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Encephalitis and Sandfly Fever (Sicilian) Virus Infection: Case Report and Review of the Literature

Lesho, Emil P. DO*; Ludwig, George V. PhD; Wortmann, Glenn MD*

Infectious Diseases in Clinical Practice: November 2004 - Volume 12 - Issue 6 - p 352-354
doi: 10.1097/01.idc.0000144907.96816.2e
Case Reports and Reviews: Case Report

Abstract: A 30-year-old man developed severe encephalitis with status epilepticus following 2 days of an acute gastroenteritislike illness while in Iraq. Tests for usual arboviral and enteroviral pathogens were negative, but the sandfly fever virus (Sicilian type) immunoglobulin M was positive. Neurologic deficits persist 3 months after the onset of his illness. To our knowledge, this is the first report of sandfly fever virus (Sicilian type)-associated encephalitis. When tests for more common pathogens are negative, providers taking care of soldiers or travelers returning from endemic areas should consider sandfly fever in the differential diagnosis of unexplained encephalitis.

*Walter Reed Army Medical Center, Washington, DC; and †Diagnostic Systems Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD.

The opinions or assertions contained herein are the private views of the authors and are not be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.

Address correspondence and reprint requests to Emil P. Lesho, MD, 611 Forest Glen Road, Silver Spring, MD 20901. E-mail: or Glenn Wortmann, MD, is to be contacted at Walter Reed Army Medical Center, Building 2 Ward 63, Washington, DC 20307.

Sandfly fever viruses (SFVs) are members of the Phlebovirus genus of the Bunyaviridae Family. Three distinct serotypes are prevalent throughout Europe, parts of Asia, and the Mediterranean basin: Toscana, Naples, and Sicilian. All of these cause a nonfatal influenzalike illness and are spread by Phlebotomus flies. The Sicilian serotype has not previously been associated with encephalitis. The Toscana serotype is currently the only serotype believed to be neurovirulent,1-4 as it has been the only serotype isolated from patients with aseptic meningitis in all previous reports.4-8 We describe what appears to be the first case of encephalitis associated with the Sicilian serotype of SFV.

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A 30-year-old military officer was found convulsing amidst copious oral secretions, urine, and feces in northern Iraq during the month of August. He had been experiencing an acute gastrointestinal-like illness for the last 48 hours. His seizures persisted, and he developed status epilepticus that was refractory to several standard anticonvulsants. He required endotracheal intubation, vasopressors for hypotension, and a phenobarbital-induced coma for seizure suppression. In Iraq, initial computed tomography scan of his head and results of his lumbar puncture were normal. He was transferred to a military hospital in Germany, where repeat lumbar puncture and computed tomography scan of the head were again normal.

Two days later, he was transferred to a military tertiary care facility in the United States. Physical examination of his chest, abdomen, extremities, skin, ears, nose, and mouth were normal. There was mild conjunctival suffusion and subconjunctival hemorrhages bilaterally. Complete blood count and differential were normal. Serum electrolytes and glucose were normal. Alanine aminotransferase was 65, and aspartamine aminotransferase was 45. Cerebrospinal fluid analysis revealed a glucose level of 89 mg/dL, protein of 25 mg/dL, 39 red blood cells mm3, and 1 white blood cell mm3. There were no organisms on Gram stain, and cultures were negative. Chest x-ray, computed tomography, and magnetic resonance imaging of the head were normal. Electroencephalogram showed diffuse slowing and no epileptiform activity. Over the next 72 hours, the patient remained unresponsive on a ventilator with a Glasgow coma scale of 8T.

The following tests on his cerebrospinal fluid were negative: routine bacterial, viral and fungal cultures, polymerase chain reaction for adenovirus, HSV-1, and HSV-2; HSV and adenovirus immunoglobulin (Ig)G and IgM; and West Nile virus IgG and IgM. The following tests on his serum for were also negative for both IgG and IgM: coxsackie A and B, echovirus, eastern equine encephalitis, St. Louis encephalitis, La Crosse Virus, and West Nile virus. Anti-SFV IgG and IgM detection immunoassays were conducted as described.9 Antigens used in the analysis were prepared from infected cell culture lysates or culture supernatants. Test negative controls included known negative normal serum. In addition, all samples were tested against uninfected cell culture lysates (IgG detection assays) or culture supernatant (IgM detection assays). Positive test controls included sera from infected SFV patients (Rossi C, personal communication, September 2, 2003). SFV Naples type was negative, but SFV Sicilian type IgM was strongly positive.

The patient gradually became more responsive over the ensuing weeks but required extended inpatient rehabilitation. Motor and neurocognitive deficits currently persist 3 months after the onset of his illness.

A professionally assisted search of Google and the following data bases: Medline 1954 to present, EMBASE, BIOSIS, and the Defense Technology Information Center, using the following search terms: "encephalitis," "meningoencephalitis," "Phlebotomus fever," "sandfly fever," "sand-fly," "sandfly," "sandflies," and "Sicilian," yielded no reports of SFV Sicilian type causing encephalitis. There was 1 case of mild aseptic meningitis in a 15-year-old German female.10 As in our patient, the diagnosis was based on the presence of SFV Sicilian type IgM.

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Descriptions of an acute illness that probably represented sandfly fever (SFF) date back to the time of the Napoleonic Wars, when a similar disease was reported as Mediterranean fever.11 In Italy, the disease was known as Papatacchi fever, and its relationship to sandflies was first suggested in 1905.11 In 1909, an Austrian military commission reproduced the illness by inoculating serum from acute cases into human volunteers and also demonstrated that infection could be transmitted by Phlebotomus papatasii. In 1937, transovarial transmission from infected flies to their offspring that could then transmit the disease to human volunteers was demonstrated. Interest in Phlebotomus fever increased during World War II due to the occurrence of epidemics of the disease in Allied troops in Italy in 1943 and 1944. Some units, especially those stationed in the Persian Gulf, had attack rates as high as 50%.12 The Sicilian and Naples serotypes were thought to have disappeared following the widespread application of dichlorodiphenyltrichloroethane during the malaria eradication campaigns in Europe during the 1940s and 1950s.13 There were no cases of SFF during the Persian Gulf War of 1990 to 1991,14 presumably due to aggressive preventive medicine efforts and the fact that most of the troops were redeployed before the summer months.14

SFVs are members of the Phlebovirus genus of the Bunyaviridae family. There are 3 distinct serotypes: Naples, Toscana, and Sicilian. They are spread by Phlebotomus, Sergentomyia, or Lutzomyia species of sandflies and cause an acute nonfatal influenzalike illness in humans (sandfly or "papatasii fever"). SFVs have also been isolated from some species of Aedes mosquitoes, but there are no reports of Aedes transmitting SFF to humans.15 However, there are reports of healthcare workers contracting SFF while caring for infected patients, suggesting that contact or aerosol transmission is possible.12 After a 2- to 6-day incubation period, typical features of SFF include fever, malaise, abdominal pain, headache, and severe retroorbital pain.

Peak incidence occurs in August and correlates with the time that the vectors are most active.1 Vectors are found in Europe, Central and Southwest Asia, and the Middle East.1 Seroprevalence studies demonstrated some of the highest rates of SFF infection in the Mediterranean Basin, especially Cyprus.16 In one study, significant risk factors for SFF infection were residence within 3 km of a wastewater treatment facility and the presence of livestock inside the home.17 Seroconversion can be demonstrated by indirect immunofluorescence antibody assay and the plaque reduction neutralization test.1 Recently, an enzyme-linked immunosorbent assay was developed by the Egyptian Public Health Department to detect specific IgG and IgM antibodies to SSV.1 IgM is a reliable marker of acute infection.1 Molecular studies are available only for the Toscana serotype, and a 1-step duplex polymerase chain reaction has been used to identify that serotype.18 The high genetic divergence of the SSV makes it difficult to develop consensus primers for amplification.19 This also impedes vaccine development and may explain why infection with one serotype may not immunize against infection with other serotypes.1,19 There is little or no serologic cross-reactivity between SFF serotypes.1,4 While the testing completed in support of this patient does not conclusively demonstrate the connection between SSV infection and disease, it does provide evidence of very recent infection with the virus and may have served as the etiology of disease in this patient. Furthermore, some authors state that IgM-specific antibodies, as demonstrated in this patient, are more useful than nucleic acid amplification techniques for arboviral infections because of the transient nature of the viremia characteristic of arboviral infections.20

Treatment is supportive. For severe or rapidly decompensating cases, ribavirin can be considered. It has been shown to prevent infection when given prophylactically to human volunteers at doses of 400 mg TID for 8 days.12

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The authors thank Ms Tamara Clements for performing sandfly fever virus serologic testing.

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© 2004 Lippincott Williams & Wilkins, Inc.