Yellow fever is a disease caused by infection with the yellow fever virus. The virus is a 40 to 50 nm enveloped RNA virus with positive sense of the family, Flaviviridae.

The virus is transmitted by the bite of mosquitos (the yellow fever mosquito, Aedes aegypti, and other species) and is found in tropical and subtropical areas in South America and Africa, but not in Asia. The only known hosts of the virus are primates and several species of mosquito. The origin of the disease is most likely to be Africa, from where it was introduced to South America through the slave trade in the 16th century. Since the 17th century, several major epidemics of the disease have been recorded in the Americas, Africa and Europe. In the 19th century, yellow fever was deemed one of the most dangerous infectious diseases.

The disease presents itself in most cases with fever, nausea and pain and it disappears after several days. In some patients, a toxic phase follows, in which liver damage with jaundice (giving the name of the disease) can occur and lead to death. Because of the increased bleeding tendency (bleeding diathesis), yellow fever belongs to the group of hemorrhagic fevers. The WHO estimates that yellow fever causes 200,000 illnesses and 30,000 deaths every year in unvaccinated populations; around 90 % of the infections occur in Africa.
A safe and effective vaccine against yellow fever has existed since the middle of the 20th century and some countries require vaccinations for travelers. Since no therapy is known, vaccination programs are, along with measures to reduce the population of the transmitting mosquito, of great importance in affected areas. Since the 1980s, the number of cases of yellow fever have been increasing, making it a reemerging disease.

Signs and symptoms

Yellow fever begins suddenly after an incubation period of three to six days. Most cases only cause a mild infection with fever, headache, chills, back pain, loss of appetite, nausea and vomiting. In these cases the infection lasts only three to four days. 15% of cases enter a second, toxic phase of the disease with recurring fever, this time accompanied by jaundice due to liver damage, as well as abdominal pain. Bleedings in the mouth, the eyes and in the gastrointestinal tract can cause vomitus containing blood (giving the name "vómito negro"). The toxic phase is fatal in approximately 20% of cases.
Surviving the infection causes life-long immunity and normally there are no remaining organ damages.

Cause

Yellow fever is caused by the yellow fever virus, a 40 to 50 nm wide enveloped RNA virus belonging to the family Flaviviridae. The positive sense single-stranded RNA is approximately 11.000 nucleotides long and has a single open reading frame encoding a polyprotein. Host proteases cut this polyprotein into 3 structural (C, prM, E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome.
The viruses infect amongst others monocytes, macrophages and dendritic cells. They attach to the cell surface via specific receptors and are taken up by an endosomal vesicle. Inside the endosome, the decreased pH induces the fusion of the endosomal membrane with the virus envelope. Thus, the capsid reaches the cytosol, decays and releases the genome. Receptor binding as well as membrane fusion are catalyzed by the protein E, which changes its conformation at low pH, which causes a rearrangement of the 90 homodimers to 60 homotrimers.
After entering the host cell, the viral genome is replicated in the rough ER and in the so-called vesicle packets. 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 and is therefore denoted as prM (precursor M) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin, which cleaves prM to M. This releases E from the complex which can now take its place in the mature, infectious virion.

Transmission

thumb|Aedes aegypti feeding

Adults of the yellow fever mosquito Aedes aegypti. The male on the left, females on the right. Only the female mosquito bites and can transmit the disease

The yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but other mosquitos can also serve as a vector for the virus. Like other Arboviruses which are transmitted via mosquitos, the yellow fever virus is taken up by a female mosquito which sucks the blood of an infected person. 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 mosquitos) and from there the salivary glands. When the mosquito sucks blood the next time, it injects its saliva into the wound, and thus the virus reaches the blood of the bitten person. There are also indications for vertical infection of the yellow fever virus within A. aegypti, i.e. the transmission from a female mosquito to her eggs and then larvae. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease.

There are three epidemiologically different infectious cycles, in which the virus is transmitted from mosquitos to humans or other primates. In the urban cycle, only the yellow fever mosquito Aedes aegypti is involved, which is well adapted to urban centres and can also transmit other diseases including Dengue and Chikungunya. The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except in an outbreak in 1999 in Bolivia, this urban cycle no longer exists in South America and is only present in Africa.

Besides the urban cycle there is, both in Africa and South America, a sylvatic cycle (Forest cycle or Jungle cycle), where Aedes africanus (in Africa) or mosquitos of the genus Haemagoggus and Sabethes (in South America) serve as a vector. In the jungle, mainly non-human primates get infected; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can infect themselves, which explains the low incidence of yellow fever cases on this continent. People who become infected in the jungle can carry the virus to urban centres, where Ae. aegypti acts as a vector. It is due to this sylvatic cycle that yellow fever cannot be eradicated.
In Africa there is a third infectious cycle, also known as savannah cycle or intermediate cycle, which occurs between the jungle and urban cycle. Different mosquitos of the genus Aedes are involved. In recent years this is the most common form of yellow fever seen in Africa.

Pathogenesis

After transmission of the virus 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. Necrotic masses (Councilman bodies) appear in the cytoplasm of hepatocytes.
When the disease takes a deadly course, a cardiovascular shock and multi organ failure with strongly increased cytokine levels (cytokine storm) follow.

Diagnosis

Yellow fever is a clinical diagnosis, which often relies on the whereabouts of the diseased person during the incubation time. Milde courses of the disease can only be confirmed virologically. Since also milde courses of yellow fever can significantly contribute to regional outbreaks, every suspected yellow fever has to be treated seriously (six to ten days after leaving the affected area symptoms of fever, pain, nausea and vomiting).

If yellow fever is suspected, the virus can be confirmed until six to ten days after the illness. A direct confirmation can be obtained by Reverse transcription polymerase chain reaction where the genome of the virus is amplified. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take one to four weeks.

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. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is considered sufficient indication for yellow fever. Since these tests can cross-react with other Flaviviruses, like Dengue virus, these indirect methods can never prove yellow fever infection.
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.

In a differential diagnosis, infections with yellow fever have to be distinguished from other feverish illnesses like malaria. Other viral hemorrhagic fever, such as Ebola virus, Lassa virus, Marburg virus or Junin virus have to be excluded as cause.

Prevention

Personal prevention of yellow fever includes vaccination as well as avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures of controlling mosquitos.

Vaccination

Injection of protective vaccination into the deltoid muscle

thumb|The cover of a certificate that confirms that the holder has been vaccinated against yellow fever

For journeys into affected areas, vaccination is highly recommended since mostly non-native people are affected by severe cases of yellow fever. The protective effect is established after 10 days after vaccination in 95% of the vaccinated people and lasts for at least 10 years (even 30 years later, 81 % of patients retained the immunity).
The attenuated live vaccine (stem 17D) was developed in 1937 by Max Theiler from a diseased patient in Ghana and is produced in chicken eggs. WHO recommends routine vaccinations for people living in endemic areas between the 9th and 12th month after birth..

Quite often (in about 20 % of all cases) mild, flu-like symptoms may develop.
In rare cases (less than one in 200,000 to 300,000), the vaccination can cause YEL-AVD (yellow fever vaccine-associated viscerotropic disease), which is fatal in 60% of all cases. It is probably due to a genetic defect in the immune system. But in some vaccination campaigns, a 20 fold higher incidence rate has been reported. Age is an important risk factor; in children the complication rate is less than one case per 10 million vaccinations.
Another possible side effect is an infection of the nervous system that occurs in one in 200,000 to 300,000 of all cases, causing YEL-AND (yellow fever vaccine-associated neurotropic disease), which can cause meningoencephalitis and is less than 5% of all cases fatal.

Compulsory vaccination

Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitos with the capability to transmit yellow fever and susceptible monkeys are present), even though the disease does not yet occur there. To prevent introduction of the virus, some counties demand previous vaccination of foreign visitors, if they have passed through yellow fever areas. Vaccination has to be proven in a vaccination certificate which is valid 10 days after the vaccination and lasts for 10 years. A list of the countries which require yellow fever vaccination is published by the WHO. If the vaccination cannot be conducted for some reasons, dispensation is possible. In this case an exemption certificate issued by an WHO approved vaccination center is required.

Even though 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries fewer than 50% of their population is vaccinated.

Vector control

thumb|left|Information campagne for prevention of Dengue and yellow fever in Paraguay
Besides vaccination, control of the yellow fever mosquito Aedes aegypti is of major importance, especially because the same mosquito can also transmit Dengue and Chikungunya disease. Ae. aegypti breeds preferentially in water, for example in installations by inhabitants of areas with precarious drinking water supply, or in domestic waste; especially tires, cans and plastic bottles. Especially in proximity to urban centres of developing countries these conditions are very common and make a perfect habitat for Ae. aegypti. Two strategies are employed to fight the mosquito:

One approach is to kill the developing larva. Measures are taken to reduce water build-ups (the habitats of the larva), and larvicides are used as well as larva-eating fish and copepods, which reduce the number of larva and thus indirectly the number of disease-transmitting mosquitos. For many years, copepods of the genus Mesocyclops have been used in Vietnam for fighting Dengue fever (yellow fever does not occur in Asia), with the effect that in the affected areas no cases of Dengue fever occurred since 2001. Similar mechanisms are probably also effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide mainly, because it is safe for humans and effective even in small doses.
Besides larva, also the adult yellow fever mosquitos are targeted. Curtains and lids of water tanks are sprayed with insecticides. Spraying insecticides inside houses is another measure, although not recommended by the WHO. Similar to the malaria carrier, the Anopheles mosquito, insecticide treated mosquito nets are used successfully against A. aegypti.

Treatment

For yellow fever there is, like for all diseases caused by Flaviviruses, no causative cure. Hospitalization is advisable and intensive care may be necessary due to rapid deterioration in some cases. Different methods for acute treatment of the disease have been shown to not be very successful; passive immunisation after emergence of symptoms is probably without effect. Ribavirin and other antiviral drugs as well as treatment with interferons does not have a positive effect in patients.
A symptomatic treatment includes rehydration and pain relief with drugs like paracetamol. Acetlysalicylic acid (for example Aspirin) should not be given due to its haemodiluting effect, which can be devastating in the case of inner bleeding that can occur with yellow fever.

Epidemiology

Endemic range of yellow fever in South America (2009)

Endemic range of yellow fever in Africa (2009)

Yellow fever is endemic in tropical and subtropical areas of South America and Africa. Even though the main vector Aedes aegypti also occurs in Asia, in the pacific and the middle east, yellow fever does not occur in these areas; the reason for this is unknown. Worldwide there are about 600 million people living in endemic areas and the official estimations of the WHO amount to 200,000 cases of disease and 30,000 deaths a year; the number of officially reported cases is far lower. An estimated 90 % of the infections occur on the African continent.
Phylogenetic analysis identified seven genotypes of yellow fever viruses, and it is assumed that they are differently adapted to humans and to the vector A. aegypti. Five genotypes occur solely in Africa, and is assumed that the West Africa-genotype I is especially virulent or infectious, because this type is often associated with major outbreaks of yellow fever. In South America two genotypes have been identified.

History

thumb|150px|Carlos Finlaythumb|150px|Walter Reed
The evolutionary origins of yellow fever most likely lie in Africa.
It is thought, that the virus originated in East or Central Africa and spread from there to West Africa. The virus as well as the vector A. aegypti were probably brought to South America by ship after 1492. The first probable outbreak of the disease was in 1648 in Yucatan, where the illness was termed xekik (black vomit). At least 25 major outbreaks followed, such as in Philadelphia 1793, where several thousand people died and the American administration as well as George Washington had to flee the city. Major outbreaks also occurred in Europe, e.g. in 1821 in Barcelona with several thousand victims. 1878, about 20,000 people died in an epidemic in the Mississippi River Valley and the last major outbreak in the US occurred in 1905 in New Orleans.
Carlos Finlay, a Cuban doctor and scientist, first proposed in 1881 that yellow fever may be transmitted by mosquitoes rather than direct human contact. Since the losses in the invasion of Cuba in the 1890s due to yellow fever were 13fold higher than the losses due to military operations, further experiments conducted by a team under Walter Reed successfully proved the ″Mosquito Hypothesis″. Yellow fever was thus the first virus shown to be transmitted by mosquitos. The physician William Gorgas then applied these insights and eradicated yellow fever from Havanna and fought yellow fever during the construction of the Panama Canal – after a French effort to build the canal had failed due, among other reasons, to the high incidence of yellow fever and malaria.

In 1927, the yellow fever virus was isolated in West Africa, which lead to the development of two vaccines in the 1930s. The vaccine D17 was developed by the South African microbiologist Max Theiler at the Rockefeller Institute. He used chicken eggs to extract the vaccine and won the Nobel Prize for this achievement in 1951. A French team developed the vaccine FNV (french neurotropic vaccine), which was extracted from mouse brain tissue – since it was associated with a higher incidence of encephalitis, it was not recommended any more after 1961. 17D on the other hand is still in use and over 400 million doses have been distributed. Since little has been invested in the development of new vaccines, the 60 year old technology cannot adopt fast enough to a yellow fever epidemic. Newer vaccines based on vero cells are in development and should replace 17D at some point.
Using vector control and strict vaccination programs, the urban cycle of yellow fever has been eridicated from South America and since 1943 – apart from a urban outbreak in Santa Cruz de la Sierra (Bolivia) – there has been no yellow fever transmission by A. aegypti reported. Since the 1980s, the number of yellow fever cases have been increasing again and A. aegypti has returned to the urban centres of South America; partly because the vector control program was abandoned. Even though, no new urban cycle has yet established itself, it is feared that this might happen at any point. An outbreak in Paraguay in 2008 was first thought to be urban in nature, but this turned out to not be the case.
In Africa on the other hand, vaccination programs were mostly used to eradicate the virus. This was never accomplished since the sylviatic cycle could not be eradicated. After the measures to fight yellow fever were abandoned and few countries established regular vaccination programs, the illness could spread again.

Current research

In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective early treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in target organs (liver and spleen), prevented hepatocellular steatosis, and normalised alanine aminotransferase (a liver damage marker) levels. The results of this study suggest that ribavirin may be effective in the early treatment of yellow fever, and that its mechanism of action in reducing liver pathology in yellow fever virus infection may be similar to that observed with ribavirin in the treatment of hepatitis C, a virus related to yellow fever. Because ribavirin had failed to improve survival in a virulent primate (rhesus) model of yellow fever infection, it had been previously discounted as a possible therapy.
In the past, yellow fever has been researched by several countries as a potential biological weapon."", James Martin Center for Nonproliferation Studies, Middlebury College, April 9, 2002, accessed November 14, 2008.