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Yellow fever

Yellow jack, Yellow plage, Bronz john

Overview

Yellow fever, (known historically as yellow jack, yellow plague, or bronze john), is an acute viral disease. In most cases, symptoms include fever, chills, loss of appetite, nausea, muscle pains particularly in the back, and headaches. Symptoms typically improve within five days. In some people within a day of improving, the fever comes back, abdominal pain occurs, and liver damage begins causing yellow skin. If this occurs, the risk of bleeding and kidney problems is also increased.

The disease is caused by the yellow fever virus and is spread by the bite of the female mosquito. It infects only humans, other primates, and several species of mosquitoes. In cities, it is spread primarily by mosquitoes of the Aedes aegypti species. The virus is an RNA virus of the genus Flavivirus. The disease may be difficult to tell apart from other illnesses, especially in the early stages. To confirm a suspected case, blood sample testing with polymerase chain reaction is required.

Symptoms - Yellow fever

Yellow fever begins after an incubation period of three to six days. Most cases only cause a mild infection with fever, headache, chills, back pain, fatigue, loss of appetite, muscle pain, nausea, and vomiting. In these cases, the infection lasts only three to four days.

In 15 percent of cases, however, people 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. Bleeding in the mouth, the eyes, and the gastrointestinal tract will cause vomit containing blood, hence the Spanish name for yellow fever, vomito negro ("black vomit"). The toxic phase is fatal in about 20% of cases, making the overall fatality rate for the disease 3%. In severe epidemics, the mortality may exceed 50%.

Surviving the infection provides lifelong immunity,and normally there is no permanent organ damage.

Causes - Yellow fever

Yellow fever is caused by the yellow fever virus, a 40- to 50-nm-wide enveloped RNA virus, the type species and namesake of the family Flaviviridae. It was the first illness shown to be transmissible by filtered human serum and transmitted by mosquitoes, by Walter Reed around 1900. The positive-sense, single-stranded RNA is around 11,000 nucleotides long and has a single open reading frame encoding a polyprotein. 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. Minimal yellow fever virus (YFV) 3’UTR region is required for stalling of the host 5'-3' exonuclease XRN1. 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. The sfRNAs are a result of incomplete degradation of the viral genome by the exonuclease and are important for viral pathogenicity. Yellow fever belongs to the group of hemorrhagic fevers.

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. The capsid enters 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, causing a rearrangement of the 90 homodimers to 60 homotrimers.

After entering the host cell, the viral genome is replicated in the rough endoplasmic reticulum (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

Yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but other mosquitoes such as the tiger mosquito (Aedes albopictus) can also serve as a vector for this virus. Like other Arboviruses which are transmitted by mosquitoes, the yellow fever virus is taken up by a female mosquito when it ingests the blood of an infected human or other primate. 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. When the mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the bloodstream of the bitten person. Transovarial and transstadial transmission of the yellow fever virus within A. aegypti, that is, the transmission from a female mosquito to her eggs and then larvae, are indicated. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease.

Three epidemiologically different infectious cycles occur, in which the virus is transmitted from mosquitoes to humans or other primates. 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 dengue fever 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.

Besides the urban cycle, both in Africa and South America, a sylvatic cycle (forest cycle or jungle cycle) is present, where Aedes africanus (in Africa) or mosquitoes of the genus Haemagogus and Sabethes (in South America) serve as vectors. In the jungle, the mosquitoes infect mainly non-human primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can infect each other, which explains the low incidence of yellow fever cases on the continent. 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, the yellow fever cannot be eradicated.

In Africa, a third infectious cycle known as "savannah cycle" or intermediate cycle, occurs between the jungle and urban cycles. 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.

Prevention - Yellow fever

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 mosquitoes. Programmes for distribution of mosquito nets for use in homes are providing reductions in cases of both malaria and yellow fever.

Vaccination

Vaccination is recommended for those traveling to affected areas, because non-native people tend to suffer more severe illness when infected. Protection begins by the 10th day after vaccine administration in 95% of people, and lasts for at least 10 years. About 81% of people are still immune after 30 years. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler. The World Health Organization (WHO) recommends routine vaccinations for people living in affected areas between the ninth and 12th month after birth. Up to one in four people experience fever, aches, and local soreness and redness at the site of injection.

In rare cases (less than one in 200,000 to 300,000 ), 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% of cases.

In 2009, the largest mass vaccination against yellow fever began in West Africa, specifically Benin, Liberia, and Sierra Leone. When it is completed in 2015, more than 12 million people will have been vaccinated against the disease. According to the WHO, the 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. The WHO plans to continue the vaccination campaign in another five African countries — the Central African Republic, Ghana, Guinea, Ivory Coast, and Nigeria — and stated that about 160 million people in the continent could be at risk unless the organization acquires additional funding to support widespread vaccinations.

In 2013, the WHO stated, "a single dose of vaccination is sufficient to confer life-long immunity against yellow fever disease.

Compulsory vaccination

Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitoes with the capability to transmit yellow fever and susceptible monkeys are present), although the disease does not yet occur there. To prevent introduction of the virus, some countries 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 that require yellow fever vaccination is published by the WHO. If the vaccination cannot be conducted for some reasons, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated.

Vector control

Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitoes with the capability to transmit yellow fever and susceptible monkeys are present), although the disease does not yet occur there. To prevent introduction of the virus, some countries 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 that require yellow fever vaccination is published by the WHO. If the vaccination cannot be conducted for some reasons, dispensation may be possible. In this case, an exemption certificate issued by a WHO-approved vaccination center is required. Although 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries, less than 50% of their population is vaccinated.


Diagnosis - Yellow fever

Yellow fever is a clinical diagnosis, which often relies on the whereabouts of the diseased person during the incubation time. Mild courses of the disease can only be confirmed virologically. Since mild courses of yellow fever can also contribute significantly to regional outbreaks, every suspected case of yellow fever (involving symptoms of fever, pain, nausea and vomiting six to 10 days after leaving the affected area) is treated seriously.

If yellow fever is suspected, the virus cannot be confirmed until six to 10 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 cannot conclusively 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 must be distinguished from other feverish illnesses like malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as cause.

Prognosis - Yellow fever

Not supplied.

Treatment - Yellow fever

As for other flavivirus infections, no cure is known for yellow fever. Hospitalization is advisable and intensive care may be necessary because of 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, do not have a positive effect in patients. A symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen in the United States). Acetylsalicylic acid (aspirin) should not be given because of its anticoagulant effect, which can be devastating in the case of internal bleeding that can occur with yellow fever.

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