Date: Thu 5 Jul 2012
Source: Eurosurveillance 2012; 17(27) [abbrev., edited]
1st report of sandfly fever virus infection imported from Malta into Switzerland, Oct 2011
D Schultze, W Korte [Center of Laboratory Medicine, St. Gallen, Switzerland] P Rafeiner [Department of Internal Medicine, Division of Infectious
Diseases, Cantonal Hospital, St Gallen, Switzerland] M Niedrig [Center for Biological Security (ZBS-1), Robert Koch Institute, Berlin, Germany]
We report the 1st documented cases of sandfly fever virus [family _Bunyaviridae_, genus _Phlebovirus_, species _Sandfly Fever Naples virus_] infection in travellers returning from Malta to Switzerland in autumn 2011. These cases illustrate the importance of considering sandfly-borne viral infection in the differential diagnosis of febrile patients from the Mediterranean island Malta. Raising awareness among physicians is relevant especially now at the beginning of the summer tourist season.
On 17 Oct 2011, a Swiss citizen was hospitalised with fever, nausea, vomiting, and intensifying headache 2 days after his return from the Mediterranean island of Malta, where he had spent 2 weeks on Gozo Island. 9 days before his admission, the patient had suffered back pain, tiredness, and subfebrile temperatures, but had recovered after medication with the non-steroidal anti-inflammatory drug ibuprofen. The patient's wife had suffered from similar, less intense symptoms. Both had multiple insect bites and were diagnosed with laboratory-confirmed sandfly fever. The couple's 2 accompanying children and 2 further travel companions had been frequently bitten by small flying insects, but suffered no symptoms.
Phleboviruses [viruses classified in the family _Bunyaviridae_], transmitted to humans by arthropods, are found in Europe, Africa, central Asia, and the Americas. In Mediterranean Europe, the phleboviruses Toscana virus (TOSV), sandfly fever Naples virus (SFNV), sandfly fever Sicilian virus (SFSV), and sandfly fever Cyprus virus (SFCV) are transmitted by phlebotomine sandflies. Among these, TOSV circulates in countries around the Mediterranean Sea (Algeria, Cyprus, France, Greece, Italy, Portugal, Spain, and Turkey) [1,2].
TOSV may cause an acute, nonfatal, influenza-like symptomatology or even aseptic meningitis and meningoencephalitis [2-4]. SFNV, SFSV and other related viruses can cause the so-called '3-day fever' or 'pappataci fever'. Patients present with influenza-like symptoms including fever, retro-orbital pain, myalgia, and malaise and usually recover fully within a week. However, infections with these viruses, even when mild, have been shown to be highly incapacitating during the time the patients are affected .
Case 1, a man in his late 40s, was admitted to hospital in Switzerland 2 days after his return from Malta and presented in a reduced general condition. He had fever (38.4 degC/101.12 degF), a generalised rash and complained of severe headache, without meningism. Multiple skin lesions due to insect bites were visible on the extremities. Laboratory tests for this patient, including C-reactive protein, electrolytes, and transaminases revealed no abnormalities, and a complete blood cell count showed relative lymphopenia (17.9 per cent, normal range: 20-52 per cent).
Because of the recent stay in a Mediterranean country and the multiple skin lesions, a sandfly fever virus (SFV) infection (pappataci fever) was assumed. Serology for SFV was positive on a serum sample taken on the day after admission -- that is, 10 days after onset of 1st symptoms on Malta. An immunoblot (IB) for bunyaviruses (Mikrogen, Munich, Germany) showed reactivity with the TOSV bands, with stronger intensity than the cut-off reference, indicating the presence of IgM and IgG antibodies against TOSV. An indirect immunofluorescence test (IIFT) (Sandfly fever virus Mosaic 1, Sandfly fever virus serotypes Sicilian, Naples, Toscana, Cyprus; Euroimmun, Lubeck, Germany) revealed high serum antibody titres against Toscana and Naples SFV, indicating an infection with a phlebovirus belonging to the SFNV serological complex. In a convalescent serum, taken 52 days after onset of illness, an 8-fold increase of anti-TOSV IgM was demonstrated, accompanied by a 5-fold increase for anti-TOSV IgG.
The patient gradually improved under analgesic and anti-emetic therapy. On day 15 after onset of illness he could be transferred to a rehabilitation centre and fully recovered 21 days after onset of symptoms. The patient suffered no relapse in the following 8 months.
[Interest readers can find corresponding case histories of the patient's unaffected companions in the original text at the source URL. - ProMed Mod.CP]
Viruses in the genus _Phlebovirus_ can cause a variety of clinical syndromes ranging from a brief, self-limiting febrile illness to encephalitis, meningoencephalitis, and fatal haemorrhagic fever. Of our cases, the male patient suffered from symptoms of a SFV infection that incapacitated him for 2 weeks, while his wife had less severe symptoms. The other 4 travellers accompanying the couple were not infected, despite multiple insect bites.
The genus _Phlebovirus_ genus consists of more than 60 distinct virus serotypes. While antigenically unrelated to members of other genera in the family _Bunyaviridae_, various degrees of cross-reactivity in serological tests can occur within the genus, as reported for the SFNV and SFSV antigenic complexes [6,7]. Our patients showed cross-reactions in the IIFT using SFNV and TOSV antigens, both members of the SFNV antigenic complex. Although IIFT using SFSV and SFCV as antigens yielded negative results, reactions with other serotypes in the genus _Phlebovirus_ cannot be ruled out.
Viral neutralisation tests (VNT) using early convalescent sera remain the serological reference method to identify these viruses or to assess the specificity of the antibody response . Although generally regarded as the gold standard assay for specificity, the VNT is relatively labour-intensive and only established in few laboratories. SFV-specific commercial assays such as IIFT, enzyme-linked immunoassay and IB are much more commonly used. For the diagnosis of the cases described here, we used IIFT for screening purposes and the IB as confirmatory assay .
Direct viral diagnosis by isolation and RT-PCR from blood or cerebrospinal fluid is only possible in the early stages of infection, i.e., the 1st 2 days after onset of symptoms and before seroconversion . Case 1 presented on day 9 after symptom onset, at a time when SFV-specific serology was already positive. Diagnosis was therefore attempted by serological investigation, using 2 commercial kits. That the increase in anti-TOSV IgM and IgG in the convalescent serum of Case 1 was higher than the increase in antibodies against SFNV, was suggestive of an infection with TOSV rather than with SFNV. Similarly in Case 2, anti-TOSV IgM increased more than anti-SFNV IgM and was accompanied by higher seroconversion for anti-TOSV IgG than for SFNV-IgG.
Most cases of TOSV infection have been reported in residents of or travellers to central Italy and Spain, and sporadically in other Mediterranean regions such as Portugal, Cyprus, southern France, and Greece . Asymptomatic infections have also been described . Unlike the other SFV serotypes, TOSV shows a peculiar neurotropism. It can cause meningitis or meningoencephalitis from which patients generally recover within 2 to 10 days . TOSV infections occur particularly during the summer and correlate with the life cycle of the insect vectors _Phlebotomus perniciosus_ and P. perfiliewi .
TOSV has been isolated from _P. perfiliewi_ and _P. perniciosus_. The latter vector is distributed throughout the Mediterranean region as 2 races. SFNV has been isolated in Italy from _P. perniciosus_, in Serbia from _P. perfiliewi_ and in Egypt from _P. papatasi_ . The typical_P. perniciosus_ race occurs in Italy as well as in Tunisia, Morocco, and Malta . However, to the best of our knowledge, neither TOSV nor SFNV infections have been reported from Malta so far. Thus, in connection with the beginning of the summer season, it is now of particular relevance to consider sandfly-borne phleboviruses in the differential diagnosis of patients returning from Malta and presenting with febrile illness.
[Interested readers should consult the original text via the source URL for the list of references cited. - ProMed Mod.CP]
[This report establishes the importance of considering specific sandfly-borne viral infections in the differential diagnosis of febrile patients coming from the Mediterranean island of Malta, although previously neither SFNV nor TOSV had been recorded there although present in the Mediterranean region. Raising awareness among physicians is relevant especially now that the summer tourist season has begun. It is likely also with enforced human populations movements in the region that these sandfly fever virus infections will be encountered with increasing frequency.
The HealthMap interactive map of the island of Malta can be accessed at