Flaviviruses

Yellow Fever Virus

YFV, the prototype flavivirus, is transmitted to humans primarily by infected Aedes species and Haemagogus species mosquitoes in tropical areas of Africa and South America. ^, YFV has three transmission cycles: jungle (sylvatic), intermediate (savannah), and urban. In the jungle cycle, the virus is transmitted between non-human primates and tree-hole-breeding mosquitoes, and humans can be infected when they enter the jungle during occupational or recreational activities. In Africa, an intermediate cycle exists in which YFV can be transmitted by tree-hole-breeding Aedes spp. to humans living or working in the savannah that borders jungle areas. The urban cycle involves the anthroponotic transmission of the virus between humans and urban mosquitoes, primarily Aedes aegypti . Large urban outbreaks occur when viremic humans infect peridomestic Ae. aegypti mosquitoes, which can then transmit the virus to other humans. Perinatal transmission of YFV also has been reported, and YFV had been detected in breast milk, but no transmission through breastfeeding has been confirmed. ^, Additionally, the live, attenuated vaccine strain of the virus has been transmitted transplacentally, through breastfeeding, and through blood transfusion.

Most YFV infections are asymptomatic. In symptomatic infection, after an incubation period of 2–9 days, yellow fever begins with the acute onset of fever, chills, headache, and myalgia, often accompanied by photophobia, back pain, anorexia, or vomiting. ^, During this phase, patients are viremic. Viremia usually clears about 4 days after illness onset, as fever and other symptoms subside. Most patients remain anicteric and then fully recover. However, about 15% of all infected people develop severe yellow fever. After a brief remission lasting from a few hours up to 2 days, these patients have a recurrence of initial symptoms with progression to jaundice and sometimes hemorrhagic symptoms, including epistaxis, gingival bleeding, hematemesis, hematuria, or melena. ^, Patients can develop dysfunction of multiple organs, including the hepatic, renal, and cardiovascular systems. Viral invasion of the central nervous system is rare, but neurologic manifestations can include delirium, convulsions, and coma. Laboratory abnormalities include elevated aspartate and alanine aminotransferases, proteinuria, thrombocytopenia, leukopenia, and prolonged blood coagulation. Complications include bacterial pneumonia and parotitis. ^, Most persons with mild yellow fever recover without long-term sequelae. For those with severe disease with jaundice or hemorrhagic symptoms, the case-fatality rate ranges from 30% to 60%.

The treatment of yellow fever is supportive and based on symptoms and organ systems involved. Supportive care should include maintenance of nutrition, optimization of fluid and metabolic balance, nasogastric suction to prevent gastric distention and aspiration, treatment of bleeding with fresh frozen plasma, and treatment of secondary infections as necessary. Although multiple drugs have been evaluated or used empirically to treat yellow fever, to date, none has demonstrated specific benefit.

An effective live, attenuated yellow fever vaccine has been available since 1937 and is recommended for persons aged ≥9 months who reside in or travel to endemic areas. For travelers, a single dose of yellow fever vaccine provides long-lasting protection and is adequate for most persons. The vaccine is contraindicated in infants aged <6 months and should only be given to infants aged 6–8 months when the risk for yellow fever outweighs the risk for adverse events in this age group. In children aged ≥9 months, serious adverse events are rare but have been described, including cases of neurotropic and viscerotropic disease. Limited data suggest that vaccination during pregnancy does not increase the risk for congenital malformations or other adverse pregnancy outcomes. However, three infants developed encephalitis after being exposed to the yellow fever vaccine virus through breastfeeding. ^{, ,} Thus, the yellow fever vaccine should not be given to pregnant or breastfeeding women unless travel cannot be avoided and they have a clear risk for acquiring yellow fever.

Dengue Viruses

There are four dengue virus (DENV) types, designated as DENV-1, DENV-2, DENV-3, and DENV-4; all are transmitted to humans through the bite of Aedes spp. mosquitoes, most frequently Ae. aegypti and Aedes albopictus. Infection with any of the DENVs produces long-term immunity specific to the infecting DENV. Cross-protective heterotypic immunity usually is short-term. Dengue occurs throughout the tropics worldwide. In the US, DENV outbreaks have occurred in Texas, Hawaii, and Florida.

The incubation period of dengue usually is from 3 to 10 days. About 75% of infections with DENVs are asymptomatic or cause a relatively mild febrile illness. World Health Organization (WHO) guidelines divide the clinical course of dengue into three phases: febrile, critical, and convalescent. The acute febrile phase typically begins abruptly with high-grade fever. Other symptoms include headache, retro-orbital pain, myalgia, anorexia, nausea, vomiting, arthralgia, facial flushing, maculopapular rash, and conjunctival injection. Many patients with dengue have a positive tourniquet test (appearance of ≥10 petechiae in a 2.5-cm square patch of skin after inflation of a blood pressure cuff), and about 25% have mild hemorrhagic manifestations such as epistaxis or gum bleeding. Common laboratory abnormalities include thrombocytopenia, leukopenia, hyponatremia, and elevated aspartate and alanine aminotransferases. Differentiating acute phase dengue from other acute febrile illnesses is difficult, and the discriminating manifestations may vary with age. In a report from one endemic area, the presence of retro-orbital pain was predictive of laboratory-confirmed dengue in patients of all ages, whereas rash was predictive of dengue only in patients aged ≥9 years. Leukopenia was predictive of dengue in patients aged >20 years, whereas thrombocytopenia was predictive for those aged >10 years.

After the febrile phase, most patients improve, and their illness resolves. However, some patients progress to the critical phase of dengue that commences in the 24–48 hours after defervescence and typically occurs 2–7 days after illness onset. Warning signs for the development of severe dengue include abdominal pain, persistent vomiting, extravascular fluid accumulation, severe mucosal bleeding, lethargy, restlessness, hepatomegaly, and increasing hematocrit with decreasing platelet count. A chest radiograph or abdominal ultrasound may reveal pleural effusion or ascites. Plasma leakage can progress to shock, often associated with narrowed pulse pressure and disseminated intravascular coagulation. In rare cases, severe hemorrhage or critical organ dysfunction occurs without evidence of plasma leakage or shock.

The critical phase of dengue usually resolves within 48 hours, and patients enter the convalescent phase. This phase is characterized by reabsorption of extravascular fluid over 2–3 days, typically with diuresis. Some patients develop a confluent erythematous rash with “isles of white,” pruritus, bradycardia, or electrocardiographic abnormalities during this phase. Pulmonary edema or congestive heart failure can occur, particularly with excessive fluid administration.

WHO classifies dengue into three categories for the purpose of clinical triage: dengue, dengue with warning signs, and severe dengue. Dengue can be acutely incapacitating but is self-limited and usually resolves within 7 days without sequelae. Severe dengue occurs in about 5% of clinically apparent cases in endemic areas and is characterized by one or more of the following: severe plasma leakage, leading to shock or fluid accumulation with respiratory distress; severe hemorrhage; or severe organ dysfunction. If not appropriately treated, severe dengue has a case-fatality rate of up to 5%. ^, Secondary infection with a different DENV has been associated with an increased risk for developing severe dengue. Rarer manifestations of dengue include hepatitis, myocarditis, and encephalitis.

Detailed Pan American Health Organization guidelines are available for treatment and management of severe dengue with carefully monitored intravenous fluid administration. The case-fatality rate of severe dengue can be reduced to ≤0.5% with early detection and appropriate fluid management. ^, Patients with dengue who do not have warning signs or other indications for hospitalization can be managed as outpatients with rest, vigilant monitoring of clinical parameters, attention to hydration, and pain management with acetaminophen. Aspirin and other nonsteroidal anti-inflammatory drugs should be avoided because of an increased risk for bleeding. The Centers for Disease Control and Prevention (CDC) has an online clinical case management course and other resources for healthcare providers ( https://www.cdc.gov/dengue/healthcare-providers/index.html ).

Congenital DENV infection has been described, but accurate estimates of the risk for maternal-fetal transmission are not available. Some studies have suggested that maternal dengue infection during pregnancy might increase the risk for preterm birth and low birth weight. Neonates with congenital dengue have had clinical manifestations ranging from fever with thrombocytopenia to pleural effusions, severe hemorrhage, and shock.

One dengue vaccine (CYD-TDV; Dengvaxia) has been licensed for use in several countries. CYD-TDV is a live attenuated, recombinant tetravalent vaccine that uses an attenuated yellow fever 17D virus strain as the replication backbone. In the US, the Food and Drug Administration approved CYD-TDV in May 2019 for the prevention of dengue in individuals aged 9–16 years with laboratory-confirmed previous dengue infection and living in endemic areas; in June 2021, the Advisory Committee on Immunization Practices (ACIP) recommended use of the vaccine in this population. The vaccine is not recommended for travelers. Several other dengue vaccine candidates are in clinical trials.

Japanese Encephalitis Virus

JEV is the leading vaccine-preventable cause of encephalitis in Asia. Japanese encephalitis (JE) occurs throughout most of Asia and parts of the Western Pacific. ^, JEV is maintained in an enzootic cycle between mosquitoes and amplifying vertebrate hosts, primarily pigs and wading birds. ^, The virus is transmitted to humans through the bites of infected mosquitoes. Humans usually do not develop a level or duration of viremia sufficient to infect mosquitoes and, therefore, are dead-end hosts. ^, Culex species mosquitoes, especially Culex tritaeniorhynchus, are the principal JEV vectors. There are rare reports of other modes of JEV transmission, including transplacental transmission, through blood transfusion, and laboratory-associated infections.

The risk for JE is increased in rural areas, particularly where residences are proximal to rice fields where mosquitoes typically breed and where pigs are raised close to human dwellings. In temperate areas of Asia, transmission is seasonal, and human disease usually peaks in summer and fall. ^{, ,} In the subtropics and tropics, seasonal transmission varies with monsoon rains and irrigation practices and may be extended or even occur year-round. Most JE cases occur among children, but in areas of recent viral introduction or where population immunity has waned, adults also develop the disease. ^, For most travelers to Asia, the risk for JE is very low but varies on the basis of destination, duration, season, activities, and accommodations. During the 46 years from 1973 through 2019, 87 JE cases among travelers or expatriates from nonendemic countries were published in the literature or reported to the CDC. ^{, ,}

Most human JEV infections are asymptomatic; <1% of infected people develop neurologic disease. ^, Acute encephalitis is the most commonly identified clinical syndrome, but aseptic meningitis and undifferentiated febrile illness also can occur. ^{, ,} Among patients who develop clinical symptoms, the illness usually begins with acute onset of fever, headache, and vomiting after an incubation period of 5–15 days. Mental status changes, focal neurologic deficits, generalized weakness, parkinsonism, and other movement disorders often develop over the next few days, and seizures are common, especially among children. Acute flaccid paralysis, with clinical and pathologic features similar to poliomyelitis, also has been associated with JEV infection. Laboratory findings can include moderate leukocytosis, mild anemia, and hyponatremia. ^, Cerebrospinal fluid (CSF) typically shows a mild to moderate pleocytosis with a lymphocytic predominance, slightly elevated protein, and normal glucose concentration. The case-fatality rate is approximately 20%–30%. Among survivors, 30%–50% have significant neurologic, cognitive, or psychiatric sequelae. There is no specific treatment. Supportive care includes maintenance of adequate cerebral perfusion and management of increased intracerebral pressure, aspiration, seizures, hypoglycemia, hyponatremia, and secondary infections.

One JE vaccine, the inactivated Vero cell culture−derived vaccine Ixiaro (Valneva Austria GmbH), is available in the US. Ixiaro is licensed for use in persons aged ≥2 months. The primary series is 2 intramuscular doses administered 28 days apart. For adults aged 18‒65 years, the second dose can be given at an interval as short as 7 days. For children aged 2 months through 2 years, each dose is 0.25 mL; for adults and children aged ≥3 years, each dose is 0.5 mL. JE vaccine is recommended for persons moving to a JE-endemic country to take up residence, longer-term (e.g., ≥1 month) travelers to JE-endemic areas, and frequent travelers to JE-endemic areas. JE vaccine should be considered for shorter-term (e.g., <1 month) travelers whose itinerary or activities might increase their risk for exposure to JEV. JE vaccine is not recommended for travelers with very low-risk itineraries, such as shorter-term travel limited to urban areas or travel that occurs outside of a well-defined JEV transmission season. Other inactivated and live, attenuated JE vaccines are available in Asia and Australia but are not licensed for use in the US.

West Nile Virus

WNV is transmitted primarily through the bite of several Culex spp. mosquitoes. WNV is found in many parts of Africa, Europe, and North America and in some areas of Latin America, Asia, and Australia. After the first detection of WNV in the Western Hemisphere in New York City in 1999, the virus spread over the entire continental US, with the most intense transmission occurring in the central and western Great Plains states.

Mosquitoes that acquire WNV from birds incidentally infect humans. In immunocompetent people, viremia usually lasts <7 days, and viral concentrations in blood are too low to effectively infect mosquitoes. However, WNV can be transmitted through the transfusion of infected blood and organ transplantation. Screening of blood donations for WNV began in 2003 and has substantially reduced the risk for transmission through transfusion, but rare instances of breakthrough transmission can occur. ^, Guidance on testing to reduce the risk of WNV transmission from living donors of human cells, tissues, and cellular and tissue-based products is available. Occupationally acquired WNV infection has raised the possibility of aerosol transmission. ^,

Transplacental transmission of WNV and possible transmission through breastfeeding have been described but appear to occur infrequently. Most women known to have been infected with WNV during pregnancy have delivered infants without evidence of infection or clinical abnormalities. In the best-documented case of congenital WNV infection, the mother developed neuroinvasive WNV disease during the 27th week of gestation, and the infant was born with cystic destruction of cerebral tissue and chorioretinitis. One infant who apparently acquired WNV infection through breastfeeding remained healthy.

Most WNV infections are asymptomatic. After an incubation period of 2–14 days, about 20%–30% of infected people develop a systemic febrile illness (i.e., West Nile fever). Less than 1% of infected people develop neuroinvasive disease (e.g., meningitis, encephalitis, or acute flaccid paralysis). The risk for neuroinvasive disease is highest in elderly people, solid-organ transplant recipients, and individuals with chronic renal failure, cancer, alcohol abuse, diabetes, or hypertension. From 2009 to 2018, a total of 12,835 WNV neuroinvasive disease cases were reported in the US. Of these, 424 (3%) occurred in children and adolescents aged ≤19 years, for an average annual incidence of 0.52 neuroinvasive disease cases per 1 million children and adolescents. Overall, 237 (56%) of the pediatric cases were classified as meningitis, 166 (39%) as encephalitis, 12 (3%) as acute flaccid paralysis, and 9 (2%) as an unspecified neurologic presentation. For up-to-date WNV surveillance data, see https://www.cdc.gov/westnile/index.html

Patients with WNV non-neuroinvasive disease typically have an abrupt onset of fever, headache, myalgia, and weakness, variably accompanied by abdominal pain, nausea, vomiting, diarrhea, or a maculopapular rash. ^, The acute phase of the illness usually resolves within several days, but fatigue, malaise, and weakness can linger for weeks. Patients with neuroinvasive disease can present with neck stiffness, headache, mental status changes, movement disorders such as tremor or parkinsonism, seizures, or acute flaccid paralysis with or without meningitis or encephalitis. CSF reveals neutrophilic pleocytosis early in the infection, evolving over several days to lymphocytosis. ^, Isolated limb paralysis can occur without fever or apparent viral prodrome. ^, Flaccid paralysis caused by WNV infection is similar clinically and pathologically to poliomyelitis caused by poliovirus, with damage of anterior horn cells. ^, Progression can occur to respiratory muscle paralysis requiring mechanical ventilation. Guillain-Barré syndrome can follow WNV infection and can be distinguished from anterior horn cell damage by CSF findings of elevated protein with few white cells and electrophysiologic findings indicating damage to peripheral myelin. Chorioretinitis, cardiac dysrhythmias, myocarditis, rhabdomyolysis, optic neuritis, uveitis, orchitis, pancreatitis, and hepatitis have been reported. ^{, ,} The mortality rate after WNV neuroinvasive disease in adults is about 10%; the case-fatality rate for neuroinvasive disease in children in the US is <1%. ^,

Clinical management of WNV disease is supportive. No antiviral or adjunctive therapies are approved or recommended for treatment. ^, There are numerous case reports and case series regarding the use of various products; however, the studies often had small sample sizes, and the results from some of the clinical trials have not been published. Because polyclonal immune globulin and interferon α-n3 are available, some physicians have chosen to use them to treat transplant recipients and other severely immunocompromised patients, but there is no proven benefit. ^, No vaccine is licensed for humans. Despite the development of several vaccine candidates, phase 3 clinical trials have not been initiated because of the uncertain market potential and variations in incidence by year and location, which create logistical difficulties in conducting efficacy trials. ^,