The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito.[3][8] It infects humans, other primates,[9] and several types of mosquitoes.[3] In cities, it is spread primarily by Aedes aegypti, a type of mosquito found throughout the tropics and subtropics.[3] The virus is an RNA virus of the genus Flavivirus.[10][11] The disease may be difficult to tell apart from other illnesses, especially in the early stages.[3] To confirm a suspected case, blood-sample testing with a polymerase chain reaction is required.[4]
A safe and effective vaccine against yellow fever exists, and some countries require vaccinations for travelers.[3] Other efforts to prevent infection include reducing the population of the transmitting mosquitoes.[3] In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks.[3] Once a person is infected, management is symptomatic; no specific measures are effective against the virus.[3] Death occurs in up to half of those who get severe disease.[3][12]
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In 2013, yellow fever was estimated to have caused 130,000 severe infections and 78,000 deaths in Africa.[3][5] Approximately 90 percent of an estimated 200,000 cases of yellow fever per year occur in Africa.[13] Nearly a billion people live in an area of the world where the disease is common.[3] It is common in tropical areas of the continents of South America and Africa,[14] but not in Asia.[3][15] Since the 1980s, the number of cases of yellow fever has been increasing.[3][16] This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate increasing the habitat for mosquitoes.[3]
The disease originated in Africa and spread to the Americas starting in the 17th century with the European trafficking of enslaved Africans from sub-Saharan Africa.[1][17] Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe.[1] In the 18th and 19th centuries, yellow fever was considered one of the most dangerous infectious diseases; numerous epidemics swept through major cities of the US and in other parts of the world.[1]
Yellow fever begins after an incubation period of three to six days.[19] Most cases cause only mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting.[20] In these cases, the infection lasts only three to six days.[21]
But in 15% of cases, people enter a second, toxic phase of the disease characterized by recurring fever, this time accompanied by jaundice due to liver damage, as well as abdominal pain.[22] Bleeding in the mouth, nose, eyes, and the gastrointestinal tract cause vomit containing blood, hence one of the names in Spanish for yellow fever, vmito negro ("black vomit").[23] There may also be kidney failure, hiccups, and delirium.[24][25]
Yellow fever can lead to death for 20% to 50% of those who develop severe disease. Jaundice, fatigue, heart rhythm problems, seizures and internal bleeding may also appear as complications of yellow fever during recovery time.[8][31]
Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but other mostly Aedes mosquitoes such as the tiger mosquito (Aedes albopictus) can also serve as a vector for this virus.[46] Like other arboviruses, which are transmitted by mosquitoes, yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or another primate.[47] Viruses reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there, they reach the haemocoel (the blood system of mosquitoes) and from there the salivary glands.[48] When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person.[49] Transovarial transmissionial and transstadial transmission of yellow fever virus within A. aegypti, that is, the transmission from a female mosquito to its eggs and then larvae, are indicated.[50] This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease.[51]
Three epidemiologically different infectious cycles occur[16] in which the virus is transmitted from mosquitoes to humans or other primates.[52] In the "urban cycle", only the yellow fever mosquito A. aegypti is involved. It is well adapted to urban areas, and can also transmit other diseases, including Zika fever, dengue fever, and chikungunya.[53] The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except for an outbreak in Bolivia in 1999, this urban cycle no longer exists in South America.[54]
Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors.[55] In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates.[49] In South America, the sylvatic cycle is currently the only way unvaccinated humans can become infected, which explains the low incidence of yellow fever cases on the continent.[46] People who become infected in the jungle can carry the virus to urban areas, where A. aegypti acts as a vector. Because of this sylvatic cycle, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors.[16]
In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles.[56] Different mosquitoes of the genus Aedes are involved. In recent years, this has been the most common form of transmission of yellow fever in Africa.[57]
Serologically, an enzyme-linked immunosorbent assay during the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG titer (compared to an earlier sample) can confirm yellow fever.[62] Together with clinical symptoms, the detection of IgM or a four-fold increase in IgG titer is considered sufficient indication for yellow fever. As these tests can cross-react with other flaviviruses, such as dengue virus, these indirect methods cannot conclusively prove yellow fever infection.[63]
Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Because of the bleeding tendency of yellow fever patients, a biopsy is only advisable post mortem to confirm the cause of death.[64]
In a differential diagnosis, infections with yellow fever must be distinguished from other feverish illnesses such as malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as the cause.[65]
Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic.[46] Institutional measures for prevention of yellow fever include vaccination programmes and measures to control mosquitoes. Programmes for distribution of mosquito nets for use in homes produce reductions in cases of both malaria and yellow fever. Use of EPA-registered insect repellent is recommended when outdoors. Exposure for even a short time is enough for a potential mosquito bite. Long-sleeved clothing, long pants, and socks are useful for prevention. The application of larvicides to water-storage containers can help eliminate potential mosquito breeding sites. EPA-registered insecticide spray decreases the transmission of yellow fever.[66]
Vaccination is recommended for those traveling to affected areas, because non-native people tend to develop more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people,[72] and had been reported to last for at least 10 years. The World Health Organization (WHO) now states that a single dose of vaccine is sufficient to confer lifelong immunity against yellow fever disease.[73] The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler.[72] The WHO recommends routine vaccination for people living in affected areas between the 9th and 12th month after birth.[4]
Up to one in four people experience fever, aches, and local soreness and redness at the site of injection.[74] In rare cases (less than one in 200,000 to 300,000),[72] the vaccination can cause yellow fever vaccine-associated viscerotropic disease, which is fatal in 60% of cases. It is probably due to the genetic morphology of the immune system. Another possible side effect is an infection of the nervous system, which occurs in one in 200,000 to 300,000 cases, causing yellow fever vaccine-associated neurotropic disease, which can lead to meningoencephalitis and is fatal in less than 5%[72] of cases.[4][26]
The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa.[75] No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa.[76] According to the WHO, mass vaccination cannot eliminate yellow fever because of the vast number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected.[77]
Demand for yellow fever vaccine has continued to increase due to the growing number of countries implementing yellow fever vaccination as part of their routine immunization programmes.[78] Recent upsurges in yellow fever outbreaks in Angola (2015), the Democratic Republic of Congo (2016), Uganda (2016), and more recently in Nigeria and Brazil in 2017 have further increased demand, while straining global vaccine supply.[78][79] Therefore, to vaccinate susceptible populations in preventive mass immunization campaigns during outbreaks, fractional dosing of the vaccine is being considered as a dose-sparing strategy to maximize limited vaccine supplies.[78] Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations.[78][80] The first practical use of fractional dose yellow fever vaccination was in response to a large yellow fever outbreak in the Democratic Republic of the Congo in mid-2016.[78] Available evidence shows that fractional dose yellow fever vaccination induces a level of immune response similar to that of the standard full dose.[81] ff782bc1db
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