Yellow Fever.

Yellow fever is an acute viral disease. The virus, a 40 to 50 nm enveloped RNA virus of the family of Flaviviridae is transmitted by the bite of mosquitoes (the yellow fever mosquito, Aedes aegypti, and other species). Yellow fever is an important cause of hemorrhagic illness in tropical and subtropical areas of African and South American despite existence of an effective vaccine. The yellow refers to the jaundice symptoms that affect some patients.
Since the 17th century, yellow fever has been a source of many devastating epidemics in America, Africa and Europe. 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.
Cause
Yellow fever is caused by the yellow fever virus, a 40 to 50 nm big enveloped RNA virus belonging to the family Flaviviridae. The positive sense single-stranded RNA is approximately 11.000 nucleotides long and has a single open reading frame encoding a polyprotein. Host proteases cut this polyprotein into 3 structural (C, prM, E) and 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding genes in the genome. The viruses infect amongst others monocytes, macrophages and dendritic cells. They attach to the cell surface via specific receptors and are taken up by an endosomal vesicle. Inside the endosome, the dropping pH induces the fusion of the endosomal membrane with the virus envelope. Thus, the capsid reaches the cytosol, decays and releases the genome. Receptor binding as well as membrane fusion are catalyzed by the protein E, which changes its conformation at low pH, which causes a rearrangement of the 90 homodimers to 60 homotrimers.
After entering the host cell, the viral genome is replicated in the rough ER and in the so-called vesicle packets. At first, an immature form of the virus particle is produced inside the ER, whose M-protein is not yet cleaved to its mature form and is therefore denoted as prM (precursor M) and forms a complex with protein E. The immature particles are processed in the Golgi apparatus by the host protein furin, which cleaves prM to M. This releases E from the complex which can now take its place in the mature, infectious virion.
Transmission
Adults of the yellow fever mosquito Aedes aegypti. The male on the left, females on the right. Only the female mosquito bites and can transmit the disease.The yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but other mosquitos can also serve as a vector for the virus. Like other Arboviruses which are transmitted via mosquitos, the yellow fever virus is taken up by a female mosquito which sucks the blood of an infected person. Viruses thus reach the stomach of the mosquito, and if the virus concentration is high enough, the virions can infect epithelial cells and replicate there. From there they reach the haemocoel (the blood system of mosquitos) and from there the salivary glands. When the mosquito sucks blood the next time, it injects its saliva into the wound, and thus the virus reaches the blood of the bitten person. There are also indications for a vertical infection of the yellow fever virus with A. aegypti, i.e. the transmission from a female mosquito to her clutch and thus the larva. This infection of vectors without a previous blood meal seems to play a role in single, sudden breakouts of the disease.
There are three epidemiologically different infectious cycles, in which the virus is transmitted from mosquitos to humans or other primates. In the urban cycle, only the yellow fever mosquito Aedes aegypti is involved, which is well adapted to urban centres and can, besides yellow fever, also transmit other diseases such as Dengue and Chikungunya. The urban cycle is responsible for the major outbreaks of yellow fever, as they occur in Africa. Except an outbreak in Bolivia 1999, this urban cycle no longer exists in South America and is only observed in Africa.
Besides the urban cycle there exists, both in Africa and South America, a silvatic cycle (Forest cycle or Jungle cycle), where Aedes africanus (in Africa) or mosquitos of the genus Haemagoggus and Sabethes (in South America) serve as a vector. In the jungle it is mainly non-human primates that are infected; the disease in African primates is mainly asymptomatic. In South America this is at the moment the only way of infection for humans, which explains the low incidence of yellow fever cases on this continent. People who become infected in the jungle can carry the virus to urban centres, where Ae. aegypti occurs as a vector. It is due to this silvatic cycle that yellow fever cannot be eradicated. In Africa there is a third infectious cycle, also known as savannah cycle or intermediate cycle, which occurs between the jungle and urban cycle. Different mosquitos of the genus Aedes are involved.
Prevalence
Yellow fever is endemic in tropical and subtropical areas of South America and Africa. Even though the main vector Aedes aegypti also occurs in Asia, in the pacific and the middle east, yellow fever does not occur in these areas; the reason for this is unknown. Worldwide there are about 600 million people living in endemic areas and the official estimations of the WHO amount to 200.000 cases of disease and 30.000 deaths a year; the number of officially reported cases is far lower. Estimated 90 % of the infections occur on the African continent. Endemic range of yellow fever in South America (2005). Endemic range of yellow fever in Africa (2005).
Phylogenetic analysis identified seven genotypes of yellow fever viruses, and it is assumed that they are differently adapted to humans and to the vector Ae. aegypti. Five genotypes occure solely in Africa, and it can be assumed that the Westafrica-genotype I is especially virulent or infectious, because it is this type that is often associated with major outbreaks of yellow fever. In South America there are two genotypes identified.
Signs and symptoms
Yellow fever begins suddenly after an incubation period of three to six days. Most of the cases cause only a mild infection with fever, headache, chills, back pain, loss of appetite, nausea and vomiting.[10] In these cases the infection abates after three to four days. 15 % of the cases enter a second phase (the toxic phase) of the disease with recurring fever, this time accompanied by jaundice due to liver damage, as well as abdominal pain. Bleedings in the mouth, the eyes and in the gastrointestinal tract can cause vomitus containing blood (thus the name "vómito negro"). This toxic phase is fatal in approximately 20 % of cases. Surviving the infection causes life-long immunity and normally there are no remaining organ damages.
Pathogenesis
After transmission of the virus from a mosquito the viruses replicate in the lymph nodes and infect in particular dendritic cells. From there they reach the liver and infect hepatocytes (probably indirectly via Kupffer cells), which leads to eosinophilic degradation of these cells and to the release of cytokines. Necrotic masses (Councilman bodies) appear in the cytoplasm of hepatocytes. When the disease takes a deadly course, a cardiovascular shock and multi organ failure with strongly increased cytokine levels (cytokine storm) follow.
Diagnosis
Yellow fever is a clinical diagnosis, which often relies on the whereabouts of the diseased person during the incubation time. Liver biopsy can verify inflammation and necrosis of hepatocytes and detect viral antigens. Serologically an enzyme linked immunosorbent assay confirm IgM during the acute phase of the disease, or an increase in titer as compared to the healthy condition. Further, a reverse transcription polymerase chain reaction can amplify and demonstrate viral genetic information, this can also help distinguish between different flaviviruses. This is essential for the differential diagnosis, because other viral infections can cause similar symptoms.
Treatment
For yellow fever there is, like for all diseases caused by Flaviviruses, no causative cure. Hospitalisation is advisable and intensive care may be necessary due to in some cases rapid deterioration in state of health. Different methods for acute treatment of the disease were shown to be not very successful, for example is passive immunisation after emergence of symptoms probably without effect. Also did Ribavirin and other antiviral drugs as well as treatment with interferons not have a positive effect on the patient A symptomatic treatment includes rehydration and pain relief with drugs like Paracetamol. Acetlysalicylic acid (for example Aspirin®) should not be given due to its haemodiluting effect, which can be devastating in the case of inner bleeding that can occur with yellow fever.
Prevention
Personal prevention of yellow fever includes vaccination as well as prevention of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures of controlling tiger mosquitos.
Vaccination
For journeys into affected areas vaccination is highly recommended. The protective effect is established after 10 days after vaccination in 95% of the vaccinated people and lasts for at least 10 years. The attenuated live vaccine (stem 17D) was developed in 1937 by Max Theiler and is produced in chicken eggs. WHO recommends to vaccinate people living in endemic areas routinely between the 9th and 12th month after birth.
In a few cases (less than one in 200,000 to 300,000[15]), the vaccination can cause YEL-AVD (yellow fever vaccine-associated viscerotropic disease), which is fatal in 60% of all cases. It is probably due to a genetic defect in the immune system. Age is an important risk factor; in children the complication rate is less than one case per 10 million vaccinations. Further an infection of the nervous system can occur in one in 200,000 to 300,000, causing YEL-AND (yellow fever vaccine-associated neurotropic disease), which can cause meningoencephalitis and is in less than 5% fatal.
Compulsory vaccination
Some countries in Asia are theoretically in danger of yellow fever epidemics (responsible mosquitos and infectable monkeys), even though the disease does not yet occur there. To prevent introduction of the virus, some counties demand previous vaccination of foreign visitors, if they had passed through yellow fever areas. Vaccination has to be proven in a vaccination certificate which is valid 10 days after the vaccination and lasts for 10 years. A list of the countries which require yellow fever vaccination was published by the WHO. If vaccination is for some reasons not possible, dispensation is possible. In this case an exemption certificate of WHO standard is required.
Even though 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, many of these countries have less than 50 % of their population vaccinated.
Vector control
Besides vaccination, control of the yellow fever mosquito Aedes aegypti is of major importance, especially because the same mosquito can, besides yellow fever, transmit Dengue and Chikungunya disease. Ae. aegypti breeds preferentially in water, for example in installations by inhabitants of areas with precarious drinking water supply, or in civilising rubbish; especially tires, cans and plastic bottles. Especially in proximity to urban centres of developing countries these conditions are very frequent and present a perfect habitat for Ae. aegypti. Two strategies are used fighting the mosquito:
One approach is to deaden the developing larva. Measures are taken to reduce water build-ups (the habitats of the larva), and larvicides are used as well as larva-eating fish and copepods, which reduce the number of larva and thus indirectly the number of disease-transmitting mosquitos. For many years, copepods of the genus Mesocyclopshave been used in Vietnam for fighting Dengue fever (yellow fever does not occur in Asia), with the effect that in the affected areas no cases of Dengue fever occurred since 2001. Similar mechanisms are probably also effective against yellow fever. As a chemical larvicide mainly pyriproxyfen is recommended, because it is safe for humans and effective even in small doses.
Besides larva, also the adult yellow fever mosquitos are targeted. Curtains and lids of water tanks are sprayed with insecticides. Spraying insecticides inside houses is not recommended by the WHO. Similar to the malaria carrier, the Anopheles mosquito, insecticide treated mosquito nets are used successfully against Ae. aegypti.
History
West Africa has long been regarded as the home of yellow fever. Yellow fever has had an important role in the history of Africa, the Americas, Europe, and the Caribbean.
Cuba: 1762–1763
British and American colonial troops died by the thousands in the British expedition against Cuba between 1762 and 1763. Epidemics struck coastal and island communities throughout the area during the next 140 years, with 10% of the population dying as a result.
Philadelphia, Pennsylvania: 1793
The Yellow Fever Epidemic of 1793 killed as many as 10,000 people in Philadelphia, Pennsylvania. Thousands, including President George Washington, fled the city, including most members of the Federal (Philadelphia was the capital of the United States at this time) and city governments. As a result, civil services collapsed and almost vanished. However, the mayor remained and eventually, with the help of a "Committee of Twenty" composed of volunteer residents drawn from all walks of life, order and civil services were restored.[18] Members of the Free African Society, a charitable organization of African-Americans originally founded as a self-help group, were instrumental in this regard. They served as nurses and home-care attendants, often for no pay, and Mayor William Clarkson later praised their work when racist claims of price-gouging and theft were raised.
Although many other well-to-do citizens chose to leave the city, Stephen Girard stayed to care for the sick and dying. He supervised the conversion of a mansion outside the city limits into a hospital and recruited volunteers to nurse victims, and personally cared for patients. For his efforts, Girard was feted as a hero by the City Hall after the outbreak subsided.
The first family of Dolley Madison, née Dolley Payne, who would later become First Lady of the United States during James Madison's administration, was stricken in this epidemic. John Todd, Dolley's husband, was a Quaker and a lawyer. He felt it was his duty to remain in Philadelphia and provide legal services (wills, probate, etc.) to those who were dying or the families of those who died. However, he moved his family across the river. One day on a visit to his family, he collapsed into his wife's arms on the doorstep of their house and died soon after. Dolley and her eldest son, John Payne Todd, contracted yellow fever but survived. Dolley's youngest son William Temple Todd and John's parents also perished in the 1793 epidemic Alexander Hamilton and his wife, Elizabeth Schuyler, contracted yellow fever but survived.
Dr. Benjamin Rush also contracted yellow fever, but survived. His fame, as a signer of the Declaration of Independence and as head medical doctor for the American army in the middle Atlantic states region during the American Revolution, brought him hundreds, perhaps thousands, of patients during this epidemic. His methods were severe and split the medical community at that time, resulting in an ongoing letter-writing war in the press both during and after the epidemic. Some contemporaries, notably William Cobbett, objected to Rush's extreme use of bloodletting. Cobbett accused Rush of killing more patients than he had saved. Rush sued Cobbett for libel, winning a judgment of $500.However, unlike a number of other doctors, he remained in Philadelphia and did his best to help the residents who were struck down by the disease.
At the time of the Philadelphia epidemic, the most widespread belief was that the disease spread via contaminated water. A "Watering Committee" was appointed and recommended a municipal water supply, which came into use in 1801. The initial installation, by Benjamin Latrobe, was inefficient and unreliable, and was replaced in 1812-1815. Of course the water system did nothing directly to alleviate yellow fever, but it allowed city residents to remove their makeshift arrangements of wells and cisterns, which had provided breeding places for mosquitoes. Thus, the desired effect was actually achieved.
Haiti: 1802
In 1802, an army of forty thousand sent by First Consul Napoleon Bonaparte of France to Haiti to suppress the Haitian Revolution was decimated 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).
New Orleans, Louisiana: 1853
This outbreak claimed 7,849 residents of New Orleans. The press and the medical profession did not alert citizens of the outbreak until the middle of July, after over a thousand had already died. The reason for this silence was that the New Orleans business community feared that word of an epidemic would cause a quarantine to be placed on the city, and commerce would thus be hurt.
Norfolk, Virginia: 1855
A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern Virginia in June 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.
Memphis, Tennessee: 1878
There were several outbreaks of yellow fever in Memphis during the 1870s, culminating in the devastating 1878 epidemic, with over 5,000 fatalities in the city itself and 20,000 along the whole of the Mississippi River Valley. It has been claimed that the large death toll was due to commercial interests taking precedence over reporting the outbreak of yellow fever.
The French Panama Canal Effort: 1882–1889 The French effort to build a Panama Canal was fatally damaged by the prevalence of endemic tropical diseases in the Isthmus. Although malaria was also a serious problem for the French canal builders, the numerous yellow fever fatalities and the fear they engendered made it difficult for the French company to retain sufficient technical staff to sustain the effort. Since the mode of transmission of the disease was unknown, the French response to the disease was limited to care of the sick. Unfortunately, the French hospitals contained many pools of stagnant water, such as basins underneath potted plants, in which mosquitoes could breed. The eventual failure, as a result of the deaths, of the French company licensed to build the canal resulted in a massive financial crisis in France.
Carlos Finlay and Walter Reed
Carlos Finlay, a Cuban doctor and scientist, first proposed proofs in 1881 that yellow fever is transmitted by mosquitoes rather than direct human contact. 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. Although Dr. Reed received much of the credit in history books for "beating" yellow fever, Reed himself credited Dr. Finlay with the discovery of the yellow fever vector, and thus how it might be controlled. Dr. Reed often cited Finlay's papers in his own articles and gave him credit for the discovery, even in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the Walter Reed Commission of 1900. 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 and his Board began their efforts, twenty years during which most of the scientific community ignored Finlay's theory of mosquito transmission.
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, although efforts had been successful in Havana since 1901. A conference organized in New Orleans in 1905 by Dr. A. L. Metz resulted in President Roosevelt directing the United States' Government to take control of the matter. The United States Public Health Service put into effect a mosquito control campaign, this included, fumigating houses, inspecting cisterns for drinking water, and treating pools of standing water 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.Yellow fever can turn into a deadly disease if it is not treated properly.
Current research
In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective early treatment of many pathological features of the disease. Ribavirin treatment during the first five days after virus infection improved survival rates, reduced tissue damage in target organs (liver and spleen), prevented hepatocellular steatosis, and normalized alanine aminotransferase (a liver damage marker) levels. The results of this study suggest that ribavirin may be effective in the early treatment of yellow fever, and that its mechanism of action in reducing liver pathology in yellow fever virus infection may be similar to that observed with ribavirin in the treatment of hepatitis C, a virus related to yellow fever.] Because ribavirin had failed to improve survival in a virulent primate (rhesus) model of yellow fever infection, it had been previously discounted as a possible therapy.
In the past, yellow fever has been researched by several countries as a potential biological weapon.

Fuentes:
http://en.wikipedia.org/wiki/Yellow_fever