Human Jamestown Canyon Virus Infection --- Montana, 2009

Jamestown Canyon virus (JCV) is a mosquito-borne zoonotic pathogen belonging to the California serogroup of bunyaviruses. Although JCV is widely distributed throughout temperate North America, reports of human JCV infection in the United States are rare. This is the first report of human JCV infection detected in Montana, one of only 15 cases reported in the United States since 2004, when JCV became reportable. On May 26, 2009, a man aged 51 years with no travel history outside of Montana went to a local emergency department immediately following onset of fever, severe frontal headache, dizziness, left-sided numbness, and tingling. His blood pressure was elevated. Stroke was ruled out, oxygen was administered, medication was prescribed for hypertension, and the patient was sent home. One week later, the patient visited his primary-care physician complaining of continued neurologic symptoms consistent with acute febrile encephalitis and recent mosquito bites. Although West Nile virus (WNV) disease was diagnosed based on detection of WNV-immunoglobulin M (IgM) and G (IgG) antibodies, subsequent testing indicated that the WNV antibodies were from a past infection and that his illness was caused by JCV. The final diagnosis of JCV infection was based on positive JCV-specific IgM enzyme-linked immunosorbent assay (ELISA) results and a fourfold rise in paired sample JCV plaque reduction neutralization test (PRNT) titers. This finding represents a previously unrecognized risk for JCV infection in Montana; clinicians should consider JCV infection when assessing patients for suspected arboviral infections.

Case Report

On May 26, 2009, a previously healthy man aged 51 years with no travel history outside of Montana went to a local emergency department immediately following onset of fever, severe acute frontal headache, dizziness, left-sided numbness, and tingling. No other symptoms were noted. Results of a physical examination were normal, except for an elevated blood pressure of 214/119 mmHg. Blood chemistries and cardiac enzyme tests were within normal limits, except for an elevated glucose of 130 mg/dL (normal: 70--110 mg/dL). Results of an electrocardiogram, magnetic resonance imaging, and computed tomography scan of the brain were normal. Oxygen was administered to the patient, telmisartan was prescribed for hypertension, and he was sent home. A week later, on June 2, the patient visited his primary-care physician complaining of fever, persistent headache, and new onset of muscle pain and weakness. The physician considered the patient's symptoms to be consistent with a neurologic illness and evaluated the patient further for a possible stroke or arboviral infection. A carotid Doppler test showed no evidence of abnormal arterial blood flow. A lumbar puncture performed on June 11 showed clear, colorless cerebrospinal fluid with no leukocytes or erythrocytes, and bacterial culture showed no growth at 72 hours; no tests for virus were performed. The patient was referred to and visited a neurologist on July 6. The neurologist found no evidence of stroke, diagnosed a complex migraine, and prescribed medication for headache management. The patient's symptoms gradually improved, and he reported no residual symptoms 6 months after illness onset.

On visiting his primary-care physician and during interviews conducted by the local health department and Montana Department of Public Health and Human Services (DPHHS), the patient reported recent exposure to mosquitoes while working outdoors around his home, which was located in a rural area of Montana. An acute-phase serum sample collected on June 2 (1 week after symptom onset) tested positive for WNV-specific IgM and IgG by ELISA at the Montana Public Health Laboratory (MTPHL). These laboratory results, in combination with the patient's symptoms and history of recent mosquito bites, supported a presumptive diagnosis of WNV disease.

The acute sample was then sent to CDC's arbovirus diagnostic laboratory (CDC-ADL) in Fort Collins, Colorado, to confirm the diagnosis by PRNT. Testing at CDC-ADL was positive for WNV-specific IgM and IgG antibodies, with a neutralizing titer of 320. Testing also was positive for St. Louis encephalitis virus (SLEV)-specific IgG antibodies, but a negative SLEV-specific IgM antibody test and a neutralizing titer of 10 suggested cross-reactive flaviviral antibodies. An initial convalescent serum sample drawn on June 11 (16 days after symptom onset) also tested positive for WNV-specific IgM and IgG by ELISA at MTPHL but was not available for testing at CDC-ADL. However, another convalescent serum sample was obtained on December 1 (189 days after symptom onset) and was tested at CDC-ADL. Results indicated persistence of WNV-specific IgM and IgG antibodies and stable neutralizing titers (Table). Because the stable titers suggested a previously acquired WNV infection (>6 months before illness onset), WNV avidity testing was obtained from the Viral Zoonoses Section, National Microbiology Laboratory, Public Health Agency of Canada (NML-PHAC), in Winnipeg, Manitoba, Canada. Testing found high-avidity WNV IgG, strongly suggesting that the WNV antibodies were from a past WNV infection (1).

In addition to WNV testing, CDC-ADL tested the acute specimen collected on June 2 for antibodies against other arboviruses. Results were equivocal for IgM and IgG antibodies against La Crosse virus (LACV) by ELISA. Neutralizing titers of 40 against LACV and 80 against JCV suggested a possible recent infection with a California serogroup virus (Table). Follow-up testing on the day 189 sample was negative for LACV IgM antibodies by ELISA, but showed a twofold increase in LACV neutralizing titers and a fourfold increase in JCV titers. These results suggested that the patient's infection most likely was JCV. To confirm the diagnosis, samples were sent to NML-PHAC for testing with their recently developed IgM ELISA assays incorporating JCV antigen. Patient sera obtained June 11 and December 1 were positive for JCV-specific IgM antibodies (Table).

The presence of JCV-specific IgM and the fourfold diagnostic rise in JCV-neutralizing antibody titers confirmed the diagnosis of JCV infection. This finding indicated that JCV is present in Montana and that a risk for human infection exists.

Reported by

Jennifer Lowell, PhD, Communicable Disease Epidemiology Program, Denise P. Higgins, Laboratory Svcs Bur, Montana Dept of Public Health and Human Svcs. Michael Drebot, PhD, Kai Makowski, Viral Zoonoses, National Microbiology Laboratory, Public Health Agency of Canada. J. Erin Staples, MD, Div of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC. Corresponding contributor: Jennifer Lowell, [email protected], 406-444-0273.

Editorial Note

Arthropod-borne viruses (i.e., arboviruses) are transmitted to humans primarily through bites from infected mosquitoes or ticks. Most arboviruses of public health importance belong to one of three virus genera: Flavivirus, Alphavirus, and Bunyavirus. Human cases caused by the following domestic arboviruses are nationally reportable to CDC: West Nile, St. Louis encephalitis, Powassan, eastern equine encephalitis, western equine encephalitis, and California serogroup viruses (i.e., La Crosse, Jamestown Canyon, California encephalitis, Keystone, snowshoe hare, and trivittatus).

JCV is distributed throughout temperate North America, where it circulates primarily between deer and various mosquito species (2--4). Despite its wide geographic range, only 15 human JCV infections (mean: <3 per year) have been reported in the United States since 2004, when JCV became a reportable condition, and those have originated predominantly from the midwestern and northeastern states. JCV infections initially were described in the early 1970s to cause a mild febrile illness in humans (5). Serosurveys in Connecticut and New York have shown evidence of JCV infection in up to 12% of the population (3,6). Despite descriptions of mild illness caused by JCV, at least 11 subsequent cases with moderate-to-severe meningoencephalitis have been described; 10 in the early 1980s and one in 2001 (3,6). A retrospective study of patients with central nervous system manifestations and serologic findings for California serogroup viruses during 1971--1981 confirmed that 41 of 53 patients (77%) had antibodies to JCV, indicating that JCV originally was underdiagnosed in these patients (7). In comparison with clinical illness caused by LACV, JCV has been described as affecting adults and is more likely to cause meningitis (6,7). Furthermore, while seasonal distribution of LACV infections in humans generally occurs in August, JCV infections can occur earlier, in May and June, and continue through the end of summer, likely because the seasonal distribution of mosquito vectors differs for each virus (8).

Although the Montana patient with JCV infection was suspected to have an acute WNV infection, human cases of WNV infection in Montana typically are not reported until late July, with the majority of cases occurring in late August and early September. The onset of illness for this patient was during late spring, which is consistent with approximately 40% of recognized human JCV infections. The differences in the seasonal distribution of these diseases likely are related to the mosquito species that transmit the viruses. Mosquitoes belonging to snow-melt Aedes species are common vectors of JCV, emerge early in spring, and are distributed throughout Montana (3,9). Vertical transmission of JCV in mosquitoes, overwintering of the virus in mosquito eggs, and larval maturation in temporary ponds produced by melting snow increase the likelihood of human JCV transmission in the spring (10).

Detection of JCV previously has relied on cross-reactive antibodies in the LACV-specific ELISA (6,7). Testing of the acute serum sample for this case yielded equivocal anti-LACV IgM results, with a slightly higher neutralizing antibody titer against JCV than LACV. The titers against JCV and LACV were not different enough to determine the etiology. Although the convalescent sample confirmed a fourfold rise in JCV-neutralizing antibody titers, testing of paired acute and convalescent samples using a JCV antigen--specific ELISA was necessary to confirm JCV IgM positive results. The discordant anti-LACV and JCV IgM results suggested that cross-reactivity between LACV and JCV antibodies in the LACV-specific ELISA was incomplete, and that sole reliance on the LACV-specific ELISA to detect JCV can lead to missed JCV infections. In response to this, CDC has developed a JCV-specific IgM ELISA. Currently, testing is available only at CDC on request. As more information about the distribution and frequency of JCV infections and disease is known, testing might be expanded to include regional or state laboratories. The availability of this test will enable clinicians and public health officials to quickly differentiate between arboviral infections, especially within the California serogroup.

Initial diagnostic tests in this case included testing for several arboviral diseases. However, the lack of a readily available diagnostic test specific to JCV delayed the diagnosis and led the clinician to consider noninfectious causes of illness. For the patient, the delayed diagnosis resulted in unnecessary medical procedures, including a carotid Doppler ultrasound, plus several hours of travel, and lost work to seek additional medical evaluation from a specialist. Clinically, patient care might not have differed significantly; however, supportive care, including headache management and patient prognosis, would have been established more quickly. Treatment for JCV infection typically includes supportive care and management of complications, such as relieving increased intracranial pressure. This case underscores the importance of Montana clinicians considering JCV infection in patients with a febrile neurologic illness when an arboviral infection is suspected and WNV testing is inconclusive. Improved and timely diagnosis will aid clinicians in making patient-care and management decisions, help public health professionals perform accurate epidemiologic investigations and implement preventive measures, and provide a better understanding of California serogroup virus distribution.

Acknowledgments

Local clinicians; health department personnel; Elton Mosher, Bonnie Barnard, Communicable Disease Epidemiology Program, Montana Dept of Public Health and Human Svcs; Montana Public Health Laboratory. Viral Zoonoses Section, National Microbiology Laboratory, Public Health Agency of Canada. Laboratory personnel, Arboviral Diseases Br, Div of Vector-Borne Diseases, CDC.

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