in late october 2003 , a 41-year - old , generally healthy wisconsin man , who lived near a landfill in the suburbs of a small city on the lake michigan shore , became acutely ill with severe headache , nausea , vomiting , and fatigue . the next day , he was hospitalized with a diagnosis of acute aseptic meningitis . on admission , his body temperature was 38.4c ( 101.1f ) ; no neck stiffness , rash , or focal neurologic abnormalities were detected . cerebrospinal fluid ( csf ) examination showed 865 leukocytes / mm , with 73% lymphocytes , 15% monocytes , 12% neutrophils , and no erythrocytes ; a protein concentration of 105 mg / dl , ( normal 1545 mg / dl ) ; a glucose concentration of 47 mg / dl ( normal 5080 mg / dl ) ; negative gram stain ; negative latex agglutination test results for antigens of neisseria meningitidis groups a , b , c , y , and w135 , haemophilus influenzae type b , streptococcus pneumoniae , escherichia coli k1 , and group b streptococci ( directigen meningitis combo test kit , bd , franklin lakes , nj , usa ) ; and negative routine bacterial cultures . after 3 days , the patient 's condition improved , and he was discharged on a tapering course of oral corticosteroids . four months later , he reported feeling fully recovered except for experiencing headaches more frequently than usual . after the patient 's hospital discharge , the wisconsin state laboratory of hygiene isolated a virus ( designated strain wi-03bs7669 ) from an acute - phase csf specimen . this isolate caused extensive cytopathic effects ( cpe ) in a549 ( human lung adenocarcinoma ) cells by 3 days after infection and in rd ( human embryonal rhabdomyosarcoma ) cells by 6 days , but no cpe were seen in primary monkey kidney or wi-38 ( human embryonic lung ) cells . fluorescent - antibody test results of cell culture material were negative for adenoviruses , cytomegalovirus , varicella - zoster virus , herpes simplex virus , and enteroviruses , and polymerase chain reaction ( pcr ) assays for enteroviruses were negative . when electron microscopy of culture material showed virions morphologically similar to bunyaviruses , the isolate was sent to the arboviral diseases branch of the centers for disease control and prevention ( cdc ) for characterization . by using primers targeted to a highly conserved 251-base portion of the smallest of the 3 rna segments ( rna - s ) of members of the bunyamwera and california serogroups of the family bunyaviridae , strain wi-03bs7669 was shown by pcr to share considerable homology with members of these serogroups ( 3 ) . subsequent nucleotide sequencing of 84% of rna - s ( 795 of 950 total nucleotides in genome positions 84878 , genbank accession no . dq315775 ) followed by a blast ( basic local alignment search tool ) search in genbank showed that strain wi-03bs7669 was 99% identical to prototype cvv strain 6v633 ( genbank accession no . comm . ) but only 90% identical to several other bunyamwera serogroup viruses , including potosi , northway , maguari , and bunyamwera ( 4 ) . in addition , a 694-base fragment amplified from the rna - m segment of wi-03bs7669 , followed by nucleic acid sequence analysis and a blast search , showed 98% sequence identity with 6 cvv strains but only 77% identity with maguari virus ( 4 ) . . however , convalescent - phase serum collected from the patient 4 months after illness onset was strongly positive ( titer 1,280 ) for neutralizing antibody to cvv strain 6v633 in 90% plaque - reduction tests conducted at cdc . the bunyamwera serogroup includes 30 viruses , with known representatives on every continent except antarctica ( r. weir , pers . transmission cycles for these viruses have been little studied , but most isolates have been from culicine and anopheline mosquitoes , and mammals are considered the primary amplifying hosts . in africa and central and south america , bunyamwera serogroup viruses cause sporadic human illness , including undifferentiated febrile illness , fever with exanthem , meningitis , and rarely , encephalitis . at least 7 different bunyamwera serogroup viruses have been isolated from humans , usually from blood , including bunyamwera , germiston , ilesha , and shokwe viruses in africa ; xingu virus in south america ; wyeomyia virus and a cache valley  like virus in central america ; and cvv in the southeastern united states ( 1,2,5,7,8 ) . ngari virus , a reassortant bunyavirus with rna segments from both a bunyamwera serogroup virus and an unidentified member of the genus orthobunyavirus , has recently been associated with epidemic hemorrhagic fever in africa ( 9 ) . cvv is 1 of at least 9 bunyamwera serogroup viruses in north america ( 1,5,6,10 ) , where it was first isolated from culiseta inornata mosquitoes collected in cache valley , utah , in 1956 ( 5 ) . although it has been isolated from > 20 different species of culicine or anopheline mosquitoes , most frequently from anopheles quadrimaculatus ( 1,5 ) , the principal mosquito vectors are unknown . the vertebrate amplifying hosts of cvv have been little studied , but a high prevalance of neutralizing antibody to this virus is often found in ungulates , including deer , sheep , horses , and cattle ( 5,1012 ) . the virus has been isolated from a healthy cow and a sick sheep in texas ( 13 ) and from a healthy horse in michigan ( 12 ) . previous serosurveys have indicated that humans in some parts of the united states are commonly infected by bunyamwera serogroup viruses . for example , neutralizing antibody to cvv was found in 12% of 356 persons surveyed in maryland and virginia in the 1960s ( 15 ) . such results , however , are often difficult to interpret because of nonrandom sampling , multiple bunyamwera serogroup members circulating in the same area , inclusion of a limited number of viruses in tests , and serologic cross - reactivity among members of the serogroup . only 2 cases of human disease due to bunyamwera serogroup viruses were previously reported in temperate north america . the first was an encephalitis case in indiana attributed to tensaw virus in 1964 ( 5 ) . unfortunately , because no details about this case or the method of diagnosis were provided , and because the known range of tensaw virus does not include indiana , the validity of this report is uncertain . the second was a fatal , culture - confirmed case of cvv encephalitis in a young adult in north carolina in 1995 ( 2 ) . thus , our case of cvv meningitis is only the second documented human case of cvv disease . this case apparently lacked any unique clinical or routine laboratory features , and the diagnosis of cvv disease was made by the isolation of this virus from csf by a state public health reference laboratory . the viral genomic sequence data and high - titer neutralizing antibody to cvv in the patient 's convalescent - phase serum confirmed this case to be an acute cvv infection . few csf specimens are cultured for arboviruses because relatively few diagnostic laboratories have the expertise to do so and because even in acute , serologically confirmed cases of neuroinvasive arboviral disease , the isolation rate from csf is generally low . tests for neutralizing antibody to this virus require handling live virus under biosafety level 2 containment and thus are only available by special request at cdc ( through state health departments ) and selected reference laboratories . in conclusion , cvv disease is a neuroinvasive illness rarely diagnosed in north america , in part because laboratories rarely test for it . its true incidence , effect on public health , and full clinical spectrum remain to be determined .
we document the second known case of cache valley virus disease in a human . 
 cache valley virus disease is rarely diagnosed in north america , in part because laboratories rarely test for it . 
 its true incidence , effect on public health , and full clinical spectrum remain to be determined .