Yellow fever
From
Wikipedia, the free encyclopedia
Yellow fever, also known as Yellow Jack or "Yellow
Rainer" and other names,[1]
is an acute viral hemorrhagic disease.[2]
The virus is a 40 to 50 nm enveloped positive sense RNA virus, the first human virus discovered and the namesake of the Flavivirus
genus.[3]
In high-risk areas where vaccination
coverage is low, prompt recognition and control of outbreaks through
immunization is critical to prevent epidemics. The disease may be difficult to
distinguish from other illnesses, especially in the early stages. To confirm
any suspicions from the case history and information on the patient's journeys
abroad, the doctor must take a blood sample and then insert it through a laser
scanner.
The yellow fever virus is
transmitted by the bite of female mosquitoes
(the yellow fever mosquito, Aedes aegypti,
and other species) and is found in tropical and subtropical
areas in South America and Africa, but not in Asia.[4]
The only known hosts of the virus are primates and
several species of mosquito. 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 diseases.[5]
Yellow fever presents in most cases
in humans with fever, chills, anorexia, nausea, muscle pain (with prominent backache) and headache, which
generally subsides after several days. In some patients, a toxic phase follows,
in which liver damage with jaundice
(inspiring the name of the disease)[6]
can occur and lead to death. Because of the increased bleeding tendency (bleeding diathesis), yellow fever belongs to the group of hemorrhagic fevers. The World
Health Organization estimates that yellow fever causes
200,000 illnesses and 30,000 deaths every year in unvaccinated populations;[7]
today nearly 90% of the infections occur in Africa.[8]
A safe and effective vaccine against
yellow fever has existed since the middle of the 20th century, and some
countries require vaccinations for travelers.[9]
Since no therapy is known, vaccination programs are of great importance in
affected areas, along with measures to prevent bites and reduce the population
of the transmitting mosquito. Since the 1980s, the number of cases of yellow
fever has been increasing, making it a re-emerging disease.[10]
This is likely due to warfare and social disruption in several African nations.
Signs
and symptoms
Yellow fever begins after an
incubation period of three to six days.[11]
Most cases only cause a mild infection with fever, headache, chills, back pain,
loss of appetite, nausea, and vomiting.[12]
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 due to liver damage,
as well as abdominal pain. Bleeding in the mouth, the eyes, and the gastrointestinal tract will cause vomitus containing blood
(hence the Spanish name for yellow fever, vomito negro (black vomit)).[13]
The toxic phase is fatal in approximately 20% of cases, making the overall
fatality rate for the disease 3% (15% * 20%).[14]
In severe epidemics, the mortality may exceed 50%.[15]
Surviving the infection provides
lifelong immunity,[16]
and normally there is no permanent organ damage.[17]
Cause
Yellow fever is caused by the yellow
fever virus, a 40 to 50 nm wide enveloped RNA virus,
the type species and namesake of the family Flaviviridae.[3]
It was the first illness shown to be transmissible via filtered human serum
(i.e. a virus), and transmitted by mosquitoes, by Walter Reed
around 1900.[18]
The positive sense single-stranded RNA is approximately 11,000 nucleotides
long and has a single open reading frame encoding a polyprotein.
Host proteases cut this polyprotein into three structural (C, prM, E) and
seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5); the
enumeration corresponds to the decreased pH induces the fusion of the endosomal membrane with the virus envelope.
Thus, the capsid reaches
the cytosol, decays
and releases the genome. Receptor binding as well as membrane fusion are catalyzed
by the protein E, which changes its conformation at low pH, which causes a
rearrangement of the 90 homodimers to 60
homotrimers.[19]
After entering the host cells, the
viral genome is replicated in the rough endoplasmic reticulum (ER) and in the so-called vesicle packets.
At first, an immature form of the virus particle is produced inside the ER,
whose M-protein is not yet cleaved to its mature form and is therefore denoted
as prM (precursor M) and forms a complex with protein E. The immature
particles are processed in the Golgi apparatus
by the host protein furin, which cleaves prM to M. This releases E from the complex
which can now take its place in the mature, infectious virion.[19]
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 Arboviruses
which are transmitted via mosquitoes, the yellow fever virus is taken up by a
female mosquito which sucks the blood of an infected person or 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
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.[20]
There are three epidemiologically
different infectious cycles,[10]
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. It is well adapted to urban centres and can also transmit other
diseases, including Dengue and Chikungunya.
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.
Besides the urban cycle there is,
both in Africa and South America, a sylvatic cycle
(forest cycle or jungle cycle), where Aedes
africanus (in Africa) or mosquitoes
of the genus Haemagogus
and Sabethes (in South America) serve as a vector. In the jungle, the
mosquitoes infect mainly non-human primates; the disease is mostly asymptomatic
in African primates. In South America, the sylvatic cycle is currently the only
way humans can infect each other, 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.[10]
In Africa there is a third
infectious cycle, also known as "savannah
cycle" or intermediate cycle, which occurs between the jungle and urban
cycle. Different mosquitoes of the genus Aedes
are involved. In recent years, this has been the most common form of transmission
of yellow fever in Africa.[7]
Pathogenesis
After transmission of the virus from
a mosquito, the viruses replicate in the lymph nodes
and infect dendritic cells in particular. From there they reach the liver and infect hepatocytes
(probably indirectly via Kupffer cells),
which leads to eosinophilic degradation of these cells and to the release of cytokines.
Necrotic masses (Councilman bodies) appear in the cytoplasm
of hepatocytes.[9][21]
When the disease takes a deadly
course, a cardiovascular shock and multi-organ
failure, with strongly increased cytokine
levels (cytokine storm), follow.[14]
Diagnosis
Yellow fever is a clinical diagnosis,
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 mild
courses of yellow fever can also contribute significantly to regional
outbreaks, every suspected case of yellow fever (involving symptoms of fever,
pain, nausea and vomiting six to ten days after leaving the affected area) has
to be treated seriously.
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
where the genome of the virus is amplified.[8]
Another direct approach is the isolation of the virus and its growth in cell
culture using blood plasma; this can take one to four weeks.
Serologically, an enzyme
linked immunosorbent assay during
the acute phase of the disease using specific IgM against yellow fever or an increase in specific IgG-titer (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,
these indirect methods can never prove yellow fever infection.
Liver biopsy can verify inflammation
and necrosis of
hepatocytes and detect viral antigens. 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 have to be distinguished from
other feverish illnesses like malaria. Other viral hemorrhagic fevers, such as Ebola virus,
Lassa virus,
Marburg virus and Junin virus,
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.
Programmes for distribution of mosquito nets for use in homes are providing
reductions in cases of both malaria and yellow fever.
Vaccination
For journeys into affected areas,
vaccination is highly recommended, since mostly non-native people suffer severe
cases of yellow fever. The protective effect is established 10 days after
vaccination in 95 percent of the vaccinated people[22]
and lasts for at least 10 years (even 30 years later, 81% of patients retained
immunity). The attenuated live vaccine (stem
17D) was developed in 1937 by Max Theiler[22]
from a diseased patient in Ghana and is produced in chicken eggs. The WHO
recommends routine vaccinations for people living in endemic areas between the
9th and 12th month after birth.[8]
In rare cases (less than one in
200,000 to 300,000[22]),
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 and is fatal in less than 5%[22]
of all cases.[8][14]
In 2009, the largest mass vaccination
against yellow fever began in West Africa,
specifically Benin, Liberia, and Sierra Leone.[24][25]
When it is completed in 2015, more than 12 million people will have been
vaccinated against the disease.[24]
According to the World
Health Organization (WHO), the 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.[24]
The WHO plans to continue the vaccination campaign in another five African
countries — Central
African Republic, Ghana, Guinea, Côte d'Ivoire,
and Nigeria — and
stated that approximately 160 million people in the continent could be at
risk unless the organization acquires additional funding to support widespread
vaccinations.[26]
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),
although 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 that require yellow fever vaccination is
published by the WHO.[27]
If the vaccination cannot be conducted for some reasons, 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.[8]
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 fever and chikungunya
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 larvicides
are used, as well as larva-eating fish and copepods, which
reduce the number of larva and thus indirectly the number of
disease-transmitting mosquitoes. For many years, copepods of the genus Mesocyclops
have been used in Vietnam for fighting Dengue fever (yellow fever does not occur in Asia). This has
resulted in the treated areas with no cases of Dengue fever having occurred
since 2001. Similar mechanisms are probably also effective against yellow
fever. Pyriproxyfen is recommended as a chemical larvicide, mainly because it
is safe for humans and effective even in small doses.[8]
The adult yellow fever mosquitoes
are also targeted. The curtains and lids of water tanks are sprayed with insecticides.
Spraying insecticides inside houses is another measure, although it is not
recommended by the WHO because of danger to humans. In prevention similar to
that against the malaria carrier, the Anopheles
mosquito, insecticide-treated mosquito nets
to protect people in beds have been used successfully against Aedes aegypti.[8]
Treatment
For yellow fever there is, like for
all diseases caused by Flaviviruses, 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 and other antiviral drugs
as well as treatment with interferons
do not have a positive effect in patients.[14]
A symptomatic treatment includes rehydration and pain relief with drugs like paracetamol
(known as acetaminophen in the United States). Acetylsalicylic acid (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 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 in
the Middle East, yellow fever does not occur in these areas; the reason for
this is unknown. Worldwide there are about 600 million people living in endemic
areas. WHO officially estimates that there are 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.[8]
In 2008, the largest number of recorded cases were in Togo.
Phylogenetic analysis identified seven genotypes
of yellow fever viruses, and it is assumed that they are differently adapted to
humans and to the vector Aedes aegypti. Five genotypes (Angola,
Central/East Africa, East Africa, West Africa I, and West Africa II) occur
solely in Africa. West Africa genotype I is found in Nigeria and the
surrounding areas.[28]
This appears to be especially virulent or infectious as this type is often
associated with major outbreaks. The three genotypes in East and Central Africa
occur in areas where outbreaks are rare. Two recent outbreaks in Kenya
(1992–1993) and Sudan (2003 and 2005) involved the East African genotype, which
had remained unknown until these outbreaks occurred.[29]
In South America, two genotypes have
been identified (South American genotype I and II).[10]
Based on phylogenetic analysis these two genotypes appear to have originated in
West Africa[30]
and were first introduced into Brazil.[31]
The date of introduction into South America appears to be 1822 (95% confidence
interval 1701 to 1911).[31]
The historical record shows that there was an outbreak of yellow fever in Recife, Brazil between 1685 and 1690. The disease seems to have
disappeared, with the next outbreak occurring in 1849. It seems likely that it
was introduced with the importation of slaves through the slave trade
from Africa. Genotype I has been divided into five subclades (A-E).[32]
History
The evolutionary origins of yellow
fever most likely lie in Africa, with transmission of the disease from primates
to humans.[33]
It is thought that the virus originated in East or Central Africa and spread
from there to West Africa. As it was endemic in Africa, the natives had
developed some immunity to it. When an outbreak of yellow fever would occur in
an African village where colonists resided, most Europeans died, while the
native population usually suffered nonlethal symptoms resembling influenza.[34]
This phenomenon, in which certain populations develop immunity to yellow fever
due to prolonged exposure in their childhood, is known as acquired immunity.[35]
The virus, as well as the vector A. aegypti, were probably transferred
to North and South America with the importation of slaves from Africa.
The first definitive outbreak of
yellow fever was in 1647 on the island of Barbados.[36]
An outbreak was recorded by Spanish colonists in 1648 in Yucatan, Mexico,
where the indigenous Mayan people called the illness xekik (black vomit).In 1685
Brazil experienced its first epidemic, in Recife.
Although yellow fever is most
prevalent in so-called “tropical” climates, the Northern United States was not
exempted from the fever. The first outbreak in English-speaking North America
occurred in New York in 1668 and a serious outbreak afflicted Philadelphia in
1793.[37]
English colonists in Philadelphia and the French in the Mississippi
River Valley recorded major outbreaks in 1669,
as well as those occurring later in the eighteenth and nineteenth centuries.
The southern city of New Orleans was plagued with major epidemics during the nineteenth
century, most notably in 1833 and 1853. At least 25 major outbreaks took place
in the Americas throughout the eighteenth and nineteenth centuries, including
particularly serious ones in Cartagena
in 1741, Cuba in 1762
and 1900, Santo Domingo in 1803, and Memphis in 1878.
Major outbreaks have also occurred in southern Europe. Gibraltar
lost many to an outbreak in 1804.[38]
Barcelona
suffered the loss of several thousand citizens during an outbreak in 1821.
Urban epidemics continued in the United States until 1905, with the last
outbreak affecting New Orleans.[39]
Due to yellow fever, in colonial
times and during the Napoleonic wars, the West Indies were known as a
particularly dangerous posting for soldiers. Both English and French forces
posted there were decimated by the "Yellow Jack". Wanting to regain
control of the lucrative sugar trade in Saint-Domingue,
and with an eye on regaining France's New World empire, Napoleon sent an army
under the command of his brother-in-law to Saint-Domingue to seize control
after a slave revolt. The historian J. R. McNeill asserts that yellow fever
accounted for approximately 35,000 to 45,000 casualties during the fighting.[40]
Only one-third of the French troops survived for withdrawal and return to
France, and in 1804 Haiti proclaimed its independence as the second republic in the
western hemisphere.
The yellow
fever epidemic of 1793 in Philadelphia,
which was then the capital of the United States, resulted in the deaths of
several thousand people, more than nine percent of the population. The national
government fled the city, including president George Washington.[41]
Additional yellow fever epidemics in North America struck Philadelphia, as well
as Baltimore
and New York in the
eighteenth and nineteenth centuries, and traveled along steamboat routes of
interior rivers from New Orleans. They have caused some 100,000–150,000 deaths
in total.[42]
In 1858 St. Matthew's German Evangelical Lutheran Church in Charleston,
South Carolina suffered 308 yellow fever deaths,
reducing the congregation by half.[43]
In 1873, Shreveport, Louisiana lost almost a quarter of its population to yellow fever. In
1878, about 20,000 people died in a widespread epidemic in the Mississippi
River Valley.[44]
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.[45]
The last major U.S. outbreak was in 1905 in New Orleans.[10]
Ezekiel Stone Wiggins, known as the Ottawa Prophet, proposed that the cause of a
Yellow fever epidemic in Jacksonville, Florida in 1888 was astronomical.
The planets were in the same line as
the sun and earth and this produced, besides Cyclones, Earthquakes,
etc., a denser atmosphere holding more carbon and creating microbes. Mars had an uncommonly dense atmosphere, but its inhabitants
were probably protected from the fever by their newly discovered canals, which
were perhaps made to absorb carbon and prevent the disease. [46]
Carlos Finlay, a Cuban doctor and scientist, first proposed in 1881 that
yellow fever might be transmitted by mosquitoes
rather than direct human contact.[47][48]
Since the losses from yellow fever in the Spanish–American War in the 1890s were extremely high, Army doctors began
research experiments with a team led by Walter Reed,
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 applied these insights and eradicated yellow fever from Havana. He also campaigned against yellow fever during the
construction of the Panama Canal, after a previous construction effort on the part of the
French failed (in part due to the high incidence of yellow fever and malaria, which
decimated the workers).[10]
Although Dr. Reed has received much
of the credit in American history books for "beating" yellow fever,
Reed had fully credited Dr. Finlay with the discovery of the yellow fever
vector, and how it might be controlled. Dr. Reed often cited Finlay's papers in
his own articles and also gave him credit for the discovery in his personal
correspondence.[49]
The acceptance of Finlay's work was one of the most important and far-reaching
effects of the Walter Reed Commission of 1900.[50]
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 Dr. Reed built off of the research of Carlos Finlay,
historian François Delaporte notes that yellow fever research was a contentious
issue, and scientists, including Finlay and Reed, became successful by building
off of the work of less prominent scientists, without giving them the credit
they were due.[51]
Regardless, Dr. Reed's research was essential in the fight against yellow fever
and he should receive full credit for his use of the first type of medical
consent form during his experiments in Cuba.[52]
The Rockefeller Foundation’s
International Health Board (IHB) undertook an expensive and successful yellow
fever eradication campaign in Mexico during 1920-1923. 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 past. The eradication of yellow fever was a major
step toward better global health.[53]
In 1927, scientists isolated the
yellow fever virus in West Africa, which led to the development of two vaccines in the
1930s. The vaccine 17D was developed by the South African
microbiologist Max Theiler at the Rockefeller Institute.This vaccine was widely used by the U.S. Army during World
War II.[54]
Following the work of Ernest Goodpasture, he used chicken eggs to culture the virus and won a Nobel
Prize in 1951 for this achievement. 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, after 1961 FNV was not recommended. 17D is still in use
and more than 400 million doses have been distributed. Little research has been
done to develop new vaccines. Some researchers worry that the 60-year-old
technology for vaccine production may be too slow to stop a major new yellow
fever epidemic. Newer vaccines, based on vero cells,
are in development and should replace 17D at some point.[8]
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, Bolivia has occurred. But, 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
available insecticides, as well as habitat dislocations caused by climate
change, and partly because the vector control program was abandoned. Although
no new urban cycle has yet been established, scientists fear that this could
happen again at any point. An outbreak in Paraguay in 2008
was feared to be urban in nature, but this ultimately proved not to be the
case.[8]
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
involving wild primates. With few countries establishing regular vaccination
programs, measures to fight yellow fever have been neglected, making the virus
a dangerous threat to spread again.[8]
Research
In the hamster model of yellow
fever, early administration of the antiviral ribavirin
is an effective early treatment of many pathological features of the disease.[55]
Ribavirin treatment during the first five days after virus infection improved
survival rates, reduced tissue damage in target organs (liver and spleen),
prevented hepatocellular steatosis, and 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,
a virus related to yellow fever.[55]
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.[56]
In the past, yellow fever has been
researched by several countries as a potential biological weapon.[57]
The entire wiki article with pictures and references is at: http://en.wikipedia.org/wiki/Yellow_fever
Yellow
fever is one of those diseases that may come back during hard times.
President
Theodore Roosevelt had a relative die from yellow fever. So have I .
Mosquito
borne diseases use to sicken and kill a lot of people in the USA, too.
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