Although yellow fever and dengue are not endemic in the United States, extensive travel by Americans to tropical areas means that imported cases occur. It is reasonable, therefore, that physicians in the United States be acquainted with these two diseases.
Yellow fever virus, dengue virus, and Zika virus are classified as flaviviruses. Chikungunya virus is a member of the Togavirus family. Table 42–3 describes the epidemiology of the important arboviral diseases that occur primarily outside the United States. Japanese encephalitis virus, also a flavivirus and an important cause of epidemic encephalitis in Asia, is described in Chapter 46.
TABLE 42–3Epidemiology of Important Arboviral Diseases Outside the United States ||Download (.pdf) TABLE 42–3 Epidemiology of Important Arboviral Diseases Outside the United States
|Disease ||Vector ||Animal Reservoir ||Geographic Distribution ||Vaccine Available |
|Yellow fever || || || ||Yes |
Tropical Africa and South America
Tropical Africa and South America
|Dengue ||Aedes mosquito ||Humans; probably monkeys also ||Tropical areas, especially Caribbean ||No |
|Chikungunya virus ||Aedes mosquito ||Humans ||Tropical areas, especially Caribbean ||No |
|Zika virus ||Aedes mosquito ||Humans and nonhuman primates ||Tropical areas of Central and South America ||No |
Note that all four viruses described in this section: yellow fever virus, dengue virus, chikungunya virus, and Zika virus are transmitted by Aedes mosquitoes.
As the name implies, yellow fever is characterized by jaundice and fever. It is a severe, life-threatening disease that begins with the sudden onset of fever, headache, myalgias, and photophobia. After this prodrome, the symptoms progress to involve the liver, kidneys, and heart. Prostration and shock occur, accompanied by upper gastrointestinal tract hemorrhage with hematemesis (“black vomit”).
Yellow fever occurs primarily in the tropical areas of Africa and South America. In the epidemiology of yellow fever, two distinct cycles exist in nature, with different reservoirs and vectors.
Jungle yellow fever is a disease of monkeys in tropical Africa and South America; it is transmitted primarily by the treetop mosquitoes of the Haemagogus species. Monkeys are the permanent reservoir, whereas humans are accidental hosts. Humans (e.g., tree cutters) are infected when they enter the jungle occupationally.
In contrast, urban yellow fever is a disease of humans that is transmitted by the mosquito Aedes aegypti, which breeds in stagnant water. In the urban form of the disease, humans are the reservoir. For effective transmission to occur, the virus must replicate in the mosquito during the 12- to 14-day extrinsic incubation period. After the infected mosquito bites the person, the intrinsic incubation period is 3 to 6 days.
Diagnosis in the laboratory can be made either by isolating the virus or by detecting a rise in antibody titer. No antiviral therapy is available, and the mortality rate is high. If the patient recovers, no chronic infection ensues and lifelong immunity is conferred.
Prevention of yellow fever involves mosquito control and immunization with the vaccine containing live, attenuated yellow fever virus. Travelers to and residents of endemic areas should be immunized. Protection lasts up to 10 years, and boosters are required every 10 years for travelers entering certain countries. Epidemics still occur in parts of tropical Africa and South America. Because it is a live vaccine, it should not be given to immunocompromised people or to pregnant women.
Although dengue fever is not endemic in the United States, some tourists to the Caribbean and other tropical areas return with this disease. In recent years, there were 100 to 200 cases per year in the United States, mostly in the southern and eastern states. No indigenous transmission occurred within the United States. It is estimated that about 20 million people are infected with dengue virus each year worldwide. Dengue is the most common insect-borne viral disease in the world.
Classic dengue fever (breakbone fever) begins suddenly with an influenzalike syndrome consisting of fever, malaise, retro-orbital pain, and headache. Severe pains in muscles (myalgia) and joints (arthralgia, breakbone) occur. Enlarged lymph nodes, facial flushing, a maculopapular rash, and leukopenia are common. After a week or so, the symptoms regress, but weakness may persist. Although unpleasant, this typical form of dengue is rarely fatal and has few sequelae.
In contrast, dengue hemorrhagic fever is a much more severe disease, with a fatality rate that approaches 10%. The initial picture is the same as classic dengue, but then shock and hemorrhage, especially into the gastrointestinal tract and skin, develop. Dengue hemorrhagic fever occurs particularly in southern Asia, whereas the classic form is found in tropical areas worldwide.
Hemorrhagic shock syndrome is due to the production of large amounts of cross-reacting antibody at the time of a second dengue infection. The pathogenesis is as follows: The patient recovers from classic dengue caused by one of the four serotypes, and antibody against that serotype is produced. When the patient is infected with another serotype of dengue virus, an anamnestic, heterotypic response occurs, and large amounts of cross-reacting antibody to the first serotype are produced. There are two hypotheses about what happens next. One is that immune complexes composed of virus and antibody are formed that activate complement, causing increased vascular permeability and thrombocytopenia. The other is that the antibodies increase the entry of virus into monocytes and macrophages, with the consequent liberation of a large amount of cytokines. In either scenario, shock and hemorrhage result.
Dengue virus is transmitted by the A. aegypti mosquito, which is also the vector of yellow fever virus. Humans are the reservoir for dengue virus, but a jungle cycle involving monkeys as the reservoir and other Aedes species as vectors is suspected.
The diagnosis can be made in the laboratory either by isolation of the virus in cell culture or by serologic tests that demonstrate the presence IgM antibody or a fourfold or greater rise in antibody titer in acute and convalescent sera. A PCR assay that detects virus in the blood is also available.
No antiviral therapy or vaccine for dengue is available. Outbreaks are controlled by using insecticides and draining stagnant water that serves as the breeding place for the mosquitoes. Personal protection includes using mosquito repellent and wearing clothing that covers the entire body (Note that a dengue vaccine composed of live attenuated yellow fever vaccine virus genetically engineered to produce proteins from dengue virus that serve as the immunogen was approved by Mexico in 2015 but is not available in the United States.)
This virus causes chikungunya fever characterized by the sudden onset of high fever and joint pains, especially of the wrists and ankles. Joint involvement is bilateral and symmetric. Severe arthritis, especially of the hands, can last for months. A macular or maculopapular rash over much of the body is common. Encephalitis may occur.
Outbreaks involving millions of people in India, Africa, and the islands in the Indian Ocean have occurred in the years from 2004 to 2006. In 2013 to 2014, this virus moved to the Western Hemisphere, causing outbreaks involving thousands of people on many Caribbean islands and in the state of Florida.
Chikungunya virus is an RNA enveloped virus and is a member of the Togavirus family. It has a single-stranded, positive-polarity RNA genome. It is transmitted by species of Aedes mosquitoes, both A. aegypti and Aedes albopictus. The latter mosquito is found in the United States, so the potential for outbreaks exists. Humans are the most important reservoir, but infection of nonhuman primates is thought to sustain the virus in nonpopulated areas.
Individuals returning to the United States from areas where outbreaks have occurred have been diagnosed with chikungunya fever. Laboratory diagnosis involves detecting the virus in blood either by PCR assay for viral RNA or by enzyme-linked immunosorbent assay (ELISA) for IgM antibody. There is no antiviral therapy, and no vaccine is available.
Zika virus (ZIKV) is a flavivirus that causes Zika fever, an illness similar to dengue characterized by fever, arthralgia, myalgia, pruritic maculopapular rash, and nonpurulent conjunctivitis. Approximately 80% of infections are asymptomatic. The typical illness lasts a few days to a week. Most symptomatic adults recover without sequelae. However, infection predisposes to Guillain-Barré syndrome. Unlike dengue, hemorrhagic shock does not occur.
The most important aspect of ZIKV infection is vertical transmission from mother to fetus across the placenta. Infection in pregnant women can cause serious fetal abnormalities, including microcephaly. The risk of microcephaly is greatest when the mother is infected in the first trimester. Other fetal abnormalities include visual defects, hearing loss, and cerebral calcifications. In addition to the brain, other organs can be affected, and the term “Zika congenital syndrome” is used to describe the various effects on the fetus. Fetal death also occurs. ZIKV is the only arbovirus documented to cause microcephaly.
The vector is the Aedes mosquito, and the vertebrate hosts are humans and nonhuman primates. Almost all infections are transmitted by mosquitoes, but semen can contain the virus and sexual transmission occurs. There is no confirmed report of transmission by blood transfusion or breast milk. ZIKV has a single serotype.
Disease caused by ZIKV was very rare until 2007 when an outbreak occurred on Yap, an island in Micronesia. In 2015, ZIKV caused outbreaks in the Caribbean and South America. By March 2016, ZIKV had spread to 33 countries in the Americas, causing disease in thousands of people.
The diagnosis is established either by finding viral RNA in the serum or urine using a PCR assay or by finding IgM antibody in the serum using an ELISA test. Interpretation of the antibody test is complicated by cross-reacting antibody in people infected with other flaviviruses, such as dengue virus, or in those who have received the yellow fever vaccine.
Treatment of ZIKV infection in adults is symptomatic. There is no effective antiviral drug and no vaccine against ZIKV.
The main goal of prevention is to eliminate infection in pregnant women. As there is no vaccine, prevention involves various environmental and personal measures, such as protective clothing, mosquito repellent, bed nets, and screened windows (Table 42–4). Pregnant women should not travel to areas where outbreaks are occurring. A man who has been diagnosed with ZIKV infection should use condoms or refrain from having sex for at least 6 months after symptoms began. A man who has traveled to an area where ZIKV is endemic and who is asymptomatic should refrain from having sex for at least 2 months after return from endemic area.
TABLE 42–4Public Health Measures to Prevent Zika Virus Transmission ||Download (.pdf) TABLE 42–4 Public Health Measures to Prevent Zika Virus Transmission
|Type of Prevention ||Specific Measure |
|Environmental measures || |
Use screens on doors and windows
Remove standing water around home
Sleep under mosquito net
Use insecticide spray around home
|Personal protection || |
Use mosquito repellant
Wear long sleeves and long pants
Do not travel to endemic area if pregnant
|Prevent sexual transmission ||Use condoms or abstain from sexual activity during pregnancy |