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Arboviruses of Medical Importance
Abstract
Arboviruses are transmitted to humans primarily through the bites of arthropod vectors such as mosquitoes, ticks, and sandflies. Half of the world’s population live in areas endemic for arboviruses, which cause significant morbidity and mortality in both developed and developing countries. More than 130 arboviruses are known to infect humans, but only a much smaller number are medically important. Since 2015, there have been major outbreaks of emerging (and reemerging) arboviruses such as dengue, Zika, chikungunya (CHIKV), and yellow fever (YF). The 2015–2016 Zika pandemic was declared a public health emergency of international concern by the World Health Organization (WHO) because of the association of Zika infection with microcephaly and Guillain-Barré syndrome (GBS). In 2019, more infections and deaths from eastern equine encephalitis virus (EEEV) were reported in the United States than in the previous 5 years combined. Arboviruses are also a major cause of illness in international travelers, and imported infections have resulted in localized outbreaks in nonendemic areas (e.g., dengue in Hawaii, Zika in Texas and Florida, and CHIKV in Italy and France). In addition to vector-associated infections, some arboviruses can be transmitted through blood transfusions from viremic donors, and Zika can be transmitted sexually. Climate change, demographic shifts, and increased international travel have resulted in a greater incidence of arboviral infections; it is therefore important for healthcare providers to be familiar with the distribution and clinical aspects of the more common arboviruses. Treatment is supportive, as there are no specific antiarboviral therapies. Personal protective measures such as the use of insect repellents and utilization of available vaccines can decrease the risk for acquiring arboviral infections.
Clinical Vignette
A 60-year-old man presented to the emergency department (ED) reporting 2 days of fever, chills, body aches, and a rash on his arms that appeared the day after he returned from a trip to Thailand to visit relatives. A complete blood count (CBC), liver transaminases, and malaria rapid diagnostic test and smear were normal; he was then diagnosed with a nonspecific viral infection. Four days later he presented to clinic because the rash had spread to his trunk and he continued to have fevers until the day before his clinic visit. Laboratory tests were repeated, and his CBC was notable for leukopenia, a 25% increase in his hematocrit, and a drop in platelets to 28,000 (from 218,000 4 days prior); he also had new liver transaminase elevations. His physical exam was notable for diffuse erythematous macules on his trunk and extremities, a positive tourniquet test, and right-upper-quadrant abdominal tenderness. He had been born and raised in Thailand and did not know whether he had had dengue as a child. He was diagnosed with presumptive dengue with warning signs of severe dengue and was hospitalized. During his hospital stay he remained afebrile, his laboratory abnormalities improved, and he was discharged after 2 days. Dengue serology obtained during his initial ED visit and a week later demonstrated IgM seroconversion from 0.09 to 1.61 (reference range <0.90); IgG was positive at 2.48 initially and increased to 8.34 on the follow-up specimen.
COMMENT: This patient was in the critical phase of dengue and had warning signs of severe dengue: his platelets dropped precipitously, he had a hemoconcentration suggestive of plasma leakage, and he developed liver enzyme abnormalities and abdominal tenderness. Because he was originally from Thailand, it was suspected that he had likely had a prior dengue infection (which was subsequently confirmed by the positive IgG) and was therefore at increased risk for severe dengue. An opportunity to perform polymerase chain reaction (PCR) testing for dengue (and Zika and CHIKV) was missed at his ED visit. A rapid rise in IgG during the first week of illness is commonly seen in patients with a secondary dengue infection.
Geographic Distribution and Risk Factors
Arboviruses are endemic to every continent except Antarctica, and they are found in both tropical and temperate zones. The risk for exposure to arboviruses is dependent on the presence of competent vectors in addition to a variety of factors including the vector-host cycle, the ecologic niches of arthropods, temporal influences such as seasonality, and human factors (both biologic and behavioral). Thus the probability of acquiring an arboviral infection within a specific area is more nuanced than might be suggested from maps that highlight only endemic countries. Since arboviral infections provide strain-specific lifelong immunity, population susceptibility (and thus the epidemic potential of the virus) is influenced by the frequency of past outbreaks and the proportion of the population affected during each outbreak.
Aedes aegypti , the “yellow fever mosquito,” is the vector for dengue, Zika, CHIKV, and YF. This anthropophilic mosquito is found throughout the tropics and subtropics, is abundant in urban and peridomestic environments, and can bite multiple people in a short period of time. Outbreaks triggered by Ae. aegypti are more common in the rainy season, during which mosquitoes lay eggs in small collections of standing water; these hatch and rapidly develop into more adult mosquitoes. Ae. aegypti is responsible for most dengue outbreaks and was also the vector implicated in the 2015–2016 Zika pandemic. Aedes mosquitoes are daytime feeders; consequently, the risk for exposure to dengue, Zika, CHIKV, and YF is greatest during daylight hours.
Aedes albopictus (the Asian tiger mosquito) is a secondary vector for dengue, Zika, and CHIKV. This mosquito has adapted to both temperate and tropical climates and has been found as far north as central Europe. The broad geographic distribution of Ae. albopictus was facilitated by the international transport of mosquito eggs in used tires and bamboo. Although Ae. albopictus is less efficient than Ae. aegypti in transmitting dengue and Zika, it was responsible for the 2005–2006 CHIK outbreak in Réunion Island, where over 250,000 residents were infected. A genetic mutation of an Asian CHIKV strain resulted in enhanced transmission by Ae. albopictus, the principal mosquito species in Réunion.
Yellow fever is endemic in parts of sub-Saharan Africa and tropical South America. Sylvatic (jungle) and savannah cycles are maintained by Haemagogus and Sabethes mosquitoes in South America and Aedes mosquitoes in Africa, respectively. Nonhuman primates are the natural reservoirs. When YF is introduced into urban environments (the preferred habitat of Ae. aegypti ) by viremic humans who acquired infection in the jungle or savannah, urban epidemics can occur. Estimates of the risk for YF in travelers spending 2 weeks in endemic areas are 50 per 100,000 for West Africa and 5 per 100,000 for South America. However, these estimates do not take into account the occurrence of YF outbreaks or the use of protective measures such as mosquito repellents. From 2016 to 2018, Brazil experienced the largest number of human YF cases in decades. The outbreak was confined to an epizootic cycle that spilled over to humans and did not become urbanized.
Culex mosquitoes, the vector of Japanese encephalitis virus (JEV) and West Nile virus (WNV), are present in tropical and temperate regions. JEV is endemic throughout Asia, where C. tritaeniorhynchus is the primary vector; water birds and pigs serve as amplifying hosts. JEV is transmitted year round in the tropics but is seasonal in more temperate climates, with peak transmission occurring during the rainy season. The risk for JEV illness in travelers to Asia has been estimated at 1 per 1 million. Long-term travel to rural areas (especially near pig farms or rice paddies) is a risk factor for infection. However, travelers visiting endemic areas for less than 2 weeks during periods of active transmission have contracted JEV. In contrast to Ae. aegypti, Culex mosquitoes feed during the evening and at night.
WNV is endemic in North America, Europe, Africa, and the Middle East. It was first detected in North America in 1999 and has since been found in every state in the continental United States. WNV is maintained by bird reservoirs; humans are dead-end hosts who do not develop sufficient viremia to sustain transmission.
The transmission cycle of EEEV involves Culiseta melanura mosquitoes and avian reservoirs in North America. Most cases of EEEV in the United States are sporadic and occur along the East and Gulf Coasts. Aedes , Culex , and Coquillettidia mosquitoes act as bridge vectors that infect horses and humans, who are dead-end hosts. Transmission of WNV and EEEV is seasonal, with peak transmission occurring in the summer and early fall. A typical arbovirus transmission cycle is shown in Fig. 70.1 .
The flavivirus responsible for tick-borne encephalitis (TBE) is spread by Ixodes ticks in forested regions of Europe and Central Asia (see Chapter 72 ). In North America, Ixodes ticks transmit Powassan virus. Humans are exposed to Powassan virus through outdoor activities in the Great Lakes region of Canada and the United States from late spring until early fall, when the ticks are most active.
Clinical Presentation
A febrile illness with a potential exposure history (e.g., international travel or outdoor activity during the summer or early fall) should alert the clinician to the possibility of an arboviral infection. Online resources—such as the US Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and the Program for Monitoring Emerging Diseases (Pro-MED)—can help healthcare providers keep up to date about ongoing outbreaks. The incubation period of most arboviruses ranges from 2 to 14 days, so arboviral infections can usually be ruled out in patients who present with a fever that started more than 2 weeks after return from an at-risk area. Many arboviral infections—including dengue, Zika, CHIKV, WNV, and EEEV—are nationally notifiable diseases in the United States. Therefore healthcare providers should consult with state or local health departments as soon as an infection is suspected so that diagnostic assistance can be obtained and public health measures can be undertaken to reduce the threat of local transmission.
With the exception of CHIKV, the majority of arboviral infections are asymptomatic. Symptomatic infections present as febrile illnesses with or without rash or fever with arthritogenic, neurologic, or hemorrhagic manifestations. There is significant overlap of the clinical presentations of arboviral infections; shared symptoms include fever, headache, myalgias, and malaise. A maculopapular rash is commonly seen in dengue, Zika, and CHIKV. The features of selected arboviruses are described in the following text and summarized in Table 70.1 . These features, when combined with a detailed epidemiologic and travel history, can help narrow the differential diagnosis in a febrile patient with a potential arboviral infection.
TABLE 70.1
Selected Medically Important Arboviruses
| Clinical Syndrome a | Virus/Taxonomic Family | Geographic Distribution | Transmission b | Incubation Period |
|---|---|---|---|---|
| Febrile illness | Dengue 1-4/Flaviviridae | Tropical and subtropical Central and South America, Africa, Asia, Australia, Oceania | Mosquito–anthroponotic c : urban, peridomestic | 2–7 days |
| Oropouche/Bunyaviridae | Central and South America | Mosquito and midge–vertebrates, anthroponotic: sylvatic, periurban | ||
| Polyarthritis | Sindbis/Togaviridae | Europe, Africa, Asia, Australia | Mosquito–bird: sylvatic | 2–7 days |
| Chikungunya/Togaviridae | Africa, Asia, Europe | Mosquito–anthroponotic: urban, peridomestic | 2–10 days | |
| Ross River/Togaviridae | Australia, Oceania | Mosquito–mammal: sylvatic, suburban | 3–21 days | |
| Neurologic infection | Tick-borne encephalitis/Flaviviridae | Europe, Asia | Tick–mammal, bird: sylvatic Oral: milk products |
3–7 days |
| West Nile/Flaviviridae | Cosmopolitan | Mosquito–bird: sylvatic, periurban | 3–10 days | |
| Japanese encephalitis/Flaviviridae | Asia, Australia, Oceania | Mosquito–vertebrate: rural | 4–14 days | |
| Toscana/Bunyaviridae | Europe, Africa | Sandfly–vertebrate: periurban | 2–7 days | |
| Hemorrhagic fever | Yellow fever/Flaviviridae | Central and South America, Africa | Mosquito–mammal, anthroponotic: rural, urban | 3–6 days |
| Rift Valley fever/Bunyaviridae | Middle East, Africa | Mosquito–vertebrate, anthroponotic: rural, periurban | 3–5 days |
a The diseases listed are displayed by their principal clinical presentation; other manifestations or complications may occur.
b Reports have included nosocomial transmission by needlestick, blood transfusion (dengue, West Nile viruses), or transplantation (West Nile virus); transmission by direct contact with infected animals or meat (tickborne encephalitis, Rift Valley fever viruses); transmission through breastfeeding (yellow fever virus); and vertical transmission to the fetus (dengue, Japanese encephalitis, West Nile, western equine encephalitis viruses, and possibly Colorado tick fever and Ross River viruses).
Dengue
Forty percent of the world’s population is at risk for dengue and an estimated 50 to 100 million infections from this flavivirus occur each year. In 2019, the WHO named dengue as one of the top 10 threats to global health. Asia accounts for approximately 70% of the global burden of infection. Dengue is also the most common cause of febrile illnesses in travelers from Southeast Asia, Latin America, and the Caribbean. Symptomatic infections are notable for the abrupt onset of high fever, headache, retro-orbital pain, and intense myalgias and body aches (accounting for the colloquial name “breakbone fever”). A rash occurs in 50% to 75% of patients, but dermatologic findings can be subtle; they may consist only of flushing and may be difficult to discern in persons with darker skin. Petechiae can be seen and are the basis of the tourniquet test, a marker of capillary fragility (a sphygmomanometer is placed on the arm and inflated to halfway between the systolic and diastolic pressures; after 5 minutes, the number of petechiae in the antecubital fossa are counted greater than 10 petechiae per square inch constitutes a positive test). Minor hemorrhagic manifestations such as epistaxis, bleeding gums, and ecchymoses can also occur. In addition to the acute exanthem, a convalescent rash described as “islands of white on a sea of red” may be seen. Laboratory findings include leukopenia and thrombocytopenia on the CBC, as well as elevated liver transaminases. The febrile phase of dengue lasts 2 to 7 days.
Approximately 2% to 4% of dengue infections result in a severe, life-threatening illness characterized by vascular leakage, hemorrhage, and end-organ impairment. The risk for severe disease is increased in those with a previous dengue infection due to a phenomenon known as antibody-dependent enhancement. There are four dengue serotypes, and infection with one serotype confers lifelong type-specific immunity. Secondary infection with a heterologous serotype results in nonneutralizing antibodies that facilitate virus entry and replication in the target cells, which then triggers the inflammatory cascade responsible for the pathology of severe dengue. Infants are at increased risk for severe dengue due to transplacental transfer of antibodies from mothers with past dengue infections. The mortality rate from untreated severe dengue ranges from 10% to 20% but is less than 1% with appropriate medical care. After recovery from acute dengue, individuals may have fatigue that persists for several weeks.
Zika
The 2015–2016 Zika pandemic mostly affected countries in the Western Hemisphere, but the virus is also present in Africa and Asia. The clinical manifestations of this flavivirus are similar to those of dengue, although the fever tends to be low grade and the illness is generally milder. Nonpurulent conjunctivitis occurs in approximately half of symptomatic Zika infections. Leukopenia may be seen, but thrombocytopenia or elevated transaminases are usually absent.
Zika infection during pregnancy is associated with microcephaly and other neurologic sequelae (called congenital Zika syndrome) in newborns. It is found in 5% to 14% of newborns exposed to the virus in utero, and the risk is greatest when the infection is acquired during the first trimester. Zika is unique among arboviruses in that it can be transmitted sexually; it is transmissible for up to 3 months in semen and 2 months in cervical secretions. Therefore current guidelines recommend that couples of childbearing age delay conception for 3 months after they return from an area with Zika risk (see Chapter 92 ).
GBS is another complication of Zika infection. The incidence of GBS during the 2013–2014 French Polynesia epidemic was estimated to be 2.4 cases per 10,000 Zika infections. Other flaviviruses can also cause GBS, but the incidence appears to be higher with Zika.
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