Yellow fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Yellow fever is an acute viral disease.^[1] It is an important cause of hemorrhagic illness in many African and South American countries despite existence of an effective vaccine. The yellow refers to the jaundice symptoms that affect some patients.^[2] Yellow fever has been a source of several devastating epidemics. French soldiers were attacked by yellow fever during the 1802 Haitian Revolution; more than half of the army perished due to the disease.^[3] Outbreaks followed by thousands of deaths occurred periodically in other Western Hemisphere locations until research, which included human volunteers (some of whom died), led to an understanding of the method of transmission to humans (primarily by mosquitos) and development of a vaccine and other preventative efforts in the early 20th century. Despite the costly and sacrificial breakthrough research by Cuban physician Carlos Finlay, American physician Walter Reed, and many others over 100 years ago, unvaccinated populations in many developing nations in Africa and Central and South America continue to be at risk.^[4] As of 2001, the World Health Organization (WHO) estimates that yellow fever causes 200,000 illnesses and 30,000 deaths every year in unvaccinated populations.^[5]

Yellow fever has had an important role in the history of Africa, the Americas, Europe, and the Caribbean. Scientists believe that yellow fever evolved in Africa around 3,000 years ago. ^[6] In 1937 Max Theiler working at the Rockefeller Foundation developed a vaccine for yellow fever that gives a ten-year or more immunity from the disease and effectively protects people traveling to affected areas, while at the same time being a means to control the disease.

Yellow fever is caused by a single-stranded RNA virus that belongs to the genus Flavivirus. Vectorborne transmission occurs via the bite of an infected mosquito, primarily Aedes or Haemagogusspp. Nonhuman and human primates are the main reservoirs of the virus, with anthroponotic (human-to-vector-to-human) transmission occurring. Humans infected with YFV experience the highest levels of viremia and can transmit the virus to mosquitoes shortly before onset of fever and for the first 3–5 days of illness. Given the high level of viremia, bloodborne transmission theoretically can occur via transfusion or needlesticks.

Yellow fever virus is caused by an arthropodborne virus of the Flaviviridae family in the genus Flavivirus. Flaviviruses are single stranded ribonucleic acid (RNA) viruses that replicate in the cytoplasm of infected cells. Seven genotypes of yellow fever virus have been identified, two in South America and five in Africa.

Yellow fever must be differentiated from other diseases that cause fever, diarrhea, dehydration and tachycardia, such as ebola, typhoid fever, malaria, Zika virus, and lassa fever.

Yellow fever occurs in sub-Saharan Africa and tropical South America, where it is endemic and intermittently epidemic. Urban yellow fever occurs periodically in Africa and sporadically in the Americas. In Africa, natural immunity accumulates with age, and thus, infants and children are at highest risk for disease. In South America, yellow fever occurs most frequently in unimmunized young men who are exposed to mosquito vectors through their work in forested areas.

A traveler’s risk of acquiring yellow fever is determined by various factors, including immunization status, location of travel, season, duration of exposure, occupational and recreational activities while traveling, and the local rate of virus transmission at the time of travel.

Initial symptoms of yellow fever start 3-6 days after the mosquito bite, these include sudden onset of fever, chills, severe headache, back pain, general body aches, nausea and vomiting, fatigue, and weakness. Most people improve after these initial symptoms. However, roughly 15% of people will have a brief period of hours to a day without symptoms and will then develop a more , severe form of yellow fever disease. Possible complications include coma, disseminated intravascular coagulation (DIC), kidney failure, liver failure and shock. The prognosis is good in the majority of patients, infected persons will be asymptomatic or have mild disease with complete recovery.

Patients infected may have no symptoms; if they develop the disease, they can develop symptoms such as fever, muscle pain (with prominent backache), headache, shivers, loss of appetite, and nausea or vomiting. After three or four days most patients improve and their symptoms disappear. Fifteen percent of patients, however, enter a toxic phase within 24 hours. Fever reappears, the patient rapidly develops jaundice and abdominal pain with vomiting. Bleeding occurs and kidney function deteriorates.

Physical findings include fever, scleral and dermal icterus, hemorrhages (e.g., hematemesis, melena, petechiae, ecchymoses), and epigastric tenderness with or without hepatomegaly.^[7]

Multiple laboratory abnormalities can be observed in patients with yellow fever, including leukopenia or leukocytosis, bleeding dyscrasias, thrombocytopenia, increased bilirubin and transaminases. Laboratory diagnosis of yellow fever is generally accomplished by testing of serum to detect virus-specific IgM and neutralizing antibodies. Sometimes the virus can be found in blood samples taken early in the disease.

There is no antivirals approved for the treatment of for yellow fever, therefore vaccination is important. Treatment is symptomatic and supportive only. Fluid replacement, managing hypotension and transfusion of blood derivates is generally needed only in severe cases. In cases that result in acute renal failure, dialysis may be necessary.

The two methods to prevent yellow fever are vaccination and vector control. Yellow fever vaccine is recommended for persons aged ≥9 months who are traveling to or living in areas at risk for yellow fever virus transmission in South America and Africa. Yellow fever vaccine may be required for entry into certain countries. The best way to prevent mosquitoborne diseases, including yellow fever, is to avoid mosquito bites.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Yellow fever has had an important role in the history of Africa, the Americas, Europe, and the Caribbean. Scientists believe that yellow fever evolved in Africa around 3,000 years ago. ^[1] In 1937 Max Theiler working at the Rockefeller Foundation developed a vaccine for yellow fever that gives a ten-year or more immunity from the disease and effectively protects people traveling to affected areas, while at the same time being a means to control the disease.

Fragile after the fall of Rome, Europe was further weakened by “Yellow Plague” (Yellow Fever). The Byzantine Empire suffered as well.^[2]

• Yellow fever was imported into the Western Hemisphere on slave ships from West Africa.
• In 1648, the first definitive evidence of yellow fever in the Americas was in Mayan manuscripts describing an outbreak of the disease in the Yucatan and Guadeloupe.
• Outbreaks were reported on the eastern coast of the United States, including in New York (1668), Boston (1691), and Charleston (1699).

• In the 1700s the yellow fever spread to Europe.
• In 1730, one of the first epidemics described, 2,200 deaths were reported in Cadiz, Spain. This epidemic was followed by outbreaks in French and British seaports. Over the next century, widespread epidemics were recorded in tropical and subtropical areas of the Americas, including the West Indies, Central America, and the United States.

• British and American colonial troops died by the thousands in Havana between 1762-1763.
• Epidemics struck coastal and island communities throughout the area during the next 140 years.

• In 1793, the largest yellow fever epidemic in American history killed as many as 5,000 people in Philadelphia, Pennsylvania—roughly 10% of the population.^[3]
• At the time, the port city was the largest in the United States, as well as the seat of U.S. government (prior to establishment of the District of Columbia). Philadelphia had recently seen the arrival of political refugees from the Caribbean. The summer that year was especially hot and dry, leaving many stagnant water areas as ideal breeding grounds for mosquitoes. The yellow fever outbreak began in July and continued through November, when cold weather finally eliminated the breeding ground for mosquitoes, although the connection had not yet then been established.
• Thousands of Philadelphians, including prominent government officials like George Washington and Alexander Hamilton fled the national capital.
• Benjamin Rush, the city’s leading physician and a signer of the United States Declaration of Independence, advocated the bloodletting of patients to combat the disease, but the treatment was controversial. Stephen Girard also helped supervise a hospital established at Bush Hill, a mansion just outside Philadelphia. Though many high-ranking people of Philadelphia fled, a few officials stayed. Mayor Matthew Clarkson as well as the mayor’s committee tried to hold the city together as the death toll increased.^[4]
• Matthew Carey published a fast-selling chronicle of the yellow fever crisis, A short account of the Malignant Fever, Lately Prevalent in Philadelphia that went through four editions.
• Although other ethnic groups were included, Carey’s account failed to include the involvement of the city’s African Americans in the community’s response and relief efforts, despite the fact that African American leaders Richard Allen and Absalom Jones had rallied their church community to assist victims.
• Allen and Jones subsequently wrote a pamphlet, Narrative of the Proceedings of the Black People, During the Late Awful Calamity in Philadelphia, which detailed the contributions of the African Americans during the epidemic.^[5]

• Until the mid-1800s, scientists believed yellow fever was spread by direct contact with infected individuals or contaminated objects.
• The first suggestions that the vector might be a mosquito were made by the American physician Josiah Clark Nott in 1848 and by Cuban physician Carlos Finlay in 1881.
• Between 1839 and 1860, annual outbreaks in New Orleans led to more than 26,000 cases of yellow fever.

• Yellow fever caused difficulties for the US Army in Cuba during the Spanish-American War; reportedly more soldiers died of the disease than in battle. The ongoing outbreaks prompted military efforts for further research and the formation of the Reed Yellow Fever Commission led by Walter Reed, an American army surgeon.

• In 1802, an army of forty thousand sent by First Consul Napoleon Bonaparte of France to Haiti to suppress the Haitian Revolution was dwindled out by an epidemic of Yellow Fever (including the expedition’s commander and Bonaparte’s brother-in-law, Charles Leclerc).
• Some historians believe Haiti was to be a staging point for an invasion of the United States through Louisiana (then still under French control).

• A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June of 1855.
• The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of Norfolk and Portsmouth.
• The Howard Association, a benevolent organization, was formed to help coordinate assistance in the form of funds, supplies, and medical professionals and volunteers which poured in from many other areas, particularly the Atlantic and Gulf Coast areas of the United States.

• The Reed Yellow Fever Commission proved that yellow fever infection is transmitted to humans by the Aedes aegypti mosquito, later determined to be the vector of the urban transmission cycle of yellow fever virus.
• Following the demonstration that Ae. aegypti mosquitoes are responsible for transmission of the yellow fever virus to humans, intense sanitation programs began in Panama and Havana, Cuba. These efforts led to the eradication of the disease in these areas.
• Eradication of yellow fever in Panama enabled completion of the Panama Canal in 1906. The previous construction had been hampered severely by yellow fever infection among the workers.
• In 1930s, two yellow fever vaccines were developed, the 17D vaccine and the French neurotropic vaccine.

• Yellow fever vaccine was incorporated into the routine childhood vaccinations of several South American and African countries.
• Although this strategy decreases the number of persons susceptible to the disease over time, a large portion of the at-risk population is not covered in the short term.
• Hundreds of cases of yellow fever from endemic countries in South America and Africa are still reported annually to the World Health Organization (WHO).

• Carlos Finlay, a Cuban doctor and scientist, first proposed proofs in 1881 that yellow fever is transmitted by mosquitoes rather than direct human contact.^[7]
• Dr.Walter Reed, M.D., (1851-1902) was an American Army surgeon who led a team that confirmed Finlay’s theory. This risky but fruitful research work was done with human volunteers, including some of the medical personnel such as Clara Maass and Walter Reed Medal winner surgeon Jesse William Lazear who allowed themselves to be deliberately infected and died of the virus.^[8]
• The acceptance of Finlay’s work was one of the most important and far-reaching effects of the Walter Reed Commission of 1900.^[9]
• Applying methods first suggested by Finlay, the elimination of Yellow Fever from Cuba was completed, as well as the completion of the Panama Canal.
• Lamentably, almost 20 years had passed before Reed’s efforts were recognized while most of the scientific community ignored Finlay’s methods of mosquito control.
• Finlay and Reed’s work was put to the test for the first time in the United States when a yellow fever epidemic struck New Orleans in 1905; according to the PBS American Experience documentary The Great Fever, houses were fumigated, cisterns for drinking water were inspected, and pools of standing water were treated with kerosene.
• The result was that the death toll from the epidemic was much lower than that from previous yellow fever epidemics, and that there has not been a major outbreak of the disease in the United States since.
• Although no cure has yet been discovered, an effective vaccine has been developed, which can prevent and help people recover from the disease.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Yellow fever is caused by a single-stranded RNA virus that belongs to the genus Flavivirus. Vectorborne transmission occurs via the bite of an infected mosquito, primarily Aedes or Haemagogusspp. Nonhuman and human primates are the main reservoirs of the virus, with anthroponotic (human-to-vector-to-human) transmission occurring. Humans infected with YFV experience the highest levels of viremia and can transmit the virus to mosquitoes shortly before onset of fever and for the first 3–5 days of illness. Given the high level of viremia, bloodborne transmission theoretically can occur via transfusion or needlesticks.

• Yellow fever is caused by an arbovirus of the family Flaviviridae, a positive single-stranded RNA virus.
• Human infection begins after deposition of viral particles through the skin in infected arthropod saliva.
• The mosquitos involved are Aedes simpsaloni, A. africanus, and A. aegypti in Africa, the Haemagogus genus in South America, and the Sasbethes genera in France.
• Yellow fever is frequently severe but more moderate cases may occur as the result of previous infection by another flavivirus.
• After infection the virus first replicates locally, followed by transportation to the rest of the body via the lymphatic system.^[1]
• Following systemic lymphatic infection the virus proceeds to establish itself throughout organ systems, including the heart, kidneys, adrenal glands, and the parenchyma of the liver; high viral loads are also present in the blood.
• Necrotic masses (Councilman bodies) appear in the cytoplasm of hepatocytes.^,[2]
• There is a difference between disease outbreaks in rural or forest areas and in towns. Disease outbreaks in towns and non-native people are usually more serious.

• Yellow fever virus is an RNA virus that belongs to the genus Flavivirus.

• It is related to West Nile, St. Louis encephalitis, and Japanese encephalitis viruses.

• Yellow fever virus is transmitted to humans primarily through the bite of infected Aedes or Haemagogus species mosquitoes.

• Mosquitoes acquire the virus by feeding on infected primates (human or non-human) and then can transmit the virus to other primates (human or non-human).

• Humans infected with yellow fever virus are infectious to mosquitoes shortly before the onset of fever and for 3–5 days after onset.

• Yellow fever virus has three transmission cycles: jungle (sylvatic), inter­mediate (savannah), and urban.^[3]

• The jungle (sylvatic) cycle involves transmission of the virus between nonhuman primates (e.g., monkeys) and mosquito species found in the forest canopy.
• The virus is transmitted by mosquitoes from monkeys to humans when humans are visiting or working in the jungle.

• In Africa, an intermediate (savannah) cycle exists that involves transmission of virus from mosquitoes to humans living or working in jungle border areas.
• In this cycle, the virus can be transmitted from monkey to human or from human to human via mosquitoes.

• The urban cycle involves transmission of the virus between humans and urban mosquitoes, primarily Aedes aegypti.
• The virus is usually brought to the urban setting by a viremic human who was infected in the jungle or savannah.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Yellow fever virus is caused by an arthropodborne virus of the Flaviviridae family in the genus Flavivirus. Flaviviruses are single stranded ribonucleic acid (RNA) viruses that replicate in the cytoplasm of infected cells. Seven genotypes of yellow fever virus have been identified, two in South America and five in Africa.

Viruses; ssRNA viruses; ssRNA positive-strand viruses, no DNA stage; Flaviviridae; Flavivirus; Yellow fever virus group ^[1]

• 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 ^[2]
• 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.^[3]
• 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 homodimer]]s 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Yellow fever must be differentiated from other diseases that cause fever, diarrhea, dehydration and tachycardia, such as ebola, typhoid fever, malaria, Zika virus, and lassa fever.

The table below summarizes the findings that differentiate Yellow Fever from other conditions that cause fever and hemorrhage:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Yellow fever occurs in sub-Saharan Africa and tropical South America, where it is endemic and intermittently epidemic. Urban yellow fever occurs periodically in Africa and sporadically in the Americas. In Africa, natural immunity accumulates with age, and thus, infants and children are at highest risk for disease. In South America, yellow fever occurs most frequently in unimmunized young men who are exposed to mosquito vectors through their work in forested areas.

• Yellow fever occurs only in Africa, South and Central America, and the Caribbean.^[3]
• Most outbreaks in South America are to people who work within the tropical rain forests and have direct contact with the organisms within the rainforest.

• The disease can remain locally unknown in humans for long periods of time and then suddenly break out in an epidemic fashion.
• In Central America and Trinidad, such epidemics have been due to a form of the disease (jungle yellow fever) that is kept alive in Red Howler monkey populations and transmitted by Haemagogus mosquito species which live only in the canopy of rain forests.
• The virus is passed to humans when the tall rainforest trees are cut down. Infected woodcutters can then pass on the disease to others via species of Aedes mosquitoes that typically live at low altitudes, thus triggering an epidemic.^[4]

• During interepidemic periods, low-level transmission may not be detected by public health surveillance.
• Such interepidemic conditions may last years or even decades in certain countries or regions.
• This “epidemiologic silence” does not equate to absence of risk and should not lead to travel without the protection provided by vaccination.
• Surveys in rural West Africa during “silent” periods have estimated an annual incidence of yellow fever of 1.1-2.4 cases per 1,000 persons and 0.2-0.5 deaths per 1,000 persons.
• Yellow fever viral transmission in rural West Africa is seasonal, with elevated risk during the 2-4 months that the rainy season ends and the dry season begins (usually July-October); therefore, the annual incidence reflects incidence during a transmission season of 2-4 months.

• The incidence of yellow fever in South America is lower than that in Africa because the mosquitoes that transmit the virus between monkeys in the forest canopy do not often come in contact with humans and because immunity in the indigenous human population is high.
• Urban epidemic transmission has not occurred in South America for many years, although the risk of introduction of the virus into towns and cities is ever present.
• For travelers, the risks of illness and death due to yellow fever are probably 10 times greater in rural West Africa than in South America; the risk varies greatly according to specific location and season.
• In West Africa, virus transmission is highest during the late rainy and early dry seasons (July-October). In Brazil, the risk of infection is highest during the rainy season (January-March) .
• The low incidence of yellow fever in South America, generally a few hundred reported cases per year, could lead to complacency among travelers.
• However, it is important to note that four of the six cases of yellow fever reported among travelers from the United States and Europe in 1996-2002 acquired yellow fever in South America .
• All six cases were fatal and occurred among unvaccinated travelers. An increase in enzootic and epizootic yellow fever transmission in South America during the 1990s and the potential for epidemiologic change in the Americas remains a concern

• The risk of acquiring yellow fever is difficult to predict because of variations in ecologic determinants of virus transmission.
• Based on data for U.S. travelers during 1996-2004, the overall risk for serious illness and death due to yellow fever in travelers has been roughly estimated to be 0.05 -0.5 per 100,000 travelers to yellow fever-endemic areas.
• This range reflects an unvaccinated population of 10-90% and assumes that all travelers visiting holo-endemic countries are at risk and 10% of travelers to non holo-endemic countries are visiting risk areas.

• The risk of acquiring yellow fever is difficult to predict because of variations in ecologic determinants of virus transmission.
• For a 2-week stay, the risks for illness and death due to yellow fever for an unvaccinated traveler visiting an endemic area in:^[5]

• West Africa are 50 per 100,000 and 10 per 100,000, respectively
• South America are 5 per 100,000 and 1 per 100,000, respectively

• These estimates are based on risk to indigenous populations and may not accurately reflect the true risk to travelers, who may have a different immunity profile, take precautions against getting bitten by mosquitoes, and have less outdoor exposure.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

A traveler’s risk of acquiring yellow fever is determined by various factors, including immunization status, location of travel, season, duration of exposure, occupational and recreational activities while traveling, and the local rate of virus transmission at the time of travel.

• Transmission in rural West Africa is seasonal, with an elevated risk during the end of the rainy season and the beginning of the dry season (usually July–October). *However, yellow fever virus may be episodically transmitted by Aedes aegypti even during the dry season in both rural and densely settled urban areas.
• The risk for infection in South America is highest during the rainy season (January–May, with a peak incidence in February and March).
• Given the high level of viremia that may occur in infected humans and the widespread distribution of Aedes aegypti in many towns and cities, South America is at risk for a large-scale urban epidemic. ^[1]
• Only a small proportion of yellow fever cases is recognized and officially reported because the involved areas are often remote and lack specific diagnostic capabilities.The risk of acquiring yellow fever is difficult to predict because of variations in ecologic determinants of virus transmission.
• During interepidemic periods, low-level transmission may not be detected by public health surveillance.
• Such interepidemic conditions may last years or even decades in certain countries or regions.
• This “epidemiologic silence” does not equate to absence of risk and should not lead to travel without the protection provided by vaccination.
• The risk of acquiring yellow fever in South America is lower than that in Africa, because the mosquitoes that transmit the virus between monkeys in the forest canopy in South America do not often come in contact with humans.
• Additionally, there is a relatively high level of immunity in local residents because of vaccine use, which might reduce the risk of transmission.

Countries with risk of yellow fever virus (YFV) transmission

Africa			Central and South America
Angola Benin Burkina Faso Burundi Cameroon Central African Republic Chad† Congo Côte d’Ivoire Democratic Republic of the Congo†	Equatorial Guinea Ethiopia† Gabon Gambia Ghana Guinea Guinea-Bissau Kenya† Liberia Mali†	Mauritania† Niger† Nigeria Rwanda Senegal Sierra Leone Sudan† South Sudan Togo Uganda	Argentina† Bolivia† Brazil† Colombia† Ecuador† French Guiana Guyana Panama† Paraguay Peru† Suriname Trinidad and Tobago† Venezuela†
†These countries are not holoendemic (only a portion of the country has risk of yellow fever transmission). Table adapted from CDC [1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Initial symptoms of yellow fever start 3-6 days after the mosquito bite, these include sudden onset of fever, chills, severe headache, back pain, general body aches, nausea and vomiting, fatigue, and weakness. Most people improve after these initial symptoms. However, roughly 15% of people will have a brief period of hours to a day without symptoms and will then develop a more , severe form of yellow fever disease. Possible complications include coma, disseminated intravascular coagulation (DIC), kidney failure, liver failure and shock. The prognosis is good in the majority of patients, infected persons will be asymptomatic or have mild disease with complete recovery.

• In its mildest form, yellow fever is a self-limited infection characterized by sudden onset of fever and headache without other symptoms.
• Other patients experience an abrupt onset of a high fever (up to 104°F/40° C), chills, severe headache, generalized myalgias, lumbosacral pain, anorexia, nausea, vomiting, and dizziness.
• The patient appears acutely ill, and examination might demonstrate bradycardia in relation to the elevated body temperature (Faget’s sign).
• The patient is usually viremic during this period, which lasts for approximately 3 days.
• Many patients have an uneventful recovery, but in approximately 15% of infected persons, the illness recurs in more severe form within 48 hours following the viremic period.
• After the third to sixth day of the onset of the symptoms the patient may present return of the fever, vomiting, renal failure (oliguria), jaundice, epigastric pain and hemorrhagic diathesis. The viremia terminates during this stage and the antibodies appear in the blood. The patient may evolve with multiorgan failure during this phase. Also in this stage, AST concentrations might exceed ALT, probably due to myocardial and skeletal muscle damage. Serum creatinine and bilirubin levels also rise at this stage. Hemorrhagic manifestations may include petechiae, ecchymoses, epistaxis, melena, metrorrhagia, hematuria, haematemesis, and oozing blood from the gingiva and needle-puncture sites. Laboratory studies may show thrombocytopenia, reduced fibrinogen levels, presence of fibrin split products, reduced factors II, V, VII, VIII, IX and X, which suggest a multifactorial cause for the bleeding with a consumption coagulopathy. Myocardial disfunction may be demonstrated by abnormalities in the ST-T segment in the electrocardiogram. Encephalitis is very rare.

The possible complications are:

• Coma
• Death (approximately 20-50% of the patients with the hepatorenal disease die after 7-10 days of the onset ^[1])
• Disseminated intravascular coagulation (DIC)
• Kidney failure
• Liver failure
• Parotitis
• Secondary bacterial infections
• Shock

• The majority of infected persons will be asymptomatic or have mild disease with complete recovery. ^[2]
• In persons who become symptomatic but recover, weakness and fatigue may last several months.
• Among those who develop severe disease, 20% – 50% may die.
• Those who recover from yellow fever generally have lasting immunity against subsequent infection.

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