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Yellow Fever

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The yellow fever , also Ochropyra or black vomit called, is a disease whose cause is infection with the yellow fever virus is. When the virus is a 40-50 nm large, enveloped RNA virus with positive polarity of the family of flaviviruses.

Yellow Fever
Yellow Fever

The virus is spread by the bite of a mosquito and is transmitted in tropical and subtropical areas in South America and Africa spread, but not in Asia . The only known hosts of the virus are primates , and various mosquito species . The origin of the disease is suspected in Africa, from where it is the slave trade and transatlantic transport from the 16th century in South America was distributed by particular. There have been since 17 Century, several major disease outbreaks in the Americas, Africa and Europe grew. The yellow fever was the 19th century as one of the most dangerous infectious diseases.

The disease manifests itself in most cases with fever, nausea and pain and disappears within a few days off again. In some patients, however, follows a toxic phase of it to liver damage with jaundice, hence the name of the disease) is (which can be fatal. With the classic symptoms of increased bleeding ( hemorrhagic diathesis ) is the yellow fever to the so-called haemorrhagic fevers . The WHO estimates that 200,000 people are diagnosed annually and 30 000 people die of yellow fever, and an estimated 90% of infections attributable to the African continent.

Against yellow fever, there is a very safe and effective vaccine in some countries there is a mandatory vaccination for persons entering. Since no treatment for yellow fever is known, transmitting, in addition to immunization programs in particular measures to control the yellow fever mosquito in the affected countries is of great importance. Since the 1980s, yellow fever are piling up the cases of yellow fever is back and so often as a reemerging disease (disease again) called spreading.

Pathogen

Yellow fever virus

Yellow fever is indicated by the yellow fever virus causes a round virus with a diameter of 40-50 nm of the family of flavi-viruses. The viral genome is (unlike that of all living organisms used DNA) from ribonucleic acid (RNA). The genome includes only one open reading frame of a polyprotein encoded (a long amino acid chain, and not in individual functional proteins which subsequently must be cut).

During an infection, the viruses attach themselves on specific receptors on the cell surface of a host cell, and are undertaking training through an endosome vesicle was added. Normally, these vesicles serve to substances to digest the virus but are used as transportation to get to the inside of the cell. Inside the endosome induces the acidic pH of the merger of Endosommembran and viral envelope, which allows the virus, into the cytosol to penetrate. The viral genome in the rough ER and in so-called vesicle packets replicated after maturation in the Golgi apparatus resulting infectious viral particles. This left the cell and infects other host cells.

Transfer

The yellow fever mosquito transmits yellow fever.

The yellow fever virus is primarily through the bite of the yellow fever mosquito (Aedes aegypti transmitted), but other than mosquitoes can vector used. As in other mosquito’s transmitted arboviruses, the yellow fever virus by a female mosquito sucks the blood of an infected person that was shot. This virus comes into the stomach of the mosquito, and if the virus concentration is high enough, the virions of the stomach epithelial cells infected and there multiply. From there they enter into the blood system of the mosquito and further into the salivary glands. When the mosquito sucks blood, the next time, it injects its saliva into the wound, which the virus enters the bloodstream of the bitten person in. There is also evidence of vertical infection of yellow fever virus in A. aegypti that is the transfer of the female mosquito to her eggs and the larvae. This infection of the vectors without blood meal appears in individuals, sudden outbursts of a role to play.

There are three epidemiologically distinct infection cycles in which the virus from mosquitoes to humans or other primates is transferred. On the urban cycle of yellow fever mosquito, only the part which is adapted to large urban centers in well and there along with other diseases such as yellow fever and dengue – and fever transfer. The urban cycle is primarily responsible for major outbreaks of yellow fever, as they occur in Africa. An outbreak in 1999, except in Bolivia, the urban cycle no longer exists in South Africa and is exclusively observed.

In addition to the urban cycle exists both in Africa and in South America a sylvatic cycle (forest cycle or jungle cycle), in which Aedes African-us (in Africa) or mosquitoes of the genus Haemagoggus and Sabethes in South America) to serve as a vector (. These are jungle mainly non-human primates infected in. While the disease in Africa in these primates mostly asymptomatic, it ends in South America often fatal. In South America, the sylvatic cycle is currently the only route of infection for humans, which include the lower incidence of yellow fever cases on the continent declared. Persons, who are infected in this way in the jungle, can bring the virus into urban centers, where the yellow fever mosquito vector occurs as. Because of this sylvatic yellow fever cycle may not be completely eradicated.

In Africa there is a third infection cycle, including savannas, or intermediate cycle, called cycle of jungle and urban cycle occurs between. Several mosquito species of the genus Aedes are involved.

Dissemination

Yellow fever is found in tropical and subtropical areas in South America and Africa are endemic. Although the main vector – the mosquito – also in Asia, the Pacific and the Middle East occurs, yellow fever occurs in these regions does not, the reason is unknown. Worldwide approximately 600 million people live in endemic areas and the official WHO estimates amount to 200 000 illnesses and 30,000 deaths per year worldwide, with the number of reported cases far below it. An estimated 90% of infections belong to the African continent.

Phylogenetic analysis identified seven genotypes of yellow fever virus, which suspected of being; the people and the yellow fever mosquito are adjusted differently. Five Genotype are exclusively found in Africa, suspects being stated that the West African genotype I particularly virulent infectious, or because he is finding more of yellow fever outbreaks in common. In South America, two genotypes were identified.

Symptoms

Yellow fever has an incubation period of 3:00 to 6:00 days, after which it rose to a sudden fever above 39 ° C (and sometimes over 40 ° C) occurs. Most cases proceed mild; the infection manifests itself only in a short febrile illness with headache, chills, and back pain, loss of appetite, nausea and vomiting. The infection can in mild cases after three to four days fade away again. In about 15% of patients manifested a second phase of disease with a recurrence of fever (a short-term improvement in the health conditions is possible), this time accompanied by jaundice due to liver damage and pain in the abdomen. As a sign of increased bleeding tendency and sensitivity of capillary vessels, occurs under pressure of the skin, the phenomenon of “Spanish flag” on. Bleeding of the oral mucosa, the blindfold hides and the nasal mucosa (epistaxis) are characteristic. Massive bleeding in the gastrointestinal tract may be bloody stool [6]and bloody vomiting result, the blood with the stomach acid black tinted contact the by, hence the historical name “Vomito negro” ( black vomit ) and the classification of the haemorrhagic fever . This second phase, also toxic phase called ends, in 20% of all fatal cases. If the infection survived, there is lifelong immunity and are usually no permanent organ damage carried away.

Pathogenesis

Infection with the yellow fever virus leads primarily to damage of epithelial cells (mucous membranes, blood vessels) and muscle cells of the heart. The transmission of infection through a mosquito increases after the virus first in lymph nodes and infect particular dendritic cells. From there the virus spread through a viremia to the whole organism and reach the liver. Here, the viruses infect the liver cells, most likely indirectly via Kupffer cells, leading to eosinophilic degradation of these cells and the release of cytokines leads. The microscopically visible accumulations of pigment in Kupffer cells during the yellow fever as “Villela-bodies” referred to. In a fatal outcome following a cardiovascular shock, and multiple organ failure with highly elevated cytokine levels (a so-called cytokine storm). Histological in liver cells and eosinophilic inclusion in bodies (Councilman Body) is visible and sometimes inclusions in the nucleus (Torres-bodies “).

Diagnosis

Yellow fever is primarily a clinical diagnosis, often on the whereabouts of the affected persons during the incubation period is based. Sporadic and only mild gradients are sure virological tests to detect by only one. Since the outbreaks of mild regional patterns play a large role in these patients and also contribute to the spread of the disease, an offer made within six to more than ten days after leaving the endemic area occurring fever with pain, nausea and vomiting as yellow fever suspect.

In case of suspected infection, the yellow fever virus 60-10 days after onset of the disease proved to be about. This can be by means of reverse transcriptase-polymerase chain reaction take place in the genome of the virus multiplies that and detected directly is. The direct detection of pathogens can also have a virus isolation growing in cell cultures made by means of, and procedures to weeks can last four of this. Both procedures with plasma heparin blood) done (. Serologically, an Enzyme Labeled immunosorbent assay in the acute phase of the disease yellow fever specific IgM or demonstrate an increase in specific IgG – titer to a laboratory test are shown in comparison. Together with clear clinical symptoms is evidence of IgM or a fourfold increase in titer of IgG as a secure link. Since the serological tests often with other flaviviruses, such as the dengue virus cross-react, however, these indirect methods are never proof of an infection.

The histological changes in liver occur in other viral hemorrhagic viral infections with liver involvement also, they are therefore no disease demonstrative character. A post-mortem conducted liver biopsy, the inclusion bodies and necrotic hepatocytes and confirmed by the detection of specific, viral antigen used. Typical signs of inflammation are often absent in the histological picture, particularly in fulminant courses. Due to the increased bleeding tendency is a liver biopsy, the patient does not appear and only serves to confirm the diagnosis after death.

Dealing with all the research material of the patient, particularly blood and biopsies is subject to strict safety regulations and may only in laboratories of level 3 are carried out.

Differential Diagnosis

Sudden fever with jaundice and bleeding tendencies at the appropriate residence in the affected areas can be the beginning of a yellow fever infection, differential diagnosis and to a Malaria think. Other, jaundice associated with infection are excluded, all the classic viral hepatitis, a leptospirosis or recurrent fever. Other viral infections with hemorrhagic fever should be distinguished, so infected with Ebola virus, the Lassa virus, Marburg virus or Junín virus. This is the course of disease in the very early onset of bleeding (“Spanish flag” as a skin symptom) more typical of yellow fever. Generalized, septic courses of herpes simplex infections or herpes B can exhibit symptoms very similar to the Yellow Fever. Non-infectious causes may also be jaundice and increased bleeding associated with, such as various forms of poisoning with hepatotoxic substances.

Treatment

For yellow fever exists as to all of flavivirus diseases caused no causal therapy. If possible, Hospitaliserung is an admission to a hospital (all) and in some cases because of the rapidly deteriorating disease condition is an intensive monitoring appropriate. Various methods for the acute treatment of the disease showed little success in studies, it is a passive immunization after the appearance of symptoms, probably without effect. Also ribavirin and other antiviral drugs were the same as treatment with interferon, no positive effects in the yellow fever patients. [8]Symptomatic treatment includes measures to re-hydration and administration of agents such as paracetamol for pain relief. To aspirin (e.g. aspirin) should be waived its anticoagulant effect because, as this in the case of internal bleeding that can occur in yellow fever, is devastating.

Prevention

The personal preventive measures against yellow fever vaccination and include avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for the prevention of yellow fever vaccination programs and include measures to control mosquitoes.

Vaccination

Immunization with an injection of vaccine into the deltoid.

When traveling to affected areas is an urgent vaccination recommended as particularly newcomers, non-indigenous people are affected during severe forms of. The immunization coverage is at 95% of vaccines after 10 days, one and lasts 10 years at least (in one study was 30 years after vaccination in 81% of the persons identified antibodies). The attenuated live vaccine (strain 17D) was in 1937 by Max Theiler one patient died from Ghana and is isolated from by multiplication in embryonated chicken eggs produced. The WHO recommends that in endemic areas, routine vaccination between 9 and 12 Month of life Making.

Quite often (in about 20% of all cases) leads to the vaccination mild, flu-like symptoms. Very rarely, in less than one case at 200000-300000 vaccinations, a YEL-AVD ( yellow fever vaccine-associated viscerotropic disease ) may occur, which 60% of all cases leads to death. This is most likely a genetic defect in the immune system caused, but has also been given a vaccination campaigns 20-fold higher incidence rate observed. Age is a major risk factor in children, the complication rate is around one case per 10 million doses. A second serious side effect is an infection of the nervous system, a so-called YEL-AND ( yellow fever vaccine-associated neurotropic disease ). This complication may be a case 200000-300000 vaccinations occur in which a meningoencephalitis may cause, and in less than 5% of cases, death.

The vaccine is not according to the manufacturer for infants under six months, according to WHO is not suitable under nine months. For persons aged 60 years, is due to an increased risk of serious side effects indication for the primary vaccination are strictly. Pregnant women should only after rigorous risk-benefit assessment will be administered the vaccine, as no data are available for security. Contraindicated is vaccination in immunocompromised persons with HIV infection should be made of existing immune function with only one vaccination. Furthermore, the vaccination of persons with a disease thymus does not appear. Due to the production method used, the vaccine not allergic to egg protein is inoculated. [10]to a previous dose of immunoglobulins passive vaccination) must at vaccination generally separated by at least three months will be a respected (. Other vaccines ( mumps, , measles, , and rubella ) should either or every four weeks administered to the same time. Around the vaccine virus is not in the transfusion recipient share should vaccination no blood donated to the after (the recommended waiting time is 2-4 weeks). The yellow fever vaccine must be administered by physician’s especially further training only (so-called “yellow fever vaccination).

Compulsory vaccinations

Some Asian countries are at risk of yellow fever in theory at least (vector mosquitoes and monkeys demonstrated infect able) without the disease so far appears there. To avoid that the virus can be introduced and set time to ask these and other countries of foreign visitors to a previous vaccination if they have traveled through yellow fever areas (including transit ). Through vaccination proved to be a must after the vaccination is valid for 10 days and 10 years applies. A list of all countries that require a yellow fever vaccination is published by the WHO. Can the vaccine described above reasons are not carried out one of, an exemption from the mandatory vaccination is possible. This is necessary in this case (Exemption Certificate) is one of WHO recognized inoculation of Safety.

Although 32 of the 44 countries where yellow fever is endemic, vaccination programs have also developed in many countries less than 50% of all persons vaccinated.

Vector control

In addition to vaccination is to control the yellow fever mosquito very important, especially since the same mosquito addition of yellow fever and other diseases such as dengue – can be transferred. The yellow fever mosquito breeds in water, preferably accumulations in areas with precarious water supply themselves were created by people or domestic waste accumulate, especially in tires but also in old cans and plastic vessels. Especially in the vicinity of urban centers of developing countries these conditions are often found to form an excellent habitat for the yellow fever mosquito. In the fight against the mosquito strategies are two fold:

On the one hand, measures to kill larvae of the evolving taken. These are in addition to measures to reduce the larvae mainly water Larvicidial , larvae-eating fish and copepods Copepoda) used (which are directly in the number of larvae and thus indirectly the number of disease-carrying mosquitoes decimated. In Vietnam for several years, copepods of the genus Mesocyclops in combating dengue fever used (yellow fever in Asia is not before), the implementation of the measures will be reviewed monthly. This resulted in the affected areas since 2001, no case of dengue fever occurred in, a similar measure against yellow fever is probably also effective, because both measures are aimed at the same organism. As a chemical larvicide is primarily Pyriproxyfen recommended because it is safe for people and even in small quantities is effective.

On the other hand yellow fever mosquito larvae, in addition to the adult fights. It will be curtains and covers of water basins with insecticide and insecticide can be sprayed into the interior treated, which is not recommended by the WHO but. As against the vectors of malaria disease, the Anopheles mosquito, are also against yellow fever mosquito insecticide treated mosquito nets used with success.

History

* Carlos Finlay
* Walter Reed

The evolutionary origins of the Yellow Fever Viruses are most likely in Africa. It is suspected that the virus originated in East or Central Africa is and from there spread to West Africa. Came to South America, both the yellow fever mosquito and the virus itself probably from shipping, which, according 1492began. The first probable outbreak of the disease was in 1648 then in Yucatan instead, in which the disease as vomiting) was called Black (. At least 25 major eruptions followed, in Philadelphia in 1793, in which several thousand people were killed and the American government along with the then-President George Washington was forced to leave the city . Also in Europe have been occasional outbreaks recorded as 1821 in Barcelona, with several thousand dead. 1878 20 000 people died during an outbreak in the Mississippi Valley and the last eruption in the U.S. was in 1905 in New Orleans.

In 1881 suggested that the Cuban doctor and scientist Carlos Juan Finlay before that mosquitoes transmit yellow fever to that. After the American invasion of Cuba the 1890s, 13 times more deaths from yellow fever as by military operations called had a lot in, hypothesis, further experiments on the “mosquito employed” and the physician Walter Reed proved that yellow fever actually by mosquitoes, has been transferred. Yellow fever virus transmission was thus the first of which was proved by mosquitoes. The American army doctor William Gorgas applied this knowledge to consistently and achieved a complete elimination of yellow fever in Havana and was also the construction of the Panama Canal successful yellow fever tackle – after a French attempt to build the canal alia, under yellow fever and malaria had failed.

West Africa in 1927 was the yellow fever virus isolated in what the 1930s to the development of two vaccines against yellow fever led. The vaccine was D17 in 1937 from which South Africa coming microbiologist Max Theiler developed at the Rockefeller Institute. He won the vaccine from chicken eggs, and received for this achievement in 1951 the Nobel Prize for Medicine . A French research team developed the vaccine FNV ( French neurotropic vaccine ), which they won from the brains of mice – but as he was with a higher incidence of encephalitis was associated with children, its use was recommended in 1961 not more off. 17D on the other hand is still used over and over 400 million doses have been delivered so far. Since then, funding has been but little invested in the development of new vaccines, which meant that 60-year-old technology to vaccine production is not fast enough to the needs of a yellow fever outbreak can be adjusted with the above. Newer vaccines, based on Vero cells are under development and will in future replace the 17D vaccine.

Through a policy of vector control and vaccination programs more consistently, South America, the urban yellow fever cycle brought under control and since 1943 – apart from an urban outbreak in Santa Cruz de la Sierra ( Bolivia ) – by yellow fever mosquito transmitted yellow fever, the more determined not. Since the 1980s, South America, the number of yellow fever cases in raised again and the yellow fever mosquito is back to urban centers in South America back in, among others, the vector control programs have been abandoned because. Even if no cycle has been established in urban, it is feared that this could happen again. During an outbreak in Paraguay in 2008 was initially feared that it was an urban outbreak, which has not proved true.

In Africa, however the majority were carried out vaccination programs to eradicate the virus. This was not received because of the sylvatic cycle remained. In particular, after the measures to combat yellow fever were abandoned and only a few countries, the yellow fever vaccine into the regular vaccination program recordings, the disease spread out again.

Potential biological weapon

Yellow fever was by several governments, including the U.S. and possibly the North Korean government as a potential biological weapon investigated. The program of the U.S. government was officially set 1969in the Second World War, an attempt was made to military personnel vaccinated against yellow fever to all American, since 1939 Army yellow fever viruses such was the Japanese, of which American intelligence knew. At that time U.S. was in no yellow fever vaccination by the FDA have been released and so vaccination was a non-approved uses, which meant that 330,000 people with the hepatitis B virus were infected (these are the largest outbreak of this viral disease at all). Furthermore, 1975 was a large-scale test of the WHO in India, the money made was with American and in which the fight against yellow fever mosquito should have been investigated by the Indian government stopped because Indian scientists had feared, the U.S. government investigates properly the possibility Yellow fever as a biological weapon to use. It is also concerned that terrorists could use as a biological weapon, the yellow fever virus.

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