What Is Yellow Fever?

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Yellow Fever

Yellow fever is a serious, potentially deadly flu-like disease spread by mosquitoes. It’s characterized by a high fever and jaundice. Jaundice is yellowing of the skin and eyes, which is why this disease is called yellow fever. This disease is most prevalent in certain parts of Africa and South America. It isn’t curable, but you can prevent it with the yellow fever vaccine.

Yellow fever is a viral disease of typically short duration. 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 about 15% of 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.

Yellow fever virus is found in tropical and subtropical areas in South America and Africa. The virus is transmitted to people by the bite of an infected mosquito. Yellow fever is a very rare cause of illness in U.S. travelers. Illness ranges in severity from a self-limited febrile illness to severe liver disease with bleeding.

Yellow fever disease is diagnosed based on symptoms, physical findings, laboratory testing, and travel history, including the possibility of exposure to infected mosquitoes. There is no specific treatment for yellow fever; care is based on symptoms. Steps to prevent yellow fever virus infection include using insect repellent, wearing protective clothing, and getting vaccinated.

Yellow Fever

Yellow Fever

The disease is caused by the yellow fever virus and is spread by the bite of an infected female mosquito. It infects only humans, other primates, and several species of mosquitoes. In cities, it is spread primarily by Aedes aegypti, a type of mosquito found throughout the tropics and subtropics. 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.

A safe and effective vaccine against yellow fever exists and some countries require vaccinations for travelers. Other efforts to prevent infection include reducing the population of the transmitting mosquito. In areas where yellow fever is common and vaccination is uncommon, early diagnosis of cases and immunization of large parts of the population is important to prevent outbreaks. Once infected, management is symptomatic with no specific measures effective against the virus. Death occurs in up to half of those who get severe disease.

In 2013, yellow fever resulted in about 127,000 severe infections and 45,000 deaths, with nearly 90% of these occurring in Africa. Nearly a billion people live in an area of the world where the disease is common. It is common in tropical areas of South America and Africa, but not in Asia. Since the 1980s, the number of cases of yellow fever has been increasing. This is believed to be due to fewer people being immune, more people living in cities, people moving frequently, and changing climate.

The disease originated in Africa, from where it spread to South America through the slave trade in the 17th century. Since the 17th century, several major outbreaks of the disease have occurred in the Americas, Africa, and Europe. In the 18th and 19th centuries, yellow fever was seen as one of the most dangerous infectious diseases. In 1927 yellow fever virus became the first human virus to be isolated.

Signs and symptoms

Once contracted, the yellow fever virus incubates in the body for 3 to 6 days. Many people do not experience symptoms, but when these do occur, the most common are fever, muscle pain with prominent backache, headache, loss of appetite, and nausea or vomiting. In most cases, symptoms disappear after 3 to 4 days.

What Is Yellow Fever?

What Is Yellow Fever?

Once contracted, the yellow fever virus incubates in the body for 3 to 6 days, followed by infection that can occur in one or two phases. The first, “acute”, phase usually causes fever, muscle pain with prominent backache, headache, shivers, loss of appetite, and nausea or vomiting. Most patients improve and their symptoms disappear after 3 to 4 days.

However, 15% of patients enter a second, more toxic phase within 24 hours of the initial remission. High fever returns and several body systems are affected. The patient rapidly develops jaundice and complains of abdominal pain with vomiting. Bleeding can occur from the mouth, nose, eyes or stomach. Once this happens, blood appears in the vomit and faeces. Kidney function deteriorates. Half of the patients who enter the toxic phase die within 10 to 14 days, the rest recover without significant organ damage.

A small percentage of patients, however, enter a second, more toxic phase within 24 hours of recovering from initial symptoms. High fever returns and several body systems are affected, usually the liver and the kidneys. In this phase people are likely to develop jaundice (yellowing of the skin and eyes, hence the name ‘yellow fever’), dark urine and abdominal pain with vomiting. Bleeding can occur from the mouth, nose, eyes or stomach. Half of the patients who enter the toxic phase die within 7 – 10 days.

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% 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 cause vomit containing blood, hence the Spanish name for yellow fever, vómito negro (“black vomit”). There may also be kidney failure, hiccups, and delirium.

Yellow fever is difficult to diagnose, especially during the early stages. More severe disease can be confused with severe malaria, leptospirosis, viral hepatitis (especially fulminant forms), other haemorrhagic fevers, infection with other flaviviruses (e.g. dengue haemorrhagic fever), and poisoning.

Blood tests (RT-PCR) can sometimes detect the virus in the early stages of the disease. In later stages of the disease, testing to identify antibodies is needed (ELISA and PRNT).

The toxic phase is fatal in about 20 to 50% of cases, making the overall fatality rate for the disease about 3.0 to 7.5%. However, the fatality rate of those with the toxic phase of the disease may exceed 50%.

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

Recognizing the Symptoms of Yellow Fever

Yellow fever develops quickly, with symptoms occurring three to six days after exposure. The initial symptoms of the infection are similar to those of the influenza virus. They include:

  • headaches
  • muscle aches
  • joint aches
  • chills
  • fever

Cause

Yellow fever is caused by a virus (Flavivirus) which is transmitted to humans by the bites of infected aedes and haemogogus mosquitoes. The mosquitoes either breed around houses (domestic), in forests or jungles (wild), or in both habitats (semi-domestic).

Occasionally, infected travellers from areas where yellow fever occurs have exported cases to countries that are free of yellow fever, but the disease can only spread easily if that country has mosquito species able to transmit it, specific climatic conditions and the animal reservoir needed to maintain it.

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.

The Flavivirus causes yellow fever, and it’s transmitted when an infected mosquito bites you. Mosquitoes become infected with the virus when they bite an infected human or monkey. The disease cannot be spread from one person to another.

Mosquitoes breed in tropical rainforests, humid, and semi-humid environments, as well as around bodies of still water. Increased contact between humans and infected mosquitoes, particularly in areas where people haven’t been vaccinated for yellow fever, can create small-scale epidemics.

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.

How Is Yellow Fever Diagnosed?

Yellow fever is difficult to diagnose, especially during the early stages. It can be confused with severe malaria, dengue hemorrhagic fever, leptospirosis, viral hepatitis (especially the fulminating forms of hepatitis B and D), other hemorrhagic fevers (Bolivian, Argentine and Venezuelan hemorrhagic fevers as well as other Flaviviridae such as the West Nile and Zika viruses) and other diseases, as well as poisoning.

Blood tests can detect yellow fever antibodies produced in response to the infection. Several other techniques are used to identify the virus in blood specimens or liver tissue collected after death. These tests require highly trained laboratory staff and specialized equipment and materials.

See your doctor right away if you’ve been traveling recently and you experience flu-like symptoms. Your doctor will ask you about the symptoms you’ve been experiencing and if you’ve traveled recently. If your doctor suspects that you have yellow fever, they’ll order a blood test.

Your blood sample will be analyzed for the presence of the virus or for the antibodies meant to fight the virus.

Transmission

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. 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.

The yellow fever virus is an arbovirus of the flavivirus genus and is transmitted by mosquitoes, belonging to the Aedes and Haemogogus species. The different mosquito species live in different habitats – some breed around houses (domestic), others in the jungle (wild), and some in both habitats (semi-domestic). There are 3 types of transmission cycles:

  • Sylvatic (or jungle) yellow fever: In tropical rainforests, monkeys, which are the primary reservoir of yellow fever, are bitten by wild mosquitoes which pass the virus on to other monkeys. Occasionally humans working or travelling in the forest are bitten by infected mosquitoes and develop yellow fever.
  • Intermediate yellow fever: In this type of transmission, semi-domestic mosquitoes (those that breed both in the wild and around households) infect both monkeys and people. Increased contact between people and infected mosquitoes leads to increased transmission and many separate villages in an area can develop outbreaks at the same time. This is the most common type of outbreak in Africa.
  • Urban yellow fever: Large epidemics occur when infected people introduce the virus into heavily populated areas with high mosquito density and where most people have little or no immunity, due to lack of vaccination. In these conditions, infected mosquitoes transmit the virus from person to person.

Treatment

Good and early supportive treatment in hospitals improves survival rates. There is currently no specific anti-viral drug for yellow fever but specific care to treat dehydration, liver and kidney failure, and fever improves outcomes. Associated bacterial infections can be treated with antibiotics.

There is no specific treatment for yellow fever, only supportive care to treat dehydration, respiratory failure, and fever. Associated bacterial infections can be treated with antibiotics. Supportive care may improve outcomes for seriously ill patients, but it is rarely available in poorer areas.

  • No specific treatments have been found to benefit patients with yellow fever. Whenever possible, yellow fever patients should be hospitalized for supportive care and close observation.
  • Treatment is symptomatic. Rest, fluids, and use of pain relievers and medication to reduce fever may relieve symptoms of aching and fever.
  • Care should be taken to avoid certain medications, such as aspirin or other nonsteroidal anti-inflammatory drugs (e.g. ibuprofen, naproxen), which may increase the risk of bleeding.
  • Yellow fever patients should be protected from further mosquito exposure (staying indoors and/or under a mosquito net) for up to 5 days after the onset of fever. This way, yellow fever virus in their bloodstream will be unavailable to uninfected mosquitoes, thus breaking the transmission cycle and reducing risk to the persons around them.

How Is Yellow Fever Treated?

There’s no cure for yellow fever. Treatment involves managing symptoms and assisting your immune system in fighting off the infection by:

  • getting enough fluids, possibly through your veins
  • getting oxygen
  • maintaining a healthy blood pressure
  • getting blood transfusions
  • having dialysis if you experience kidney failure
  • getting treatment for other infections that may develop

Yellow fever can be prevented through vaccination and mosquito control.

The yellow fever vaccine is safe and affordable, and a single dose provides life-long immunity against the disease.

Mosquito control can also help to prevent yellow fever, and is vital in situations where vaccination coverage is low or the vaccine is not immediately available. Mosquito control includes eliminating sites where mosquitoes can breed, and killing adult mosquitoes and larvae by using insecticides in areas with high mosquito density. Community involvement through activities such as cleaning household drains and covering water containers where mosquitoes can breed is a very important and effective way to control mosquitoes.

Prevention

How Is Yellow Fever Prevented?

Vaccination is the only way to prevent yellow fever. The vaccine for yellow fever is given as a single shot. It contains a live, weakened version of the virus that helps your body create immunity. The Centers for Disease Control (CDC) suggests that anyone who is 9 months through 59 years old and traveling to or living in an area where the risk of yellow fever is present should be vaccinated.

If you’re planning to travel internationally, check the CDC website to see if you need to get any new vaccinations.

Groups of people who shouldn’t get the vaccine include:

  • people who have severe allergies to eggs, chicken proteins, or gelatin
  • infants younger than 6 months old
  • people who have HIV, AIDS, or other conditions that compromise the immune system

If you’re older than 60 and you’re considering traveling to an area that may have the virus, you should discuss vaccination with your doctor.

If you’re traveling with an infant who is 6 to 8 months old or you’re a nursing mother, you should either postpone travel to these areas if possible or talk to your doctor about vaccination.

The vaccine is considered extremely safe. A single dose provides protection for at least 10 years. The side effects may include:

  • a mild headache
  • muscle pain
  • fatigue
  • a low-grade fever

Other methods of prevention include using insect repellant, wearing clothing to reduce the amount of mosquito bites, and staying inside during peak times when insects bite.

  1. Vaccination

Vaccination is the most important means of preventing yellow fever. In high-risk areas where vaccination coverage is low, prompt recognition and control of outbreaks using mass immunization is critical for preventing epidemics. It is important to vaccinate most (80 % or more) of the population at risk to prevent transmission in a region with a yellow fever outbreak.

Several vaccination strategies are used to protect against outbreaks: routine infant immunization; mass vaccination campaigns designed to increase coverage in countries at risk; and vaccination of travellers going to yellow fever endemic areas.

The yellow fever vaccine is safe and affordable and a single dose provides life-long protection against yellow fever disease. A booster dose of yellow fever vaccine is not needed.

There have been rare reports of serious side-effects from the yellow fever vaccine. The rates for these severe ‘adverse events following immunization’ (AEFI), when the vaccine provokes an attack on the liver, the kidneys or on the nervous system, leading to hospitalization, are between 0.4 and 0.8 per 100 000 people vaccinated.

The risk is higher for people over 60 years of age and anyone with severe immunodeficiency due to symptomatic HIV/AIDS or other causes, or who have a thymus disorder. People over 60 years of age should be given the vaccine after a careful risk-benefit assessment.

People who are usually excluded from vaccination include:

  • infants aged less than 9 months, except during an epidemic when infants aged 6-9 months, in areas where the risk of infection is high, should also receive the vaccine;
  • pregnant women – except during a yellow fever outbreak when the risk of infection is high;
  • people with severe allergies to egg protein; and
  • people with severe immunodeficiency due to symptomatic HIV/AIDS or other causes, or who have a thymus disorder.

In accordance with the International Health Regulations (IHR), countries have the right to require travellers to provide a certificate of yellow fever vaccination. If there are medical grounds for not getting vaccinated, this must be certified by the appropriate authorities. The IHR are a legally binding framework to stop the spread of infectious diseases and other health threats. Requiring the certificate of vaccination from travellers is at the discretion of each State Party, and it is not currently required by all countries.

  1. Mosquito control

The risk of yellow fever transmission in urban areas can be reduced by eliminating potential mosquito breeding sites by applying larvicides to water storage containers and other places where standing water collects. Insecticide spraying to kill adult mosquitoes during urban epidemics can help reduce the number of mosquitoes, thus reducing potential sources of yellow fever transmission.

Historically, mosquito control campaigns successfully eliminated Aedes aegypti, the urban yellow fever vector, from most of Central and South America. However, Aedes aegypti has re-colonized urban areas in the region, raising a renewed risk of urban yellow fever. Mosquito control programmes targeting wild mosquitoes in forested areas are not practical for preventing jungle (or sylvatic) yellow fever transmission.

  1. Epidemic preparedness and response

Prompt detection of yellow fever and rapid response through emergency vaccination campaigns are essential for controlling outbreaks. However, underreporting is a concern – the true number of cases is estimated to be 10 to 250 times what is now being reported.

WHO recommends that every at-risk country have at least one national laboratory where basic yellow fever blood tests can be performed. One laboratory-confirmed case of yellow fever in an unvaccinated population is considered an outbreak. A confirmed case in any context must be fully investigated, particularly in an area where most of the population has been vaccinated. Investigation teams must assess and respond to the outbreak with both emergency measures and longer-term immunization plans.

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