable, and she was usually fit and well. Physical examination including neurology was entirely normal, apart from a nonblanching, erythematous, maculopapular rash affecting the torso, neck, and limbs including the palms and soles. There was no eschar. A provisional diagnosis of meningococcal septicemia was duly made and intravenous cefotaxime started.
Laboratory tests showed a mild neutrophilia of 7.8 × 109/L and a C-reactive protein of 142 mg/L. Eosinophil count was normal. A computed tomography scan of the head was unremarkable. Cerebrospinal fluid (CSF) glucose was 4.7 mmol/L and protein 0.34 g/L; cell count showed only 1,440 red blood cells per cubic millimeter. Urine, CSF, and blood cultures were negative.
The patient experienced ongoing high fever with rigors, persistent headache, and mild photophobia over the following 3 days and began to complain of diarrhea. Her other vital signs were, however, within normal limits. On the fifth day of admission, she became thrombocytopenic, with a platelet count of 49 × 109/L, and a diagnosis of possible rickettsial infection was made. Treatment with intravenous ciprofloxacin 200 mg 12 hourly and doxycycline 100 mg 12 hourly was commenced. The patient became progressively hypotensive, tachycardic, and tachypnoeic and was transferred to a tertiary hospital. She died in the intensive care unit there the following day.
A postmortem examination revealed splenomegaly; mild myocarditis; a nonspecific reactive hepatitis; and focal, cutaneous lymphocytic vasculitis with fibrinoid necrosis; the brain, lungs, and other intra-abdominal organs were normal. The postmortem cause of death was recorded as multi-organ failure secondary to overwhelming sepsis. A serum sample taken 10 days after onset of illness for spotted fever group rickettsiae sent to the Special Pathogens Unit of the Health Protection Agency, Porton Down, was negative for immunoglobulin (Ig)M and positive for IgG antibodies by enzyme-linked immunosorbent assay. Additional samples were sent to the Rickettsial Zoonoses Branch at the Centers for Disease Control and Prevention (Atlanta, GA, USA), a World Health Organization collaborating center for Rickettsial- and Bartonella-associated diseases. DNA from serum, spleen, and kidney was tested in a nested polymerase chain reaction (PCR) that amplifies a fragment of the 17 kd protein gene1 using PuRe Taq Ready-To-Go PCR Beads (Amersham Biosciences, Piscataway, NJ, USA). A 208-base pair fragment of the conserved 17 kd Rickettsia antigen gene was amplified, indicating the presence of spotted fever rickettsia DNA in the serum specimen. An ompA gene fragment (70–602 nucleotides) was also amplified,2 and its nucleotide sequence had 100% similarity to the homologous ompA fragment of the R conorii ssp israelensis.
Israeli tick bite fever caused by R conorii ssp israelensis has emerged as a cause of severe forms of Mediterranean Spotted Fever (MSF) in Portugal.3 Patients have presented with atypical symptoms, major neurological manifestations, and multi-organ involvement. Advanced age, underlying chronic disease, and delay of appropriate treatment are prognostic factors for poor outcomes. In 1997, MSF cases in Beja, a Portuguese southern district, had a case fatality rate of 32.3% in hospitalized patients.4 Patients dying in 1997 were younger than those dying in previous years. The strain R conorii ssp israelensis5 may be responsible for this increased fatality rate over that due to R conorii ssp conorii. A study from Sicily also showed that five Israeli spotted fever patients developed more severe forms of human disease than with MSF.6 Moreover, in Israel, Israeli spotted fever may follow a quick, unpredictable, rapidly fatal clinical course in both children7 and adults.8 A recent review describes diagnostic and treatment options for patients with MSF.9
Israel, Southern Portugal, and other Mediterranean countries are popular destinations, with millions of tourists per year. Clinicians need to be aware of the possibility of severe Israeli tick bite fever in travelers to this region, perform definitive laboratory tests, and prescribe appropriate antibiotic therapy in suspect cases. ISF, as MSF, is transmitted by the bite of Rhipicephalus sanguineus (the brown dog tick) and travelers to endemic areas should be recommended not to pat or play with local dogs.