Yellow fever is a viral disease of typically short duration.[3] In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains—particularly in the back—and headaches.[3] Symptoms typically improve within five days.[3] In about 15% of people, within a day of improving the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin.[3][6] If this occurs, the risk of bleeding and kidney problems is increased.[3][7]
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]
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]
In 1927, yellow fever virus became the first human virus to be isolated.[10][18]
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, vómito negro ("black vomit").[23] There may also be kidney failure, hiccups, and delirium.[24][25]
Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%.[26] Severe cases may have a mortality rate greater than 50%.[27]
Surviving the infection provides lifelong immunity,[28] and normally results in no permanent organ damage.[29][30]
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 is caused by yellow fever virus (YFV), an enveloped RNA virus 40–50 nm in width, the type species and namesake of the family Flaviviridae.[10] It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by American doctor Walter Reed around 1900.[32] The positive-sense, single-stranded RNA is around 10,862 nucleotides long and has a single open reading frame encoding a polyprotein.[33] Host proteases cut this polyprotein into three structural (C, prM, E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome.[34] Minimal YFV 3′UTR region is required for stalling of the host 5′-3′ exonuclease XRN1.[35] The UTR contains PKS3 pseudoknot structure, which serves as a molecular signal to stall the exonuclease and is the only viral requirement for subgenomic flavivirus RNA (sfRNA) production.[36] The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity.[37] Yellow fever belongs to the group of hemorrhagic fevers.[38]
The viruses infect, amongst others, monocytes, macrophages, Schwann cells, and dendritic cells. They attach to the cell surfaces via specific receptors and are taken up by an endosomal vesicle.[39] Inside the endosome, the decreased pH induces the fusion of the endosomal membrane with the virus envelope.[40] The capsid enters the cytosol, decays, and releases the genome.[41] Receptor binding, as well as membrane fusion, are catalyzed by the protein E, which changes its conformation at low pH, causing a rearrangement of the 90 homodimers to 60 homotrimers.[34][42]
After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets.[43] At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form, so is denoted as precursor M (prM) and forms a complex with protein E.[44] The immature particles are processed in the Golgi apparatus by the host protein furin, which cleaves prM to M.[45] This releases E from the complex, which can now take its place in the mature, infectious virion.[34]
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]
Concern exists about yellow fever spreading to southeast Asia, where its vector A. aegypti already occurs.[58]
After transmission from a mosquito, the viruses replicate in the lymph nodes and infect dendritic cells in particular. From there, they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells), which leads to eosinophilic degradation of these cells and to the release of cytokines. Apoptotic masses known as Councilman bodies appear in the cytoplasm of hepatocytes.[59][60]
Fatality may occur when cytokine storm, shock, and multiple organ failure follow.[26]
Yellow fever is most frequently a clinical diagnosis, based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically.[47] Since mild cases of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea, and vomiting 6–10 days after leaving the affected area) is treated seriously.[47]
If yellow fever is suspected, the virus cannot be confirmed until 6–10 days following the illness. A direct confirmation can be obtained by reverse transcription polymerase chain reaction, where the genome of the virus is amplified.[4] Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take 1–4 weeks.[61][13]
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