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R. conorii subsp. israelensis is the agent of Israeli spotted fever.
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In the last few decades newly recognized tick-borne rickettsioses have been shown to be present in Europe.
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We describe here two severe cases of ISF which occurred in Italian adults.
Abstract
Mediterranean spotted fever (MSF) is endemic in Italy, where Rickettsia conorii subsp. conorii was thought to be the only pathogenic rickettsia and Rhipicephalus sanguineus the vector and main reservoir. R. conorii subsp. israelensis, which belongs to the R. conorii complex, is the agent of Israeli spotted fever (ISF); apart from Israel, it has also been found in Italy (Sicily and Sardinia) and in different regions of Portugal. We describe here two severe cases of ISF which occurred in otherwise healthy Italian adults. Their characteristics are analyzed and discussed in the light of other 91 cases found through a systematic review of international literature.
Rickettsia conorii subsp. israelensis, which belongs to the R. conorii complex, is the agent of Israeli spotted fever (ISF). It was first reported in 1974 in Israel and distribution appeared to be restricted only to that country (
The isolation of strains of rickettsiae of the spotted fever group in Israel and their differentiation from other members of the group by immunofluorescence methods.
Several cases of postmortem diagnosis of ISF have been described in children and adults in Israel using cell culture methods, animal inoculation and immunohistochemical detection of rickettsial antigen in paraffin-embedded tissue obtained at autopsy (
Aharonowitz et al., 1999). Only later was nested PCR applied to sera and tissue in several fatal cases of rickettsial infections and shown to be effective in establishing the correct diagnosis (
Rickettsia conorii subsp. conorii was thought to be the only pathogenic rickettsia of the spotted fever group in Europe where it is endemic in southern Europe, with sporadic cases reported in northern and central Europe. Rhipicephalus sanguineus is the vector and a potential reservoir of R. conorii subsp. conorii in the Mediterranean area. However, in the last few decades, newly recognized tick-borne rickettsioses have been shown to be present in Europe (
), and R. conorii subsp. israelensis has also been detected in Rhipicephalus sanguineus and in human cases in Sicily and Sardinia, Italy and in different regions of Portugal (
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
We report here two cases of ISF in otherwise healthy Sicilian adults and review all articles describing cases of ISF in which the diagnosis was made using molecular biology techniques.
Case 1
A 45-year-old Romanian man, in Italy for five years, previously healthy, except for a treated pulmonary tuberculosis ten years before, was admitted to Palermo University Hospital, Italy, in July 2016 for an history of fever (39 °C), headache, mialgia and weakness for 5 days. One day before admission a generalized rash developed. The patient was an alcoholic and lived in a rural environment in Sicily and owned a dog.
On admission, he was febrile (38.9 °C), tachycardic (120/min), tachypnoeic (40/min), oliguric and complained of severe muscle pain. A physical examination showed diffuse macular rash on the trunk and extremities, including palms and soles. The day after admission, a few petechial lesions appeared on his legs. Laboratory investigations yielded the following results: C-reactive protein level 253 mg/L (n.v. <5 mg/L); leukocyte count, 5.9 × 109/L; platelet counts, 13 × 109/L; creatinine 1.08 mg/dL; aspartate aminotransferase, 464 U/L; alanine aminotransferase, 126 U/L; γ-glutamyl-transpeptidase, 45 U/L; pH 7.45; lactate, 2.5 mmol/L; D-dimer, 19.000 ng/mL (n.v. 10–250 ng/mL). Routine blood and urine cultures, serologic tests for HIV, Leptospira spp. and Rickettsia spp. were performed but the results were not diagnostic. Treatment with intravenous piperacillin-tazobactam (4.5 gr three times a day) plus vancomicin (1 gr twice a day) and oral doxycycline (100 mg twice a day) was immediately started.
On the second day of hospitalization, the patient’s condition worsened: the skin rash became overtly petechial, and the picture of severe sepsis with multiorgan system failure worsened. Laboratory results were not diagnostic except real-time PCR assay for R. conorii subsp. Israelensis.
Rickettsial DNA was detected from full blood specimens with a highly sensitive real-time PCR assay for the detection of spotted fever and typhus group rickettsiae using previously published primers and probe to the Rickettsia rickettsii citrate synthase gene, gltA (
). The CSisr-P probe (5′-FAM-TGT AAT AGC AAG AAT CGT AGG CTG GAT G-TAMRA-3′) was specifically designed from a highly conserved region of the citrate synthase gene to detect R. conorii subsp. israelensis in addition to SFG rickettsiae.
The patient was treated with doxycycline for seven days, and fever subsided completely after three days of treatment. The patient was discharged from hospital 10 days after admission, without any sequel.
Case 2
A 65-year-old otherwise healthy Italian woman was hospitalized with a 6-day history of high fever (40 °C), headache, vomiting and, four days later, a maculopapular rash involving the trunk, limbs, palms, and soles. On admission, the patient was agitated, confused, dysarthric and exhibited bilateral dysdiadochokinesis. Mild neck stiffness and positive Kernig’s sign were present. She was febrile (39 °C), tachycardic (100 bpm), and tachypnoeic (respiratory rate 28 breaths per minute). A maculopapular rash covered the entire body surface, and petechial lesions were also present on the ankles. A brain CT scan was negative for acute ischemic-hemorrhagic events. MRI, performed with the suspect of encephalitis, showed gliotic outcomes based on hypoxic-ischemic lesions. Laboratory investigations yielded the following results: C-reactive protein level 67 mg/L, leukocyte count 52 × 109/L, platelet count 73 × 109/L, aspartate aminotransferase 172 U/L; alanine aminotransferase 289 U/L, d-dimer 2264 ng/mL. Routine blood and urine cultures, serologic tests and PCR for Rickettsia spp. were performed. (see above). The patient did not give consent for the execution of a lumbar puncture. Treatment with intravenous ceftriaxone (2 g twice a day) plus vancomicin (1 g twice a day) and oral doxycycline (100 mg twice a day) was immediately started. Laboratory results were not diagnostic except real-time PCR assay for R. conorii subsp. israelensis. The patient was treated with doxycycline for seven days and was discharged from hospital 20 days after admission. Fever subsided completely after four days of hospitalization.
Literature review and discussion
For the review of published cases, a PubMed search was performed combining the terms (israelensis OR israeli) AND (Rickettsia OR Rickettsioses OR Conorii) without limits; references were also checked for relevant articles, including review papers.
A study was considered eligible for inclusion in the review if it reported cases of ISF documented by molecular biology methods. Our search retrieved 69 articles; of them, 30 described human cases of probable ISF (
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
Data regarding the clinical characteristics, therapy, diagnosis and outcome of the above 91 patients with ISF and our two new cases are shown in Table 1.
Table 1Clinical characteristics, therapy and outcome of 91 ISF cases.
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
All but two cases were contracted in three countries: Israel, Portugal and Italy. One case was reported in a patient returning from a trip to Libya and one case in Tunisia (
Medical history was unremarkable in all reviewed cases reported except in the first of our two cases that had a history of chronic alcohol abuse.
The illness had a sudden onset with fever (81%), rash (77%), headache (44%); tache noire was present in 27% of the cases, and gastrointestinal symptoms were present in 50% of the cases. 27.3% of patients died of multiorgan failure, acute renal and hepatic failure, purpura fulminans and acute encephalitis.
In all cases, molecular biology techniques allowed the detection of copies of rickettsial DNA with amplification of specific sequences of the genes encoding 16S rRNA, the 17-kDa protein, citrate synthase (gltA), and the outer membrane proteins OmpA and OmpB (
) on blood (13 cases), eschar (3 cases) and autopsy samples (2 cases).
Serology, performed with immunofluorescence assay (IFA) or enzyme-linked immunosorbent assay (ELISA), was positive in only 11% of cases.
In all cases, therapeutic regimens included intravenous or oral doxycycline.
ISF does not appear to be limited to Israel, but is more widespread in the Mediterranean countries than first believed, and cases from Italy, Portugal, Libya and Tunisia have been reported.
The two cases of severe ISF we described had a favorable course. Case 1 experienced severe sepsis reaching new criteria for diagnosis of sepsis (
); he had a proven risk factor for developing a severe form of the disease; analysis of the relationship between comorbidities and a fatal MSF outcome demonstrated that alcoholism is a statistically significant host condition which is a risk factor for a fatal outcome and for severity of disease (
). Case 2 had encephalitic symptoms but did not have risk factors like the other cases examined. Nevertheless, most examined cases of ISF presented severe forms of the disease and a high fatality rate was found.
De Sousa et al. carried out a prospective study on 69 Portuguese patients with ISF and compared the clinical picture and severity of R. conorii subsp. israelensis and R. conorii subsp. conorii infection. They showed a statistically significantly greater severity of ISF compared to MSF infection caused by R. conorii subsp. conorii; case fatality rate for R. conorii subsp. israelensis was significantly greater than for R. conorii subsp. conorii infection (29% vs. 13%), and a greater percentage of patients with ISF strain infection required admission to ICU, compared to those with R. conorii subsp. conorii infection (36% vs 22%) (
). All cases reported in Israel have been fatal, as well as the two cases which occurred in the UK – a tourist traveling in Portugal and another subject probably infected in Libya (
). Among the cases of ISF described in Portugal, apart from the cases described by De Sousa, two of those reported by Bacellar died of shock and multiorgan failure (
). Of the 7 cases described in Italy, outcome was favorable in the two cases we have reported and in two out of five reported by Giammanco; the other 3 patients developed disseminated intravascular coagulation and progression toward coma and one of these patients died the day after admission (
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
Therefore, R. conorii subsp. israelensis would appear to be more virulent than R. conorii subsp. conorii even if the microbial pathogenic mechanism by which it causes more severe illness remains to be determined.
Gastrointestinal symptoms such as nausea, vomiting, and diarrhea have been prominent manifestations reported in patients with fatal course of ISF and, overall, more frequent in patients with ISF compared with R. conorii subsp. conorii–infected patients (
); however, it is markedly less noted in ISF, where it was present in only 27% of patients. The absence of eschar may be an obstacle to correct diagnosis especially in cases of travelers coming from non-endemic areas (
). Therefore, rickettsiosis should always be suspected in febrile travelers, especially when they present with a rash, even in the absence of history of tick exposure and inoculation eschar; patients should start appropriate therapy without delay if suspicion of rickettsiosis arises in order to prevent a poor outcome due to aggressive rickettsial strains. Indeed, the supposed ability of the ISF rickettsia to cause life-threatening disease has been also ascribed to late diagnosis due to its uncharacteristic presentation (
Tetracyclines are considered standard treatment for MSF even thought they can cause significant adverse effects like staining of the teeth and bone toxicity, especially in children. For this reason the macrolides have emerged as a potential alternative therapy in children (
). In all reviewed cases, but one, doxycycline was promptly started; delayed medical consultation and late initiation of antimicrobial therapy (6 days after symptoms onset) may have contributed to the fatal course in the UK tourist traveling in Portugal (
). Haemophagocytic lymphohistiocytosis is a rare but potentially fatal disease that can be associated with Rickettsial infection and other zoonotic diseases (
Serology was positive in only 11%. Therefore, it would be advisable to use a PCR test that allows rapid diagnosis through the detection of copies of rickettsial DNA (
). Skin biopsy specimens, particularly eschar biopsy specimens, can be used for detection of Rickettsia spp. by molecular tools, but this technique is invasive and painful for patients and is difficult to perform on certain areas of the body (
). PCR detection followed by genetic characterization can determine the genotype of the organism to the level of genus, species, and strain, and allows an update of epidemiological knowledge. To date, the genomes of all R. conorii subspecies have been sequenced. The draft genome of R. conorii subsp. Israelensis yelded a total genome of 1,252,815 nucleotides in which no plasmid has been detected. Orthologous genes between R. conorii subsp. israelensis and the other three R. conorii subspecies were identified suggesting that the genomes of these bacteria were almost perfectly syntenic. However, some genes, like those for NADH dehydrogenase I chain B (NuoB), glycerol-3-phosphate cytidyltransferase (TagD), and MazG-like protein were not detected in the R. conorii subsp. israelensis genome, while they were present in those of the other three R. conorii subspecies. Whether this difference explains the differences in clinical expression observed among subspecies remains to be demonstrated (
In conclusion, the geographic distribution of ISF is wider than previously thought and it is possible that severe cases of MSF described in literature and believed to be caused by R.conori subsp. conorii were instead caused by R. conorii subsp. israelensis (
Presence of Rickettsia conorii subsp. israelensis, the causative agent of Israeli spotted fever, in Sicily, Italy, ascertained in a retrospective study.
The isolation of strains of rickettsiae of the spotted fever group in Israel and their differentiation from other members of the group by immunofluorescence methods.
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