Saffron Scourge

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 increased.

The disease is caused by the yellow fever virus and is spread by the bite of an infected mosquito. It infects humans, other primates, and several types 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 mosquitoes. In areas where yellow fever is common, early diagnosis of cases and immunization of large parts of the population are important to prevent outbreaks. Once a person is infected, management is symptomatic; no specific measures are effective against the virus. Death occurs in up to half of those who get severe disease.

In 2013, yellow fever resulted in about 127,050 severe infections and 45,000 deaths worldwide, with nearly 90 percent 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 the continents 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 increasing the habitat for mosquitoes.

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. 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 considered one of the most dangerous infectious diseases; numerous epidemics swept through major cities of the US and in other parts of the world.

In 1927, yellow fever virus was the first human virus to be isolated.

Signs and symptoms

Yellow fever begins after an incubation period of three to six days. Most cases cause only 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 six days.

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. Bleeding in the mouth, nose, the eyes, and the gastrointestinal tract cause vomit containing blood, hence the Spanish name for yellow fever, ("black vomit"). There may also be kidney failure, hiccups, and delirium.

Among those who develop jaundice, the fatality rate is 20 to 50%, while the overall fatality rate is about 3 to 7.5%. Severe cases may have a mortality greater than 50%.

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

Complication

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.

Cause

Yellow fever is caused by yellow fever virus, an enveloped RNA virus 40–50 in width, 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 American doctor Walter Reed around 1900. The positive-sense, single-stranded RNA is around 10,862 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, Schwann cells, and dendritic cells. They attach to the cell surfaces 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 homo trimers.

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, so is denoted as precursor M (prM) 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 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, ''yellow fever virus'' is taken up by a female mosquito when it ingests the blood of an infected human or another 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 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. 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 Zika fever, dengue fever, and chikungunya. 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.

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. In the jungle, the mosquitoes infect mainly nonhuman primates; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can become infected, 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, yellow fever cannot be eradicated except by eradicating the mosquitoes that serve as vectors.

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.

Concern exists about yellow fever spreading to southeast Asia, where its vector ''A. aegypti'' already occurs.

Pathogenesis

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.

Fatality may occur when cytokine storm, shock, and multiple organ failure follow.

Diagnosis

Yellow fever is most frequently a clinical diagnosis, based on symptomatology and travel history. Mild cases of the disease can only be confirmed virologically. 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.

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. Another direct approach is the isolation of the virus and its growth in cell culture using blood plasma; this can take 1–4 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 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.

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 such as malaria. Other viral hemorrhagic fevers, such as Ebola virus, Lassa virus, Marburg virus, and Junin virus, must be excluded as the cause.

Prevention

Personal prevention of yellow fever includes vaccination and avoidance of mosquito bites in areas where yellow fever is endemic. 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.
* Use insect repellent when outdoors such as those containing DEET, picaridin, ethyl butylacetylaminopropionate (IR3535), or oil of lemon eucalyptus on exposed skin.
* Mosquitoes may bite through thin clothing, so spraying clothes with repellent containing permethrin or another EPA-registered repellent gives extra protection. Clothing treated with permethrin is commercially available. Mosquito repellents containing permethrin are not approved for application directly to the skin.
* The peak biting times for many mosquito species are dusk to dawn. However, ''A. aegypti'', one of the mosquitoes that transmits yellow fever virus, feeds during the daytime. Staying in accommodations with screened or air-conditioned rooms, particularly during peak biting times, also reduces the risk of mosquito bites.

Vaccination

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, 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. The attenuated live vaccine stem 17D was developed in 1937 by Max Theiler. The WHO recommends routine vaccination for people living in affected areas between the 9th 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.

The Yellow Fever Initiative, launched by the WHO in 2006, vaccinated more than 105 million people in 14 countries in West Africa. No outbreaks were reported during 2015. The campaign was supported by the GAVI alliance and governmental organizations in Europe and Africa. 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.

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. 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. 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. Fractional dose yellow fever vaccination refers to administration of a reduced volume of vaccine dose, which has been reconstituted as per manufacturer recommendations. 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.

In March 2017, the WHO launched a vaccination campaign in Brazil with 3.5 million doses from an emergency stockpile. In March 2017 the WHO recommended vaccination for travellers to certain parts of Brazil. In March 2018, Brazil shifted its policy and announced it planned to vaccinate all 77.5 million currently unvaccinated citizens by April 2019.

Compulsory vaccination

Some countries in Asia are considered to be potentially in danger of yellow fever epidemics, as both mosquitoes with the capability to transmit yellow fever as well as susceptible monkeys are present. The disease does not yet occur in Asia. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors who have passed through yellow fever areas. Vaccination has to be proved by a vaccination certificate, which is valid 10 days after the vaccination and lasts for 10 years. Although the WHO on 17 May 2013 advised that subsequent booster vaccinations are unnecessary, an older (than 10 years) certificate may not be acceptable at all border posts in all affected countries. A list of the countries that require yellow fever vaccination is published by the WHO. If the vaccination cannot be given for some reason, 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

Control of the yellow fever mosquito ''A. aegypti'' is of major importance, especially because the same mosquito can also transmit dengue fever and chikungunya disease. ''A. aegypti'' breeds preferentially in water, for example, in installations by inhabitants of areas with precarious drinking water supplies, or in domestic refuse, especially tires, cans, and plastic bottles. These conditions are common in urban areas in developing countries.

Two main strategies are employed to reduce ''A. aegypti'' populations. One approach is to kill the developing larvae. Measures are taken to reduce the water accumulations in which the larvae develop. Larvicides are used, along with larvae-eating fish and copepods, which reduce the number of larvae. For many years, copepods of the genus ''Mesocyclops'' have been used in Vietnam for preventing dengue fever. This eradicated the mosquito vector in several areas. Similar efforts may prove effective against yellow fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it is safe for humans and effective in small doses.

The second strategy is to reduce populations of the adult yellow fever mosquito. Lethal ovitraps can reduce ''Aedes'' populations, using lesser amounts of pesticide because it targets the pest directly. Curtains and lids of water tanks can be sprayed with insecticides, but application inside houses is not recommended by the WHO. Insecticide-treated mosquito nets are effective, just as they are against the ''Anopheles'' mosquito that carries malaria.

Treatment

As with 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. Certain acute treatment methods lack efficacy: passive immunization after the emergence of symptoms is probably without effect; ribavirin and other antiviral drugs, as well as treatment with interferons, are ineffective in yellow fever patients. Symptomatic treatment includes rehydration and pain relief with drugs such as paracetamol (acetaminophen). Acetylsalicylic acid (aspirin). However, aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided because of an increased risk of gastrointestinal bleeding due to their anticoagulant effects.

Epidemiology

Yellow fever is common in tropical and subtropical areas of South America and Africa. Worldwide, about 600 million people live in endemic areas. The WHO estimates 200,000 cases of yellow fever worldwide each year. About 15% of people infected with yellow fever progress to a severe form of the illness, and up to half of those will die, as there is no cure for yellow fever.

Africa

An estimated 90% of yellow fever infections occur on the African continent. In 2016, a large outbreak originated in Angola and spread to neighboring countries before being contained by a massive vaccination campaign. In March and April 2016, 11 imported cases of the Angola genotype in unvaccinated Chinese nationals were reported in China, the first appearance of the disease in Asia in recorded history.

Phylogenetic analysis has identified seven genotypes of yellow fever viruses, and they are assumed to be differently adapted to humans and to the vector ''A. aegypti''. Five genotypes (Angola, Central/East Africa, East Africa, West Africa I, and West Africa II) occur only in Africa. West Africa genotype I is found in Nigeria and the surrounding region. West Africa genotype I appears to be especially infectious, as it is often associated with major outbreaks. The three genotypes found outside of Nigeria and Angola occur in areas where outbreaks are rare. Two outbreaks, in Kenya (1992–1993) and Sudan (2003 and 2005), involved the East African genotype, which had remained undetected in the previous 40 years.

South America

In South America, two genotypes have been identified (South American genotypes I and II). Based on phylogenetic analysis these two genotypes appear to have originated in West Africa and were first introduced into Brazil. The date of introduction of the predecessor African genotype which gave rise to the South American genotypes appears to be 1822 (95% confidence interval 1701 to 1911). The historical record shows an outbreak of yellow fever occurred in Recife, Brazil, between 1685 and 1690. The disease seems to have disappeared, with the next outbreak occurring in 1849. It was likely introduced with the trafficking of slaves through the slave trade from Africa. Genotype I has been divided into five subclades, A through E.

In late 2016, a large outbreak began in Minas Gerais state of Brazil that was characterized as a sylvan or jungle epizootic. It began as an outbreak in brown howler monkeys, which serve as a sentinel species for yellow fever, that then spread to men working in the jungle. No cases had been transmitted between humans by the ''A. aegypti'' mosquito, which can sustain urban outbreaks that can spread rapidly. In April 2017, the sylvan outbreak continued moving toward the Brazilian coast, where most people were unvaccinated. By the end of May the outbreak appeared to be declining after more than 3,000 suspected cases, 758 confirmed and 264 deaths confirmed to be yellow fever. The Health Ministry launched a vaccination campaign and was concerned about spread during the Carnival season in February and March. The CDC issued a Level 2 alert (practice enhanced precautions.)

A Bayesian analysis of genotypes I and II has shown that genotype I accounts for virtually all the current infections in Brazil, Colombia, Venezuela, and Trinidad and Tobago, while genotype II accounted for all cases in Peru. Genotype I originated in the northern Brazilian region around 1908 (95% highest posterior density interval PD 1870–1936). Genotype II originated in Peru in 1920 (95% HPD: 1867–1958). The estimated rate of mutation for both genotypes was about 5 × 10⁻⁴ substitutions/site/year, similar to that of other RNA viruses.

Asia

The main vector (''A. aegypti'') also occurs in tropical and subtropical regions of Asia, the Pacific, and Australia, but yellow fever has never occurred there, until jet travel introduced 11 cases from the 2016 Angola and DR Congo yellow fever outbreak in Africa. Proposed explanations include:
* That the strains of the mosquito in the east are less able to transmit ''yellow fever virus''.
* That immunity is present in the populations because of other diseases caused by related viruses (for example, dengue).
* That the disease was never introduced because the shipping trade was insufficient.
But none is considered satisfactory. Another proposal is the absence of a slave trade to Asia on the scale of that to the Americas. The trans-Atlantic slave trade probably introduced yellow fever into the Western Hemisphere from Africa.

History

Early history

The evolutionary origins of yellow fever most likely lie in Africa, with transmission of the disease from nonhuman primates to humans. The virus is thought to have originated in East or Central Africa and spread from there to West Africa. As it was endemic in Africa, local populations had developed some immunity to it. When an outbreak of yellow fever would occur in an African community where colonists resided, most Europeans died, while the indigenous Africans usually developed nonlethal symptoms resembling influenza. This phenomenon, in which certain populations develop immunity to yellow fever due to prolonged exposure in their childhood, is known as acquired immunity. The virus, as well as the vector ''A. aegypti,'' were probably transferred to North and South America with the trafficking of slaves from Africa, part of the Columbian exchange following European exploration and colonization. However, some researchers have argued that yellow fever might have existed in the Americas during the pre-Columbian period as mosquitoes of the genus ''Haemagogus'', which is indigenous to the Americas, have been known to carry the disease.

The first definitive outbreak of yellow fever in the New World was in 1647 on the island of Barbados. An outbreak was recorded by Spanish colonists in 1648 in the Yucatán Peninsula, where the indigenous Mayan people called the illness ''xekik'' ("blood vomit"). In 1685, Brazil suffered its first epidemic in Recife. The first mention of the disease by the name "yellow fever" occurred in 1744.
* (John Mitchell) (1805
(Mitchell's account of the Yellow Fever in Virginia in 1741–2)
, ''The Philadelphia Medical Museum,'' 1 (1) : 1–20.
* (John Mitchell) (1814
"Account of the Yellow fever which prevailed in Virginia in the years 1737, 1741, and 1742, in a letter to the late Cadwallader Colden, Esq. of New York, from the late John Mitchell, M.D.F.R.S. of Virginia,"
''American Medical and Philosophical Register'', 4 : 181–215. The term "yellow fever" appears on p. 186. On p. 188, Mitchell mentions "… the distemper was what is generally called yellow fever in America". However, on pages 191–192, he states "… I shall consider the cause of the yellowness which is so remarkable in this distemper, as to have given it the name of the Yellow Fever."

However, Dr. Mitchell misdiagnosed the disease that he observed and treated, and the disease was probably Weil's disease or hepatitis. McNeill argues that the environmental and ecological disruption caused by the introduction of sugar plantations created the conditions for mosquito and viral reproduction, and subsequent outbreaks of yellow fever. Deforestation reduced populations of insectivorous birds and other creatures that fed on mosquitoes and their eggs.

In Colonial times and during the Napoleonic Wars, the West Indies were known as a particularly dangerous posting for soldiers due to yellow fever being endemic in the area. The mortality rate in British garrisons in Jamaica was seven times that of garrisons in Canada, mostly because of yellow fever and other tropical diseases. Both English and French forces posted there were seriously affected by the "yellow jack". Wanting to regain control of the lucrative sugar trade in Saint-Domingue (Hispaniola), and with an eye on regaining France's New World empire, Napoleon sent an army under the command of his brother-in-law General Charles Leclerc to Saint-Domingue to seize control after a slave revolt. The historian J. R. McNeill asserts that yellow fever accounted for about 35,000 to 45,000 casualties of these forces during the fighting. Only one third of the French troops survived for withdrawal and return to France. Napoleon gave up on the island and his plans for North America, selling the Louisiana Purchase to the US in 1803. In 1804, Haiti proclaimed its independence as the second republic in the Western Hemisphere. Considerable debate exists over whether the number of deaths caused by disease in the Haitian Revolution was exaggerated.

Although yellow fever is most prevalent in tropical-like climates, the northern United States were not exempted from the fever. The first outbreak in English-speaking North America occurred in New York City in 1668. English colonists in Philadelphia and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia, Baltimore, and New York City in the 18th and 19th centuries. The disease traveled along steamboat routes from New Orleans, causing some 100,000–150,000 deaths in total. The yellow fever epidemic of 1793 in Philadelphia, which was then the capital of the United States, resulted in the deaths of several thousand people, more than 9% of the population. One of these deaths was James Hutchinson, a physician helping to treat the population of the city. The national government fled the city to Trenton, New Jersey, including President George Washington.

The southern city of New Orleans