Yellow fever

Yellow fever

Overview
Yellow fever is an acute
Acute (medicine)
In medicine, an acute disease is a disease with either or both of:# a rapid onset, as in acute infection# a short course ....

 viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...

 with positive sense
Sense (molecular biology)
In molecular biology and genetics, sense is a concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules...

 of the Flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...

 family.

The yellow fever virus is transmitted by the bite of female mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

es (the yellow fever mosquito, Aedes aegypti
Aedes aegypti
The yellow fever mosquito, Aedes aegypti is a mosquito that can spread the dengue fever, Chikungunya and yellow fever viruses, and other diseases. The mosquito can be recognized by white markings on legs and a marking in the form of a lyre on the thorax...

, and other species) and is found in tropic
Tropics
The tropics is a region of the Earth surrounding the Equator. It is limited in latitude by the Tropic of Cancer in the northern hemisphere at approximately  N and the Tropic of Capricorn in the southern hemisphere at  S; these latitudes correspond to the axial tilt of the Earth...

al and subtropic
Subtropics
The subtropics are the geographical and climatical zone of the Earth immediately north and south of the tropical zone, which is bounded by the Tropic of Cancer and the Tropic of Capricorn, at latitudes 23.5°N and 23.5°S...

al areas in South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...

 and Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...

, but not in Asia
Asia
Asia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...

. The only known hosts of the virus are primates and several species of mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

.
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Encyclopedia
Yellow fever is an acute
Acute (medicine)
In medicine, an acute disease is a disease with either or both of:# a rapid onset, as in acute infection# a short course ....

 viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 hemorrhagic disease. The virus is a 40 to 50 nm enveloped RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...

 with positive sense
Sense (molecular biology)
In molecular biology and genetics, sense is a concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules...

 of the Flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...

 family.

The yellow fever virus is transmitted by the bite of female mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

es (the yellow fever mosquito, Aedes aegypti
Aedes aegypti
The yellow fever mosquito, Aedes aegypti is a mosquito that can spread the dengue fever, Chikungunya and yellow fever viruses, and other diseases. The mosquito can be recognized by white markings on legs and a marking in the form of a lyre on the thorax...

, and other species) and is found in tropic
Tropics
The tropics is a region of the Earth surrounding the Equator. It is limited in latitude by the Tropic of Cancer in the northern hemisphere at approximately  N and the Tropic of Capricorn in the southern hemisphere at  S; these latitudes correspond to the axial tilt of the Earth...

al and subtropic
Subtropics
The subtropics are the geographical and climatical zone of the Earth immediately north and south of the tropical zone, which is bounded by the Tropic of Cancer and the Tropic of Capricorn, at latitudes 23.5°N and 23.5°S...

al areas in South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...

 and Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...

, but not in Asia
Asia
Asia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...

. The only known hosts of the virus are primates and several species of mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

. The origin of the disease is most likely to be Africa, from where it was introduced to South America through the slave trade in the 16th century. Since the 17th century, several major epidemics of the disease have been recorded in the Americas, Africa and Europe. In the 19th century, yellow fever was deemed one of the most dangerous infectious disease
Infectious disease
Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

s.

Yellow fever presents in most cases with fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...

, and pain and it generally subsides after several days. In some patients, a toxic phase follows, in which liver damage with jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

 (giving the name of the disease) can occur and lead to death. Because of the increased bleeding tendency (bleeding diathesis
Bleeding diathesis
In medicine , bleeding diathesis is an unusual susceptibility to bleeding mostly due to hypocoagulability, in turn caused by a coagulopathy . Several types are distinguished, ranging from mild to lethal...

), yellow fever belongs to the group of hemorrhagic fevers
Viral hemorrhagic fever
The viral hemorrhagic fevers are a diverse group of animal and human illnesses that are caused by four distinct families of RNA viruses: the families Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress...

. The WHO
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 estimates that yellow fever causes 200,000 illnesses and 30,000 deaths every year in unvaccinated populations; around 90% of the infections occur in Africa.

A safe and effective vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 against yellow fever has existed since the middle of the 20th century and some countries require vaccinations for travelers. Since no therapy is known, vaccination programs are, along with measures to reduce the population of the transmitting mosquito, of great importance in affected areas. Since the 1980s, the number of cases of yellow fever has been increasing, making it a reemerging disease.

Signs and symptoms


Yellow fever begins after an incubation period of three to six days. Most cases only cause a mild infection with fever, headache, chills, back pain, loss of appetite, nausea and vomiting. In these cases the infection lasts only three to four days. In fifteen percent of cases, however, sufferers enter a second, toxic phase of the disease with recurring fever, this time accompanied by jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

 due to liver damage
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...

, as well as abdominal pain. Bleeding in the mouth, the eyes and in the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....

 can cause vomitus containing blood
Hematemesis
Hematemesis or haematemesis is the vomiting of blood. The source is generally the upper gastrointestinal tract. Patients can easily confuse it with hemoptysis , although the latter is more common.-Signs:...

 (giving the name black vomit). The toxic phase is fatal in approximately 20% of cases, making the overall fatality rate for the disease 3% (15% * 20%).

Surviving the infection causes life-long immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...

 and normally there is no permanent organ damage.

Cause



Yellow fever is caused by the yellow fever virus, a 40 to 50 nm wide enveloped RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...

 belonging to the family Flaviviridae
Flaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...

. The positive sense
Sense (molecular biology)
In molecular biology and genetics, sense is a concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules...

 single-stranded RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....

 is approximately 11,000 nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...

s long and has a single open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...

 encoding a polyprotein. Host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...

 protease
Protease
A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

s cut this polyprotein into three structural (C, prM, E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the enumeration corresponds to the arrangement of the protein coding gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s in the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

.
The viruses infect amongst others monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...

s. They attach to the cell surface via specific receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

s and are taken up by an endosomal vesicle
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...

. Inside the endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...

, the decreased pH
PH
In chemistry, pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at . Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline...

 induces the fusion of the endosomal membrane with the virus envelope. Thus, the capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...

 reaches the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

, decays and releases the genome. Receptor binding as well as membrane fusion are catalyzed
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....

 by the protein E, which changes its conformation at low pH, which causes a rearrangement of the 90 homodimer
Protein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...

s to 60 homotrimers.

After entering the host cells, the viral genome is replicated in the rough endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...

 (ER) and in the so-called vesicle packets
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

. 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
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....

 by the host protein furin
Furin
Furin is a protein that in humans is encoded by the FURIN gene. It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR and therefore the protein was named furin...

, which cleaves prM to M. This releases E from the complex which can now take its place in the mature, infectious virion.

Transmission



The yellow fever virus is mainly transmitted through the bite of the yellow fever mosquito Aedes aegypti, but other mosquitoes such as the "tiger mosquito" (Aedes albopictus) can also serve as a vector for the virus. Like other Arbovirus
Arbovirus
Arbovirus is a term used to refer to a group of viruses that are transmitted by arthropod vectors. The word arbovirus is an acronym . Some arboviruses are able to cause emergent disease.-Transmission:...

es which are transmitted via mosquitoes, the yellow fever virus is taken up by a female mosquito which sucks the blood of an infected person. 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 gland
Salivary gland
The salivary glands in mammals are exocrine glands, glands with ducts, that produce saliva. They also secrete amylase, an enzyme that breaks down starch into maltose...

s. 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 transovarial and transstadial transmission of the yellow fever virus within A. aegypti, i.e., the transmission from a female mosquito to her eggs and then larvae. 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 mosquitoes 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 also transmit other diseases including Dengue and Chikungunya
Chikungunya
Chikungunya virus is an insect-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes. There have been recent breakouts of CHIKV associated with severe illness...

. The urban cycle is responsible for the major outbreaks of yellow fever that occur in Africa. Except in an outbreak in 1999 in Bolivia, this urban cycle no longer exists in South America and is only present in Africa.

Besides the urban cycle there is, both in Africa and South America, a sylvatic cycle
Sylvatic cycle
The sylvatic cycle, also enzootic or sylvatic transmission cycle, is a portion of the natural transmission cycle of a pathogen. The sylvatic cycle is the fraction of the pathogen population's lifespan spent cycling between wild animals and vectors. Humans are usually an incidental or dead-end host,...

 (Forest cycle or Jungle
Jungle
A Jungle is an area of land in the tropics overgrown with dense vegetation.The word jungle originates from the Sanskrit word jangala which referred to uncultivated land. Although the Sanskrit word refers to "dry land", it has been suggested that an Anglo-Indian interpretation led to its...

 cycle), where Aedes africanus (in Africa) or mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

es of the genus
Genus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...

 Haemagoggus and Sabethes (in South America) serve as a vector. In the jungle, mainly non-human primates get infected; the disease is mostly asymptomatic in African primates. In South America, the sylvatic cycle is currently the only way humans can infect themselves, 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 Aedes aegypti acts as a vector. It is because of this sylvatic cycle that yellow fever cannot be eradicated.

In Africa there is a third infectious cycle, also known as savannah
Savannah
Savannah or savanna is a type of grassland.It can also mean:-People:* Savannah King, a Canadian freestyle swimmer* Savannah Outen, a singer who gained popularity on You Tube...

 cycle or intermediate cycle, which occurs between the jungle and urban cycle. Different mosquitoes of the genus Aedes
Aedes
Aedes is a genus of mosquito originally found in tropical and subtropical zones, but now found on all continents excluding Antarctica. Some species have been spread by human activity. Aedes albopictus, a most invasive species was recently spread to the New World, including the U.S., by the used...

are involved. In recent years this is the most common form of yellow fever seen in Africa.

Pathogenesis


After transmission of the virus from a mosquito the viruses replicate in the lymph nodes and infect dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...

s in particular. From there they reach the liver and infect hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...

s (probably indirectly via Kupffer cell
Kupffer cell
Kupffer cells, also known as Browicz-Kupffer cells and stellate macrophages, are specialized macrophages located in the liver lining the walls of the sinusoids that form part of the reticuloendothelial system .-History:The cells were first observed by Karl Wilhelm von Kupffer in 1876...

s), which leads to eosinophilic degradation
Eosinophil granulocyte
Eosinophil granulocytes, usually called eosinophils or eosinophiles , are white blood cells that are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with...

 of these cells and to the release of cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s. Necrotic masses (Councilman bodies
Councilman body
In pathology, a Councilman body, also known as Councilman hyaline body, is an eosinophilic globule often found in the liver of individuals suffering from viral hepatitis, yellow fever, or other viral syndrome...

) appear in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 of hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...

s.

When the disease takes a deadly course, a cardiovascular shock and multi organ failure
Multiple organ dysfunction syndrome
Multiple organ dysfunction syndrome ', previously known as multiple organ failure or multisystem organ failure , is altered organ function in an acutely ill patient requiring medical intervention to achieve homeostasis...

 with strongly increased cytokine levels (cytokine storm
Cytokine storm
A cytokine storm, or hypercytokinemia is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and immune cells, with highly elevated levels of various cytokines.-Symptoms:...

) follow.

Diagnosis


Yellow fever is a clinical diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...

, which often relies on the whereabouts of the diseased person during the incubation time. Mild courses of the disease can only be confirmed virologically. Since also mild courses of yellow fever can significantly contribute to regional outbreaks, every suspected yellow fever has to be treated seriously (six to ten days after leaving the affected area symptoms of fever, pain, nausea and vomiting).

If yellow fever is suspected, the virus cannot be confirmed until six to ten days after the illness. A direct confirmation can be obtained by Reverse transcription polymerase chain reaction
Reverse transcription polymerase chain reaction
Reverse transcription polymerase chain reaction is a variant of polymerase chain reaction , a laboratory technique commonly used in molecular biology to generate many copies of a DNA sequence, a process termed "amplification"...

 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
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...

; this can take one to four weeks.

Serologically an enzyme linked immunosorbent assay
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...

 during the acute phase of the disease using specific IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...

 against yellow fever or an increase in specific IgG-titer
Titer
A titer is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a positive...

 (compared to an earlier sample) can confirm yellow fever. Together with clinical symptoms, the detection of IgM or a fourfold increase in IgG-titer is considered sufficient indication for yellow fever. Since these tests can cross-react with other Flaviviruses, like Dengue virus
Dengue virus
Dengue virus in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus...

, these indirect methods can never prove yellow fever infection.
Liver biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

 can verify inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 and necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...

 of hepatocytes and detect viral antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...

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
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...

, infections with yellow fever have to be distinguished from other feverish illnesses like malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

. Other viral hemorrhagic fever
Viral hemorrhagic fever
The viral hemorrhagic fevers are a diverse group of animal and human illnesses that are caused by four distinct families of RNA viruses: the families Arenaviridae, Filoviridae, Bunyaviridae, and Flaviviridae. All types of VHF are characterized by fever and bleeding disorders and all can progress...

, such as Ebola virus
Ebola virus
Ebola virus causes severe disease in humans and in nonhuman primates in the form of viral hemorrhagic fever. EBOV is a Select Agent, World Health Organization Risk Group 4 Pathogen , National Institutes of Health/National Institute of Allergy and Infectious Diseases Category A Priority Pathogen,...

, Lassa virus, Marburg virus
Marburg virus
Marburg virus disease is the name for the human disease caused by any of the two marburgviruses Marburg virus and Ravn virus...

 or Junin virus
Junin virus
-Morphology and genome structure:The Junin virus virion is enveloped with a variable diameter of between 50 and 300 nm. The surface of the particle encompasses a layer of T-shaped glycoprotein extensions, extending up to 10 nm from the envelope, which are important for mediating...

 have to be excluded as cause.

Prevention


Personal prevention of yellow fever includes vaccination as well as avoidance of mosquito bites in areas where yellow fever is endemic. Institutional measures for prevention of yellow fever include vaccination programmes and measures of controlling mosquitoes.

Vaccination


For journeys into affected areas, vaccination is highly recommended since mostly non-native people are affected by severe cases of yellow fever. The protective effect is established 10 days after vaccination in 95% of the vaccinated people and lasts for at least 10 years (even 30 years later, 81% of patients retained the immunity).
The attenuated live vaccine
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...

 (stem 17D) was developed in 1937 by Max Theiler
Max Theiler
Max Theiler was a South African/American virologist. He was awarded the Nobel Prize in Physiology or Medicine in 1951 for developing a vaccine against yellow fever.-Career development:...

 from a diseased patient in Ghana and is produced in chicken eggs. WHO recommends routine vaccinations for people living in endemic areas between the 9th and 12th month after birth.

In about 20% of all cases, mild, flu-like symptoms may develop.
In rare cases (less than one in 200,000 to 300,000), 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. But in some vaccination campaigns, a 20 fold higher incidence rate has been reported. Age is an important risk factor; in children the complication rate is less than one case per 10 million vaccinations.
Another possible side effect is an infection of the nervous system that occurs in one in 200,000 to 300,000 of all cases, causing YEL-AND (yellow fever vaccine-associated neurotropic disease), which can cause meningoencephalitis
Meningoencephalitis
Meningoencephalitis is a medical condition that simultaneously resembles both meningitis, which is an infection or inflammation of the meninges, and encephalitis, which is an infection or inflammation of the brain.-Causes:...

 and is less than 5% of all cases fatal.

In 2009, the largest mass vaccination against yellow fever commenced in West Africa
West Africa
West Africa or Western Africa is the westernmost region of the African continent. Geopolitically, the UN definition of Western Africa includes the following 16 countries and an area of approximately 5 million square km:-Flags of West Africa:...

, specifically Benin
Benin
Benin , officially the Republic of Benin, is a country in West Africa. It borders Togo to the west, Nigeria to the east and Burkina Faso and Niger to the north. Its small southern coastline on the Bight of Benin is where a majority of the population is located...

, Liberia
Liberia
Liberia , officially the Republic of Liberia, is a country in West Africa. It is bordered by Sierra Leone on the west, Guinea on the north and Côte d'Ivoire on the east. Liberia's coastline is composed of mostly mangrove forests while the more sparsely populated inland consists of forests that open...

 and Sierra Leone
Sierra Leone
Sierra Leone , officially the Republic of Sierra Leone, is a country in West Africa. It is bordered by Guinea to the north and east, Liberia to the southeast, and the Atlantic Ocean to the west and southwest. Sierra Leone covers a total area of and has an estimated population between 5.4 and 6.4...

. When it is completed in 2015, more than 12 million people will have been vaccinated against the disease. According to the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

, the mass vaccination cannot eliminate yellow fever because of the massive number of infected mosquitoes in urban areas of the target countries, but it will significantly reduce the number of people infected. However, the WHO plans to continue the vaccination campaign in another five African countries—Central African Republic
Central African Republic
The Central African Republic , is a landlocked country in Central Africa. It borders Chad in the north, Sudan in the north east, South Sudan in the east, the Democratic Republic of the Congo and the Republic of the Congo in the south, and Cameroon in the west. The CAR covers a land area of about ,...

, Ghana
Ghana
Ghana , officially the Republic of Ghana, is a country located in West Africa. It is bordered by Côte d'Ivoire to the west, Burkina Faso to the north, Togo to the east, and the Gulf of Guinea to the south...

, Guinea
Guinea
Guinea , officially the Republic of Guinea , is a country in West Africa. Formerly known as French Guinea , it is today sometimes called Guinea-Conakry to distinguish it from its neighbour Guinea-Bissau. Guinea is divided into eight administrative regions and subdivided into thirty-three prefectures...

, Ivory Coast and Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...

—and stated that approximately 160 million people in the continent could be at risk unless the organization acquires additional funding.

Compulsory vaccination


Some countries in Asia are theoretically in danger of yellow fever epidemics (mosquitoes with the capability to transmit yellow fever and susceptible monkeys are present), even though the disease does not yet occur there. To prevent introduction of the virus, some countries demand previous vaccination of foreign visitors, if they have 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 is published by the WHO. If the vaccination cannot be conducted for some reasons, dispensation is possible. In this case an exemption certificate issued by a WHO approved vaccination center is required.

Even though 32 of 44 countries where yellow fever occurs endemically do have vaccination programmes, in many of these countries fewer than 50% of their population is vaccinated.

Vector control


Besides vaccination, control of the yellow fever mosquito Aedes aegypti is of major importance, especially because the same mosquito can also transmit Dengue and Chikungunya
Chikungunya
Chikungunya virus is an insect-borne virus, of the genus Alphavirus, that is transmitted to humans by virus-carrying Aedes mosquitoes. There have been recent breakouts of CHIKV associated with severe illness...

 disease. Aedes aegypti breeds preferentially in water, for example in installations by inhabitants of areas with precarious drinking water supply, or in domestic waste; especially tires, cans and plastic bottles. Especially in proximity to urban centres of developing countries these conditions are very common and make a perfect habitat for Aedes aegypti. Two strategies are employed to fight the mosquito:

One approach is to kill the developing larva. Measures are taken to reduce water build-up (the habitat of the larva), and larvicide
Larvicide
A larvicide is an insecticide that is specifically targeted against the larval life stage of an insect. Their most common use is against mosquitoes...

s are used as well as larva-eating fish and copepod
Copepod
Copepods are a group of small crustaceans found in the sea and nearly every freshwater habitat. Some species are planktonic , some are benthic , and some continental species may live in limno-terrestrial habitats and other wet terrestrial places, such as swamps, under leaf fall in wet forests,...

s, which reduce the number of larva and thus indirectly the number of disease-transmitting mosquitoes. For many years, copepods of the genus Mesocyclops
Mesocyclops
Mesocyclops is a genus of copepod crustaceans in the family Cyclopidae. Mesocyclops is used as a nontoxic and inexpensive form of biological mosquito control.-Biological control:...

have been used in Vietnam
Vietnam
Vietnam – sometimes spelled Viet Nam , officially the Socialist Republic of Vietnam – is the easternmost country on the Indochina Peninsula in Southeast Asia. It is bordered by China to the north, Laos to the northwest, Cambodia to the southwest, and the South China Sea –...

 for fighting Dengue fever (yellow fever does not occur in Asia), with the effect that in the affected areas no cases of Dengue fever have occurred since 2001. Similar mechanisms are probably also effective against yellow fever. Pyriproxyfen
Pyriproxyfen
Pyriproxyfen is a pyridine based pesticide which is found to be effective against a variety of arthropoda. It was introduced to the US in 1996 to protect cotton crops against whitefly...

 is recommended as a chemical larvicide, mainly because it is safe for humans and effective even in small doses.

Besides larva, the adult yellow fever mosquitoes are also targeted. The curtains and lids of water tanks are sprayed with insecticide
Insecticide
An insecticide is a pesticide used against insects. They include ovicides and larvicides used against the eggs and larvae of insects respectively. Insecticides are used in agriculture, medicine, industry and the household. The use of insecticides is believed to be one of the major factors behind...

s. Spraying insecticides inside houses is another measure, although it is not recommended by the WHO. Similar to the malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

 carrier, the Anopheles
Anopheles
Anopheles is a genus of mosquito. There are approximately 460 recognized species: while over 100 can transmit human malaria, only 30–40 commonly transmit parasites of the genus Plasmodium, which cause malaria in humans in endemic areas...

mosquito, insecticide treated mosquito net
Mosquito net
A mosquito net offers protection against mosquitos, flies, and other insects, and thus against diseases such as malaria, dengue fever, yellow fever, and various forms of encephalitis, including the West Nile virus, if used properly and especially if treated with an insecticide, which can double...

s are used successfully against Aedes aegypti.

Treatment


For yellow fever there is, like for all diseases caused by Flavivirus
Flavivirus
Flavivirus is a genus of the family Flaviviridae. This genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, and several other viruses which may cause encephalitis....

es, no causative cure. Hospitalization is advisable and intensive care may be necessary because of rapid deterioration in some cases. Different methods for acute treatment of the disease have been shown to not be very successful; passive immunisation after emergence of symptoms is probably without effect. Ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...

 and other antiviral drug
Antiviral drug
Antiviral drugs are a class of medication used specifically for treating viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses...

s as well as treatment with interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

s do not have a positive effect in patients.
A symptomatic treatment includes rehydration and pain relief with drugs like paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (known as acetaminophen in the United States). Acetylsalicylic acid
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 (for example Aspirin) should not be given because of its anticoagulant effect, which can be devastating in the case of inner bleeding that can occur with yellow fever.

Epidemiology


Yellow fever is endemic
Endemic (epidemiology)
In epidemiology, an infection is said to be endemic in a population when that infection is maintained in the population without the need for external inputs. For example, chickenpox is endemic in the UK, but malaria is not...

 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
Middle East
The Middle East is a region that encompasses Western Asia and Northern Africa. It is often used as a synonym for Near East, in opposition to Far 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
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 amount to 200,000 cases of disease and 30,000 deaths a year; the number of officially reported cases is far lower. An estimated 90% of the infections occur on the African continent. In 2008, the largest number of cases was recorded in Togo.

Phylogenetic analysis identified seven genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...

s of yellow fever viruses, and it is assumed that they are differently adapted to humans and to the vector Aedes aegypti. Five genotypes occur solely in Africa, and is assumed that the West Africa–genotype I is especially virulent or infectious, because this type is often associated with major outbreaks of yellow fever. In South America two genotypes have been identified.

History





The evolutionary origins of yellow fever most likely lie in Africa.
It is thought that the virus originated in East or Central Africa and spread from there to West Africa. When an outbreak of yellow fever would occur in an African village with colonists, it would wipe out nearly all the Europeans, while leaving the native population with usually nonlethal symptoms resembling influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

. The virus as well as the vector A. aegypti were probably transferred to South America by ship. The first recorded outbreak of the disease was in 1648 in Yucatan
Yucatán
Yucatán officially Estado Libre y Soberano de Yucatán is one of the 31 states which, with the Federal District, comprise the 32 Federal Entities of Mexico. It is divided in 106 municipalities and its capital city is Mérida....

, where the illness was termed xekik (black vomit). At least 25 major outbreaks followed. In colonial times and during the Napoleonic wars, the West Indies was a particularly dangerous posting, and both the English and French forces posted there were decimated by the "Yellow Jack". Napoleon had his eye on conquering the New World, and sent his brother-in-law in command of an army to seize control of Haiti, but over 27,000 of his troops perished of the "Yellow Jack", including their commander. An outbreak as far north as Philadelphia in 1793 resulted in the deaths of several thousand people and forced the administration to flee the city, including president George Washington
George Washington
George Washington was the dominant military and political leader of the new United States of America from 1775 to 1799. He led the American victory over Great Britain in the American Revolutionary War as commander-in-chief of the Continental Army from 1775 to 1783, and presided over the writing of...

. Yellow fever epidemics in North America have caused some 100,000-150,000 deaths. Major outbreaks have also occurred in southern Europe. Barcelona
Barcelona
Barcelona is the second largest city in Spain after Madrid, and the capital of Catalonia, with a population of 1,621,537 within its administrative limits on a land area of...

 suffered the loss of several thousand citizens during an outbreak in 1821. St. Matthew's German Evangelical Lutheran Church
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...

 in Charleston, South Carolina suffered 308 yellow fever deaths in 1858, reducing the congregation by half. In 1873, Shreveport Louisiana lost almost a quarter of its population to yellow fever, and in 1878, about 20,000 people died in an epidemic in the Mississippi River Valley. The last major U.S. outbreak was in 1905 in New Orleans. In 1878 Memphis was hit with an unusually large amount of rain, which led to an increase in the mosquito population. The result was a huge outbreak of yellow fever. The steamship John D. Porter took people fleeing Memphis northward in hopes of escaping the disease, but the ship was not allowed to disembark due to concerns of spreading yellow fever. The ship roamed the Mississippi for the next two months before unloading her passengers.

Carlos Finlay
Carlos Finlay
Carlos Juan Finlay was a Cuban physician and scientist recognized as a pioneer in yellow fever research.- Early life and education :...

, a Cuban doctor and scientist, first proposed in 1881 that yellow fever might be transmitted by mosquito
Mosquito
Mosquitoes are members of a family of nematocerid flies: the Culicidae . The word Mosquito is from the Spanish and Portuguese for little fly...

es rather than direct human contact. Since the losses from yellow fever in the Spanish–American War in the 1890s were thirteenfold higher than the losses due to military operations, further experiments were conducted by a team under Walter Reed
Walter Reed
Major Walter Reed, M.D., was a U.S. Army physician who in 1900 led the team that postulated and confirmed the theory that yellow fever is transmitted by a particular mosquito species, rather than by direct contact...

, composed of doctors James Carroll, Aristides Agramonte, and Jesse Lazear, that successfully proved the ″Mosquito Hypothesis″. Yellow fever was thus the first virus shown to be transmitted by mosquitoes. The physician William Gorgas then applied these insights and eradicated yellow fever from Havana
Havana
Havana is the capital city, province, major port, and leading commercial centre of Cuba. The city proper has a population of 2.1 million inhabitants, and it spans a total of — making it the largest city in the Caribbean region, and the most populous...

, and fought yellow fever during the construction of the Panama Canal
Panama Canal
The Panama Canal is a ship canal in Panama that joins the Atlantic Ocean and the Pacific Ocean and is a key conduit for international maritime trade. Built from 1904 to 1914, the canal has seen annual traffic rise from about 1,000 ships early on to 14,702 vessels measuring a total of 309.6...

 after a previous effort on the part of the French failed in part due to the high incidence of yellow fever and malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

.

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 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, yellow fever was eradicated in Cuba and later in Panama, allowing completion of the Panama Canal
Panama Canal
The Panama Canal is a ship canal in Panama that joins the Atlantic Ocean and the Pacific Ocean and is a key conduit for international maritime trade. Built from 1904 to 1914, the canal has seen annual traffic rise from about 1,000 ships early on to 14,702 vessels measuring a total of 309.6...

.

In 1927, the yellow fever virus was isolated in West Africa, which led to the development of two vaccines in the 1930s. The vaccine 17D was developed by the South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...

n microbiologist Max Theiler
Max Theiler
Max Theiler was a South African/American virologist. He was awarded the Nobel Prize in Physiology or Medicine in 1951 for developing a vaccine against yellow fever.-Career development:...

 at the Rockefeller Institute. Following the work of Ernest Goodpasture, he used chicken eggs to culture the virus and won a Nobel Prize
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...

 for this achievement in 1951. A French team developed the vaccine FNV (French neurotropic vaccine), which was extracted from mouse brain tissue – but since it was associated with a higher incidence of encephalitis
Encephalitis
Encephalitis is an acute inflammation of the brain. Encephalitis with meningitis is known as meningoencephalitis. Symptoms include headache, fever, confusion, drowsiness, and fatigue...

, FNV was not recommended after 1961. 17D on the other hand is still in use and over 400 million doses have been distributed. Little has been invested in the development of new vaccines, and the 60-year-old technology might be too slow to stop a yellow fever epidemic. Newer vaccines based on vero cells are in development and should replace 17D at some point.

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
Santa Cruz de la Sierra, commonly known as Santa Cruz, is the capital of the Santa Cruz department in eastern Bolivia and the largest city in the country...

, Bolivia
Bolivia
Bolivia officially known as Plurinational State of Bolivia , is a landlocked country in central South America. It is the poorest country in South America...

 has occurred. Since the 1980s, the number of yellow fever cases have been increasing again and A. aegypti has returned to the urban centers of South America. This is partly due to limitations on insecticides available, and partly because the vector control program was simply abandoned. Even though no new urban cycle has yet been established, it is feared that this could happen again at any point. An outbreak in Paraguay
Paraguay
Paraguay , officially the Republic of Paraguay , is a landlocked country in South America. It is bordered by Argentina to the south and southwest, Brazil to the east and northeast, and Bolivia to the northwest. Paraguay lies on both banks of the Paraguay River, which runs through the center of the...

 in 2008 was first feared 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, since they were unable to break the sylvatic cycle. With few countries establishing regular vaccination programs, measures to fight yellow fever have been neglected, making the virus a dangerous threat to spread again.

Research


In the hamster model of yellow fever, early administration of the antiviral ribavirin
Ribavirin
Ribavirin is an anti-viral drug indicated for severe RSV infection , hepatitis C infection and other viral infections. Ribavirin is a prodrug, which when metabolised resembles purine RNA nucleotides...

 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
Steatosis
In cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...

, and normalised 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
Hepatitis C
Hepatitis C is an infectious disease primarily affecting the liver, caused by the hepatitis C virus . The infection is often asymptomatic, but chronic infection can lead to scarring of the liver and ultimately to cirrhosis, which is generally apparent after many years...

, 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.