CONTINUING EDUCATION
To earn CEUs, see test on page 22.
LEARNING OBJECTIVES
1. List the major flaviviruses that are transmitted by mosquitoes and cause human infection.
2. Describe the clinical presentations of the diseases associated with these viruses.
3. Discuss the most common practical methods of diagnosis for this group of viruses.
4. Identify which of these viruses has an available vaccine.
5. Describe the primary immune response to an antigenic challenge, and discuss the phenomenon known as an anamnestic response.
The flavivirus family (Flaviviridae) represents an important constituent of the arthropod-borne viruses known as arboviruses. Whereas ticks represent an important flavivirus vector, transmitting tick-borne encephalitis (TBE) viruses, the mosquito is the most common arthropod vector for a number of flaviviruses.
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Flaviviruses cause disease in humans and animals. In this review, the major focus will be flaviviruses transmitted by mosquitoes and causing infection in humans, with particular reference to West Nile virus (WNV), yellow fever (YF) virus, Japanese encephalitis (JE) virus, dengue fever virus, St. Louis encephalitis (SLE) virus, and Murray Valley encephalitis (MVE) virus.
From the perspective of the recent history of the United States, a number of the flaviviruses represent rare or exotic agents. The United States, however, has experienced sporadic exposure to dengue and yellow fever, usually associated with travelers returning from outside the country. Notwithstanding, all of the flaviviruses capable of causing human disease have the potential to enter the country--the most recent and dramatic example being WNV.
West Nile virus
West Nile virus is a member of the Japanese encephalitis antigenic complex of flaviviruses. This complex, defined by shared antigenic epitopes, contains many of the important human pathogens, including JE, SLE, WNV, and MVE.
WNV is a recent import into North America, arriving in 1999 and spreading over subsequent years to most of the continental United States. Prior to the emergence of WNV in the United States, the virus was found in Africa, the Middle East, Russia, parts of Europe and Eurasia, the India subcontinent, and parts of Southeast Asia.
The spread and occurrence of WNV in human populations is driven by the maintenance of the virus in its primary host, bird species. This, together with the range of mosquito vectors able to disseminate the virus (Aedes, Culex, and Anopheles), means the virus is able to spread wherever the appropriate bird and vector species coexist.
Diagnosis
Like most disease associated with flavivirus infection, WNV infection may be either silent or overt with a range of signs and symptoms. Classical symptoms include a general malaise, fever, chills, headache, myalgia, and arthralgia. One sign is the occurrence of a maculopapular rash in up to half of the patients presenting with symptoms. While such disease may be mild and self-limiting, more severe disease is observed in a subset of infected patients.
Serology represents the most practical method of diagnosis. Virus isolation and RT-PCR (reverse transcription-polymerase chain reaction) have reduced utility because the viral load often has decreased to undetectable levels by the time symptoms appear. The recent demand for testing for WNV has been high; the volume of testing conducted across the United States in 2003 has been estimated between 500,000 and 1 million samples. According to data from the CDC (Centers for Disease Control and Prevention), this testing yielded approximately 9,000 positive cases resulting in 230 deaths.
The most common serological assays in the United States are FDA-cleared ELISAs that measure both IgM and IgG. These are supplemented with IFAs (immunofluorescent assays) and PRNT (plaque reduction neutralization) assays, the latter of which is a common confirmatory protocol.
St. Louis encephalitis virus
St. Louis encephalitis virus is another member of the Japanese encephalitis antigenic complex of flaviviruses. SLE has been circulating in the Americas for decades. As a mosquito-borne pathogen, the virus is transmitted primarily by Culex spp. Like WNV, SLE is maintained in bird populations with periodic outbreaks of disease. In the United States, SLE out-breaks tend to occur predominantly during the summer months in Florida, the Midwest, the Southwestern states, and the states traversed by the Mississippi River.
A major SLE epidemic that occurred in the mid- to late 1970s involved over 2,500 people, according to data from the CDC. Since that time, smaller outbreaks have occurred every five to 10 years. The sporadic nature of these outbreaks leaves many people vulnerable to infection. Most individuals infected with SLE experience silent or mild infection. Severe disease tends to occur in the elderly, similar to the pattern seen in cases of WNV. Meningoencephalitis is one of the more severe manifestations of disease with up to 20% mortality.
Diagnosis
The clinical presentation of SLE tends to be nonspecific and may be confused with a range of other clinical conditions that present with "flu-like" symptoms. With the emergence of WNV in North America, there is a need to differentiate SLE from WNV, even though patient care is similar for both.
Serology represents the most practical method of diagnosis, although virus isolation or RT-PCR, especially from blood samples, may be of value early in infection. Virus isolation and RT-PCR are of limited utility late in infection or when patients present with severe disease.
IFAs are commercially available. In the United States, testing of samples by hemagglutination inhibition (HAI), ELISA, and/or PRNT is commonly undertaken by state reference laboratories or by the CDC.
Dengue virus
The dengue virus causes serious disease in human populations throughout tropical and subtropical regions across the globe. The pattern of occurrence ranges from sporadic outbreaks to significant epidemics, cycling in periods of three to five years. Crowded urban slums and poor semiurban areas provide conditions for dengue vectors to flourish. Dengue is an important agent of disease in part because of the circulation of four serotypes (numbered 1-4). Infection with one serotype will confer immunity to that serotype; however, subsequent infection by a second serotype (secondary dengue) can lead to serious, life-threatening disease including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
The principle vector of the dengue virus, Aedes aegypti, thrives not only in areas where poor housing, overcrowding, and inadequate sanitation exist, but increasingly in middle-class neighborhoods where any pooling of water occurs.
Today, dengue ranks as the leading cause of viral disease carried by a mosquito-borne vector. It is now endemic in more than 100 countries across the globe, concentrating in Africa, the Americas, the eastern Mediterranean, Southeast Asia, and the Western Pacific.
Because of widespread travel, we have witnessed an increase in the spread of dengue, leading to new strains being introduced into susceptible populations. An estimated 2.5 billion people are exposed to vectors that are capable of transmitting the dengue virus. Indeed, the WHO (World Health Organization) estimates that there may be 50 million to 100 million cases of dengue virus infections each year, of which between 250,000 and 500,000 cases are DHF with 24,000 deaths.
Diagnosis
Clinical diagnosis is overutilized in many countries, especially in the developing world where health economics impact dramatically, leading to limited access to diagnostic services. In these countries, dengue continues to be both misdiagnosed and underdiagnosed due to the unreliable nature of basing a diagnosis on signs and symptoms.
While virus isolation or detection is definitive, the onset of symptoms often precedes the presence of virus. In this circumstance, detection of antibody can lead to a reliable diagnosis. Elevated IgM is a good marker of primary infection. Secondary infection, which may lead to DHF or DSS, is characterized by a marked rise in the IgG titer (HAI titer of [greater than or equal to]1280) with a weak or absent IgM response.
Clinical features of DHS and DSS include a weak pulse and hypotension. Hematological features include thrombocytopenia and elevated hematocrit levels.
Japanese encephalitis virus
Japanese encephalitis virus is centered in the Asia-Pacific region. While JE, SLE, and WNV are all members of the Japanese encephalitis antigenic complex of flaviviruses, JE infection is most severe in infants and children in contrast to the impact SLE and WNV have in the elderly.
