WEST NILE ENCEPHALITIS: AN EMERGING DISEASE IN THE UNITED STATES
[Marfin AA, Gubler, DJ CID 2001;33:1713]:
This is an invited article by authors from the Vector-Borne Infectious Diseases unit at the National Center for Infectious Diseases of the CDC at Fort Collins, Colorado. The following are important observations in this review: Transmission cycle: Most transmission is between mosquitoes (especially Culex mosquitoes) and birds (especially crows and blue jays). Birds serve as “amplifying vertebrate hosts.” Humans developed infection by the bite of an infected mosquito.
Transmission cycle: Most transmission is between mosquitoes (especially Culex mosquitoes) and birds (especially crows and blue jays). Birds serve as “amplifying vertebrate hosts.” Humans developed infection by the bite of an infected mosquito.
Epidemiology: WNV was initially isolated in 1937 in Uganda and is epizootic in Africa, Middle East, West Asia and Australia. The first epidemic in Europe was reported in Romania in 1996 and subsequent outbreaks have been reported in the US in 1999, Russia in 1999 and Israel in 2000. Molecular epidemiology studies of the WNV phylogenetic tree showed two main groups, lineage one and lineage two. Lineage two accounts for most strains that are epizootic in equatorial Africa; lineage one accounts for the epidemic strains isolated in Romania, Russia, Israel and the US. Analysis of genomic sequences show most complete homology between the 1999 New York City strain and the 1998 Israel strain suggesting that the US outbreak represented introduction of the virus that had been endemic in the Mediterranean region. The epidemics, lineage, cases, and case fatality rates are summarized in Table 1.
Clinical presentation: The incubation period is 3–15 days. Most patients have no symptoms or a nonspecific viral syndrome characterized by 3–6 days of fever, headache, myalgia and anorexia; about half develop a maculopapular rash. The illness-to-infection ratio in various epidemics has been reported at 1:134 (Lancet 2001;358:261), 1:157 (MMWR 2001;50:37); 1:140 to 1:320 (Med Trop 1999;59:490). Severe illness with neurologic disease is most common in older patients. Of 78 hospitalized patients in the US during 1999–2000, 12 (15%) were less than 50 years of age and 38 (49%) were over 75 years. There were 9 deaths in the 78 patients and all were over 65 years of age. With regard to diagnostic testing to detect encephalitis, CT scans in the US experience have been uniformly negative and MRI scans show acute meningeal enhancement suggesting encephalitis in about ⅓ (NEJM 2001;344:1807). CSF analyses show elevated protein and a lymphocytic pleocytosis with 10–100 cells/mm3. The case fatality rate for WNV encephalitis in the US is reported at 12%.
- EIA IgM antibody: This is the most common test and has a sensitivity approaching 100% with appropriate timing of CSF or serum samples. It becomes positive with resolution of viremia, which may occur through day four of clinical illness. A high level with a single acute phase serum with typical symptoms is highly supportive, but IgM may last for several months so that definitive testing requires demonstration of a four-fold rise in titer with samples collected at least 10 days apart (J Clin Microbiol 2000;38:2232). IgM in CSF is diagnostic, but does not distinguish acute, chronic or relapsing infection. With regard to specificity, this test shows cross-reactions with other flaviviruses including yellow fever, dengue, and St. Louis encephalitis. The most definitive test is demonstration of a fourfold rise in antibody titer using the plaque-reduction neutralization test. The CDC has reagents for IgM and IgG EIA, which are preferred and are available in many states and public health labs.
- PCR are not considered as sensitive as EIA serology, but may prove helpful as an immediately available test to help exclude other treatable pathogens. This would permit a specific diagnosis within hours and is available in most hospital laboratories whereas serology may take one to several weeks and are available only in specialized laboratories.
- Viral isolation: The virus may be cultured using neonatal mice and selected cell lines using blood or CSF, but viremia is present only during the first 2–4 days of illness and this technology requires both experience and a BSL3 containment facility. It is noted that there were no WNV isolates recovered from humans during the 1999–2000 epidemics in the US.
- Samples for referral: Serum for antibody testing should be shipped or stored at ambient temperatures for up to 48 hours. Specimens for viral culture should be frozen at −70°C.
- Treatment: Initial studies showed ribavirin was active in vitro (JID 2000;182:1214). However, this has not been effective against other flaviviruses (RID 1989;11 supplement 4:S750). Most important is recognition of other treatable viruses such as HSV; for WNV encephalitis the main treatments are respiratory support, management of cerebral swelling and prevention of secondary bacterial infections. The role of steroids to control cerebral swelling is not well defined.