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Yellow fever is a viral
disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...
of typically short duration. In most cases, symptoms include
fever Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
, chills, loss of appetite,
nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...
, 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 The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
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
primate Primates are a diverse order of mammals. They are divided into the strepsirrhines, which include the lemurs, galagos, and lorisids, and the haplorhines, which include the tarsiers and the simians ( monkeys and apes, the latter includin ...
s, and several types of mosquitoes. In cities, it is spread primarily by ''
Aedes aegypti ''Aedes aegypti'', the yellow fever mosquito, is a mosquito that can spread dengue fever, chikungunya, Zika fever, Mayaro and yellow fever viruses, and other disease agents. The mosquito can be recognized by black and white markings on its l ...
'', a type of mosquito found throughout the
tropics The tropics are the regions of Earth surrounding the Equator. They are defined in latitude by the Tropic of Cancer in the Northern Hemisphere at N and the Tropic of Capricorn in the Southern Hemisphere at S. The tropics are also refer ...
and
subtropics The subtropical zones or subtropics are geographical and climate zones to the north and south of the tropics. Geographically part of the temperate zones of both hemispheres, they cover the middle latitudes from to approximately 35° nort ...
. 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 The polymerase chain reaction (PCR) is a method widely used to rapidly make millions to billions of copies (complete or partial) of a specific DNA sample, allowing scientists to take a very small sample of DNA and amplify it (or a part of it) ...
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 disease An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
s; 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 Abdominal pain, also known as a stomach ache, is a symptom associated with both non-serious and serious medical issues. Common causes of pain in the abdomen include gastroenteritis and irritable bowel syndrome. About 15% of people have a m ...
. 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 Immunity may refer to: Medicine * Immunity (medical), resistance of an organism to infection or disease * ''Immunity'' (journal), a scientific journal published by Cell Press Biology * Immune system Engineering * Radiofrequence immunity de ...
, 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 A sense is a biological system used by an organism for sensation, the process of gathering information about the world through the detection of stimuli. (For example, in the human body, the brain which is part of the central nervous system re ...
, single-stranded RNA is around 10,862
nucleotide Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecu ...
s long and has a single
open reading frame In molecular biology, open reading frames (ORFs) are defined as spans of DNA sequence between the start and stop codons. Usually, this is considered within a studied region of a prokaryotic DNA sequence, where only one of the six possible readi ...
encoding a polyprotein. Host
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s 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
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s in the
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
. 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 Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vagi ...
. The viruses infect, amongst others,
monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s, 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 A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. Numerous human pathogenic viruses in circulation are encase ...
. 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 homo
dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius Dimer ( ...
s 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 The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles i ...
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 Transstadial transmission occurs when a pathogen remains with the vector from one life stage ("stadium") to the next. For example, the bacteria ''Borrelia burgdorferi'', the causative agent for Lyme disease, infects the tick vector as a larva, and ...
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 Chikungunya is an infection caused by the ''Chikungunya virus'' (CHIKV). Symptoms include fever and joint pains. These typically occur two to twelve days after exposure. Other symptoms may include headache, muscle pain, joint swelling, and a r ...
. 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 ''Sabethes'' mosquitoes are primarily an arboreal genus, breeding in plant cavities.Ralph E. Harbach. 1994. The subgenus ''Sabethinus'' of ''Sabethes'' (Diptera: Culicidae). ''Systematic Entomology'', 19: 207-234; https://www.researchgate.net/p ...
'' (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
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, ...
s (probably indirectly via Kupffer cells), which leads to eosinophilic degradation of these cells and to the release of
cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s. Apoptotic masses known as Councilman bodies appear in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
of hepatocytes. Fatality may occur when
cytokine storm A cytokine storm, also called hypercytokinemia, is a physiological reaction in humans and other animals in which the innate immune system causes an uncontrolled and excessive release of pro-inflammatory signaling molecules called cytokines. Norma ...
,
shock Shock may refer to: Common uses Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emerge ...
, and multiple organ failure follow.


Diagnosis

Yellow fever is most frequently a clinical
diagnosis Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine "cause and effect". In systems engin ...
, based on
symptomatology Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
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 Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...
; this can take 1–4 weeks. Serologically, an
enzyme-linked immunosorbent assay The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presence ...
during the acute phase of the disease using specific IgM against yellow fever or an increase in specific
IgG Immunoglobulin G (Ig G) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG an ...
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 A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
can verify
inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...
and necrosis of hepatocytes and detect viral
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
s. 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 Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. ...
. Other
viral hemorrhagic fever Viral hemorrhagic fevers (VHFs) are a diverse group of animal and human illnesses in which fever and hemorrhage are caused by a viral infection. VHFs may be caused by five distinct families of RNA viruses: the families ''Filoviridae'', ''Flavi ...
s, such as Ebola virus, Lassa virus,
Marburg virus Marburg virus (MARV) is a hemorrhagic fever virus of the '' Filoviridae'' family of viruses and a member of the species '' Marburg marburgvirus'', genus '' Marburgvirus''. It causes Marburg virus disease in primates, a form of viral hemorrhagi ...
, 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 ''N'',''N''-Diethyl-''meta''-toluamide, also called DEET () or diethyltoluamide, is the most common active ingredient in insect repellents. It is a slightly yellow oil intended to be applied to the skin or to clothing and provides protection a ...
,
picaridin Icaridin, also known as picaridin, is an insect repellent which can be used directly on skin or clothing. It has broad efficacy against various arthropods such as mosquitos, ticks, gnats, flies and fleas, and is almost colorless and odorless. A s ...
,
ethyl butylacetylaminopropionate Ethyl butylacetylaminopropionate (trade name IR3535) is an insect repellent which is applied topically to prevent bites and stings from mosquitos, ticks, and other insects. It is a colorless and almost odorless oil, has efficacy against a broad ran ...
(IR3535), or oil of lemon eucalyptus on exposed skin. * Mosquitoes may bite through thin clothing, so spraying clothes with repellent containing
permethrin Permethrin is a medication and an insecticide. As a medication, it is used to treat scabies and lice. It is applied to the skin as a cream or lotion. As an insecticide, it can be sprayed onto clothing or mosquito nets to kill the insects th ...
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 Vaccination is the administration of a vaccine to help the immune system develop immunity from a disease. Vaccines contain a microorganism or virus in a weakened, live or killed state, or proteins or toxins from the organism. In stimulat ...
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 The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
(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 GAVI, officially Gavi, the Vaccine Alliance (previously the GAVI Alliance, and before that the Global Alliance for Vaccines and Immunization) is a public–private global health partnership with the goal of increasing access to immunization ...
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 Chikungunya is an infection caused by the ''Chikungunya virus'' (CHIKV). Symptoms include fever and joint pains. These typically occur two to twelve days after exposure. Other symptoms may include headache, muscle pain, joint swelling, and a r ...
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.
Larvicide A larvicide (alternatively larvacide) is an insecticide that is specifically targeted against the larval life stage of an insect. Their most common use is against mosquitoes. Larvicides may be contact poisons, stomach poisons, growth regulators, o ...
s 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 Vietnam or Viet Nam ( vi, Việt Nam, ), officially the Socialist Republic of Vietnam,., group="n" is a country in Southeast Asia, at the eastern edge of mainland Southeast Asia, with an area of and population of 96 million, making ...
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 Passive immunity is the transfer of active humoral immunity of ready-made antibodies. Passive immunity can occur naturally, when maternal antibodies are transferred to the fetus through the placenta, and it can also be induced artificially, when ...
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 Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of ...
(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 In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups ...
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 Nigeria ( ), , ig, Naìjíríyà, yo, Nàìjíríà, pcm, Naijá , ff, Naajeeriya, kcg, Naijeriya officially the Federal Republic of Nigeria, is a country in West Africa. It is situated between the Sahel to the north and the Gulf o ...
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 Slavery and enslavement are both the state and the condition of being a slave—someone forbidden to quit one's service for an enslaver, and who is treated by the enslaver as property. Slavery typically involves slaves being made to perf ...
from Africa. Genotype I has been divided into five subclades, A through E. In late 2016, a large outbreak began in
Minas Gerais Minas Gerais () is a state in Southeastern Brazil. It ranks as the second most populous, the third by gross domestic product (GDP), and the fourth largest by area in the country. The state's capital and largest city, Belo Horizonte (literall ...
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 Brazil ( pt, Brasil; ), officially the Federative Republic of Brazil (Portuguese: ), is the largest country in both South America and Latin America. At and with over 217 million people, Brazil is the world's fifth-largest country by area ...
,
Colombia Colombia (, ; ), officially the Republic of Colombia, is a country in South America with insular regions in North America—near Nicaragua's Caribbean coast—as well as in the Pacific Ocean. The Colombian mainland is bordered by the ...
,
Venezuela Venezuela (; ), officially the Bolivarian Republic of Venezuela ( es, link=no, República Bolivariana de Venezuela), is a country on the northern coast of South America, consisting of a continental landmass and many islands and islets in th ...
, and
Trinidad Trinidad is the larger and more populous of the two major islands of Trinidad and Tobago. The island lies off the northeastern coast of Venezuela and sits on the continental shelf of South America. It is often referred to as the southernmos ...
and
Tobago Tobago () is an island and ward within the Republic of Trinidad and Tobago. It is located northeast of the larger island of Trinidad and about off the northeastern coast of Venezuela. It also lies to the southeast of Grenada. The offic ...
, while genotype II accounted for all cases in
Peru , image_flag = Flag of Peru.svg , image_coat = Escudo nacional del Perú.svg , other_symbol = Great Seal of the State , other_symbol_type = National seal , national_motto = "Firm and Happy f ...
. 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 On 20 January 2016, the health minister of Angola reported 23 cases of yellow fever with 7 deaths among Eritrean and Congolese citizens living in Angola in Viana municipality, a suburb of the capital of Luanda. The first cases (hemorrhagic feve ...
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 The Atlantic slave trade, transatlantic slave trade, or Euro-American slave trade involved the transportation by slave traders of enslaved African people, mainly to the Americas. The slave trade regularly used the triangular trade route and ...
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 Barbados is an island country in the Lesser Antilles of the West Indies, in the Caribbean region of the Americas, and the most easterly of the Caribbean Islands. It occupies an area of and has a population of about 287,000 (2019 estima ...
. 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 That it may shine on all (Matthew 5:15) , image_map = Brazil Pernambuco Recife location map.svg , mapsize = 250px , map_caption = Location in the state of Pernambuco , pushpin_map = Brazil#South Am ...
. 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 A plantation is an agricultural estate, generally centered on a plantation house, meant for farming that specializes in cash crops, usually mainly planted with a single crop, with perhaps ancillary areas for vegetables for eating and so on. The ...
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 Napoleonic Wars (1803–1815) were a series of major global conflicts pitting the French Empire and its allies, led by Napoleon I, against a fluctuating array of European states formed into various coalitions. It produced a period of Fre ...
, 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 Jamaica (; ) is an island country situated in the Caribbean Sea. Spanning in area, it is the third-largest island of the Greater Antilles and the Caribbean (after Cuba and Hispaniola). Jamaica lies about south of Cuba, and west of Hispa ...
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 Haiti (; ht, Ayiti ; French: ), officially the Republic of Haiti (); ) and formerly known as Hayti, is a country located on the island of Hispaniola in the Greater Antilles archipelago of the Caribbean Sea, east of Cuba and Jamaica, and s ...
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 The Haitian Revolution (french: révolution haïtienne ; ht, revolisyon ayisyen) was a successful insurrection by self-liberated slaves against French colonial rule in Saint-Domingue, now the sovereign state of Haiti. The revolt began on ...
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 New York, often called New York City or NYC, is the List of United States cities by population, most populous city in the United States. With a 2020 population of 8,804,190 distributed over , New York City is also the L ...
in 1668. English colonists in
Philadelphia Philadelphia, often called Philly, is the largest city in the Commonwealth of Pennsylvania, the sixth-largest city in the U.S., the second-largest city in both the Northeast megalopolis and Mid-Atlantic regions after New York City. Since ...
and the French in the Mississippi River Valley recorded major outbreaks in 1669, as well as additional yellow fever epidemics in Philadelphia,
Baltimore Baltimore ( , locally: or ) is the most populous city in the U.S. state of Maryland, fourth most populous city in the Mid-Atlantic, and the 30th most populous city in the United States with a population of 585,708 in 2020. Baltimore was ...
, 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 During the 1793 yellow fever epidemic in Philadelphia, 5,000 or more people were listed in the official register of deaths between August 1 and November 9. The vast majority of them died of yellow fever, making the epidemic in the city of 50,0 ...
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 George Washington (February 22, 1732, 1799) was an American military officer, statesman, and Founding Father who served as the first president of the United States from 1789 to 1797. Appointed by the Continental Congress as commander of ...
. The southern city of
New Orleans New Orleans ( , ,New Orleans
was plagued with major epidemics during the 19th century, most notably in 1833 and 1853. A major epidemic occurred in both New Orleans and Shreveport, Louisiana in 1873. Its residents called the disease "yellow jack". Urban epidemics continued in the United States until 1905, with the last outbreak affecting New Orleans. At least 25 major outbreaks took place in the Americas during the 18th and 19th centuries, including particularly serious ones in
Cartagena, Chile Cartagena is a Chilean commune located in the San Antonio Province, Valparaíso Region. The commune spans an area of . History In the seventeenth century the area surrounding the town became a major producer of wheat, which was shipped to Peru a ...
, in 1741; Cuba in 1762 and 1900;
Santo Domingo , total_type = Total , population_density_km2 = auto , timezone = AST (UTC −4) , area_code_type = Area codes , area_code = 809, 829, 849 , postal_code_type = Postal codes , postal_code = 10100–10699 ( Distrito Nacional) , webs ...
in 1803; and
Memphis, Tennessee Memphis is a city in the U.S. state of Tennessee. It is the seat of Shelby County in the southwest part of the state; it is situated along the Mississippi River. With a population of 633,104 at the 2020 U.S. census, Memphis is the second-mo ...
, in 1878. In the early nineteenth century, the prevalence of yellow fever in the Caribbean "led to serious health problems" and alarmed the
United States Navy The United States Navy (USN) is the maritime service branch of the United States Armed Forces and one of the eight uniformed services of the United States. It is the largest and most powerful navy in the world, with the estimated tonnage ...
as numerous deaths and sickness curtailed naval operations and destroyed morale. One episode began in April 1822 when the frigate USS
Macedonian Macedonian most often refers to someone or something from or related to Macedonia. Macedonian(s) may specifically refer to: People Modern * Macedonians (ethnic group), a nation and a South Slavic ethnic group primarily associated with North Ma ...
left
Boston Boston (), officially the City of Boston, is the state capital and most populous city of the Commonwealth of Massachusetts, as well as the cultural and financial center of the New England region of the United States. It is the 24th- mo ...
and became part of Commodore James Biddle's West India Squadron. Unbeknownst to all, they were about to embark on a cruise to disaster and their assignment "would prove a cruise through hell". Secretary of the Navy Smith Thompson had assigned the squadron to guard United States merchant shipping and suppress piracy. During their time on deployment from 26 May to 3 August 1822, 76 of the Macedonian's officers and men died, including John Cadle, surgeon USN. Seventy-four of these deaths were attributed to yellow fever. Biddle reported that another 52 of his crew were on sick-list. In their report to the secretary of the Navy, Biddle and Surgeon's Mate Charles Chase stated the cause as "fever". As a consequence of this loss, Biddle noted that his squadron was forced to return to Norfolk Navy Yard early. Upon arrival, the Macedonian's crew were provided medical care and quarantined at Craney Island, Virginia. In 1853, Cloutierville, Louisiana, had a late-summer outbreak of yellow fever that quickly killed 68 of the 91 inhabitants. A local doctor concluded that some unspecified infectious agent had arrived in a package from New Orleans. In 1854, 650 residents of
Savannah, Georgia Savannah ( ) is the oldest city in the U.S. state of Georgia (U.S. state), Georgia and is the county seat of Chatham County, Georgia, Chatham County. Established in 1733 on the Savannah River, the city of Savannah became the Kingdom of Great Br ...
, died from yellow fever. In 1858,
St. Matthew's German Evangelical Lutheran Church The German Evangelical Lutheran Church of Charleston, South Carolina, was incorporated on December 3, 1840. Through usage and custom the Church is now known as St. Matthew's German Evangelical Lutheran Church or St. Matthew's Lutheran Church and ...
in
Charleston, South Carolina Charleston is the largest city in the U.S. state of South Carolina, the county seat of Charleston County, and the principal city in the Charleston–North Charleston metropolitan area. The city lies just south of the geographical midpoint o ...
, had 308 yellow fever deaths, reducing the congregation by half. A ship carrying persons infected with the virus arrived in Hampton Roads in southeastern
Virginia Virginia, officially the Commonwealth of Virginia, is a state in the Mid-Atlantic and Southeastern regions of the United States, between the Atlantic Coast and the Appalachian Mountains. The geography and climate of the Commonwealth are ...
in June 1855. (undated newspaper clipping). The disease spread quickly through the community, eventually killing over 3,000 people, mostly residents of
Norfolk Norfolk () is a ceremonial and non-metropolitan county in East Anglia in England. It borders Lincolnshire to the north-west, Cambridgeshire to the west and south-west, and Suffolk to the south. Its northern and eastern boundaries are the Nor ...
and
Portsmouth Portsmouth ( ) is a port and city in the ceremonial county of Hampshire in southern England. The city of Portsmouth has been a unitary authority since 1 April 1997 and is administered by Portsmouth City Council. Portsmouth is the most d ...
. In 1873, Shreveport, Louisiana, lost 759 citizens in an 80-day period to a yellow fever epidemic, with over 400 additional victims eventually succumbing. The total death toll from August through November was approximately 1,200. In 1878, about 20,000 people died in a widespread epidemic in the Mississippi River Valley. That year, Memphis had an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge epidemic of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but passengers were not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi River for the next two months before unloading her passengers. Major outbreaks have also occurred in southern Europe.
Gibraltar ) , anthem = " God Save the King" , song = "Gibraltar Anthem" , image_map = Gibraltar location in Europe.svg , map_alt = Location of Gibraltar in Europe , map_caption = United Kingdom shown in pale green , mapsize = , image_map2 = Gibr ...
lost many lives to outbreaks in 1804, 1814, and 1828.
Barcelona Barcelona ( , , ) is a city on the coast of northeastern Spain. It is the capital and largest city of the autonomous community of Catalonia, as well as the second most populous municipality of Spain. With a population of 1.6 million within c ...
suffered the loss of several thousand citizens during an outbreak in 1821. The Duke de Richelieu deployed 30,000 French troops to the border between
France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...
and
Spain , image_flag = Bandera de España.svg , image_coat = Escudo de España (mazonado).svg , national_motto = '' Plus ultra'' (Latin)(English: "Further Beyond") , national_anthem = (English: "Royal March") , ...
in the Pyrenees Mountains, to establish a '' cordon sanitaire'' in order to prevent the epidemic from spreading from Spain into France.James Taylor, ''The age we live in: a history of the nineteenth century,'' Oxford University, 1882; p. 222.


Causes and transmission

Ezekiel Stone Wiggins, known as the Ottawa Prophet, proposed that the cause of a yellow fever epidemic in
Jacksonville, Florida Jacksonville is a city located on the Atlantic coast of northeast Florida, the most populous city proper in the state and is the largest city by area in the contiguous United States as of 2020. It is the seat of Duval County, with which th ...
, in 1888, was astrological. In 1848, Josiah C. Nott suggested that yellow fever was spread by insects such as moths or mosquitoes, basing his ideas on the pattern of transmission of the disease.
Carlos Finlay Carlos Juan Finlay (December 3, 1833 – August 20, 1915) was a Cuban epidemiologist recognized as a pioneer in the research of yellow fever, determining that it was transmitted through mosquitoes ''Aedes aegypti''. Biography Early life and ...
, a Cuban doctor and scientist, proposed in 1881 that yellow fever might be transmitted by previously infected mosquitoes rather than by direct contact from person to person, as had long been believed. Since the losses from yellow fever in the
Spanish–American War , partof = the Philippine Revolution, the decolonization of the Americas, and the Cuban War of Independence , image = Collage infobox for Spanish-American War.jpg , image_size = 300px , caption = (clock ...
in the 1890s were extremely high, Army doctors began research experiments with a team led by Walter Reed, and composed of doctors James Carroll, Aristides Agramonte, and Jesse William Lazear. They successfully proved Finlay's "mosquito hypothesis". Yellow fever was the first virus shown to be transmitted by mosquitoes. The physician
William Gorgas William Crawford Gorgas KCMG (October 3, 1854 – July 3, 1920) was a United States Army physician and 22nd Surgeon General of the U.S. Army (1914–1918). He is best known for his work in Florida, Havana and at the Panama Canal in abating ...
applied these insights and eradicated yellow fever from
Havana Havana (; Spanish: ''La Habana'' ) is the capital and largest city of Cuba. The heart of the La Habana Province, Havana is the country's main port and commercial center.
. He also campaigned against yellow fever during the construction of the
Panama Canal The Panama Canal ( es, Canal de Panamá, link=no) is an artificial waterway in Panama that connects the Atlantic Ocean with the Pacific Ocean and divides North and South America. The canal cuts across the Isthmus of Panama and is a condui ...
. A previous effort of canal building by the French had failed in part due to mortality from the high incidence of yellow fever and malaria, which killed many workers. Although Reed has received much of the credit in United States history books for "beating" yellow fever, he had fully credited Finlay with the discovery of the yellow fever vector, and how it might be controlled. Reed often cited Finlay's papers in his own articles, and also credited him for the discovery in his personal correspondence. The acceptance of Finlay's work was one of the most important and far-reaching effects of the U.S. Army Yellow Fever Commission of 1900. Applying methods first suggested by Finlay, the United States government and Army eradicated yellow fever in Cuba and later in Panama, allowing completion of the Panama Canal. While Reed built on the research of Finlay, historian François Delaporte notes that yellow fever research was a contentious issue. Scientists, including Finlay and Reed, became successful by building on the work of less prominent scientists, without always giving them the credit they were due. Reed's research was essential in the fight against yellow fever. He is also credited for using the first type of medical consent form during his experiments in Cuba, an attempt to ensure that participants knew they were taking a risk by being part of testing. Like Cuba and Panama, Brazil also led a highly successful sanitation campaign against mosquitoes and yellow fever. Beginning in 1903, the campaign led by Oswaldo Cruz, then director general of public health, resulted not only in eradicating the disease but also in reshaping the physical landscape of Brazilian cities such as Rio de Janeiro. During rainy seasons, Rio de Janeiro had regularly suffered floods, as water from the bay surrounding the city overflowed into Rio's narrow streets. Coupled with the poor drainage systems found throughout Rio, this created swampy conditions in the city's neighborhoods. Pools of stagnant water stood year-long in city streets and proved to be a fertile ground for disease-carrying mosquitoes. Thus, under Cruz's direction, public health units known as "mosquito inspectors" fiercely worked to combat yellow fever throughout Rio by spraying, exterminating rats, improving drainage, and destroying unsanitary housing. Ultimately, the city's sanitation and renovation campaigns reshaped Rio de Janeiro's neighborhoods. Its poor residents were pushed from city centers to Rio's suburbs, or to towns found in the outskirts of the city. In later years, Rio's most impoverished inhabitants would come to reside in ''favelas''. During 1920–1923, the Rockefeller Foundation's
International Health Board The Rockefeller Foundation is an American private foundation and philanthropic medical research and arts funding organization based at 420 Fifth Avenue, New York City. The second-oldest major philanthropic institution in America, after the Car ...
undertook an expensive and successful yellow fever eradication campaign in Mexico. The IHB gained the respect of Mexico's federal government because of the success. The eradication of yellow fever strengthened the relationship between the US and Mexico, which had not been very good in the years prior. The eradication of yellow fever was also a major step toward better global health. In 1927, scientists isolated the ''yellow fever virus'' in West Africa. Following this, two vaccines were developed in the 1930s. Max Theiler led the completion of the 17D yellow fever vaccine in 1937, for which he was subsequently awarded the
Nobel Prize in Physiology or Medicine The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, accordi ...
. That vaccine, 17D, is still in use, although newer vaccines, based on vero cells, are in development (as of 2018)..


Current status

Using vector control and strict vaccination programs, the urban cycle of yellow fever was nearly eradicated from South America. Since 1943, only a single urban outbreak in
Santa Cruz de la Sierra Santa Cruz de la Sierra (; "Holy Cross of the Mountain Range"), commonly known as Santa Cruz, is the largest city in Bolivia and the capital of the Santa Cruz department. Situated on the Pirai River in the eastern Tropical Lowlands of Bolivia ...
, Bolivia, has occurred. Since the 1980s, however, the number of yellow fever cases has been increasing again, and ''A. aegypti'' has returned to the urban centers of South America. This is partly due to limitations on available insecticides, as well as habitat dislocations caused by climate change. It is also because the vector control program was abandoned. Although no new urban cycle has yet been established, scientists believe this could happen again at any point. An outbreak in
Paraguay Paraguay (; ), officially the Republic of Paraguay ( es, República del Paraguay, links=no; gn, Tavakuairetã Paraguái, links=si), is a landlocked country in South America. It is bordered by Argentina to the south and southwest, Brazil to t ...
in 2008 was thought to be urban in nature, but this ultimately proved not to be the case. In Africa, virus eradication programs have mostly relied upon vaccination. These programs have largely been unsuccessful because they were unable to break the sylvatic cycle involving wild primates. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the future spread of the virus more likely.


Research

In the hamster model of yellow fever, early administration of the antiviral ribavirin is an effective 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 the liver and
spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .
, prevented hepatocellular steatosis, and normalised levels of alanine aminotransferase, a liver damage marker. The mechanism of action of ribavirin in reducing liver pathology in ''yellow fever virus'' infection may be similar to its activity in treatment of
hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, ...
, a related virus. Because ribavirin had failed to improve survival in a virulent rhesus model of yellow fever infection, it had been previously discounted as a possible therapy. Infection was reduced in mosquitoes with the wMel strain of '' Wolbachia''. Yellow fever has been researched by several countries as a potential biological weapon.


Notes


References


Further reading

* * * * * *


External links

* *
"U.S. Army Yellow Fever Commission."
Claude Moore Health Sciences Library,
University of Virginia The University of Virginia (UVA) is a public research university in Charlottesville, Virginia. Founded in 1819 by Thomas Jefferson, the university is ranked among the top academic institutions in the United States, with highly selective ad ...
* {{DEFAULTSORT:Yellow Fever Biological weapons Epidemics Wikipedia medicine articles ready to translate Wikipedia infectious disease articles ready to translate Tropical diseases Vaccine-preventable diseases