FEBRE AMARELA/

YELLOW FEVER

Yellow fever virus is found in tropical and subtropical areas in South

America and Africa. The virus is transmitted to people by the bite of an
infected mosquito. Yellow fever is a very rare cause of illness in U.S.
travelers. Illness ranges in severity from a self-limited febrile illness to
severe liver disease with bleeding.
Yellow fever disease is diagnosed based on symptoms, physical findings,
laboratory testing, and travel history, including the possibility of exposure
to infected mosquitoes. There is no specific treatment for yellow fever;
care is based on symptoms. Steps to prevent yellow fever virus infection
include using insect repellent, wearing protective clothing, and getting
vaccinated.

1) Prevention of Yellow Fever:

Avoid Mosquito Bites
Use insect repellent. When you go outdoors, use an EPA-registered
insect repellent such as those containing DEET, picaridin, IR3535,
or oil of lemon eucalyptus on exposed skin. Even a short time
outdoors can be long enough to get a mosquito bite. For details on
when and how to apply repellent, see Insect Repellent Use and
Safety.
Wear proper clothing to reduce mosquito bites. When weather
permits, wear long-sleeves, long pants and socks when outdoors.
Mosquitoes may bite through thin clothing, so spraying clothes with
repellent containing permethrin or another EPA-registered repellent
will give extra protection. Clothing pre-treated with permethrin is
commercially available. Mosquito repellents containing permethrin
are not approved for application directly to skin.
Be aware of peak mosquito hours. The peak biting times for many
mosquito species is dusk to dawn. However, Aedes aegypti, one of
the mosquitoes that transmits yellow fever virus, feeds during the
daytime. Take extra care to use repellent and protective clothing
during daytime as well as during the evening and early morning.
Staying in accommodations with screened or air-conditioned rooms,
particularly during peak biting times, will also reduce risk of
mosquito bites.

2) Yellow Fever Vaccine

Yellow fever vaccine is a live-virus vaccine that has been used for several
decades. A single dose provides lifelong protection for most people.

2.1) Yellow Fever Vaccine Recommendations:

Yellow fever vaccine is recommended for people aged 9 months who are
traveling to or living in areas at risk for yellow fever virus transmission in
South America and Africa. Yellow fever vaccine may be required for entry
into certain countries. Yellow fever vaccine is available only at designated
vaccination centers. For most travelers, a single dose of yellow fever
vaccine provides long-lasting protection and a booster dose of the vaccine
is not needed. However, some travelers may require a booster dose. Also,
certain countries might require a booster dose of the vaccine.

2.2) Vaccine Safety and Adverse Reactions

Common adverse reactions

Reactions to yellow fever vaccine are generally mild; 10%30% of

vaccinees report mild systemic adverse events. Reported events typically
include low-grade fever, headache, and myalgia that begin within days
after vaccination and last 510days. Approximately 1% of vaccinees
temporarily curtail their regular activities because of these reactions.

Severe adverse reactions

Hypersensitivity
Immediate hypersensitivity reactions, characterized by rash, urticaria, or
bronchospasm are uncommon. Anaphylaxis after yellow fever vaccine is
reported to occur at a rate of 1.3 cases per 100,000 doses administered.

Yellow fever vaccineassociated neurologic disease (YEL-AND)

YEL-AND represents a conglomerate of clinical syndromes, including
meningoencephalitis, Guillain-Barr syndrome, acute disseminated
encephalomyelitis, and rarely, cranial nerve palsies. Historically, YEL-AND
was seen primarily among infants as encephalitis, but more recent reports
have been among people of allages. YEL-AND is rarely fatal.
Among all cases of YEL-AND reported globally, almost all occurred in
first-time vaccine recipients. The onset of illness for documented cases in
the United States is 256days after vaccination. The incidence of YEL-
AND in the United States is 0.8 per 100,000 doses administered. The rate
is higher in people aged 60years, with a rate of 2.2 per 100,000 doses.

Yellow fever vaccineassociated viscerotropic disease (YEL-AVD)

YEL-AVD is a severe illness similar to wild-type disease, with vaccine
virus proliferating in multiple organs and often leading to multiple organ
dysfunction syndrome or multiorgan failure and death. Since the initial
cases of YEL-AVD were published in 2001, >100 confirmed and
suspected cases have been reported throughout theworld.
YEL-AVD has been reported to occur only after the first dose of yellow
fever vaccine; worldwide, there have been no laboratory-confirmed reports
of YEL-AVD following booster doses. For YEL-AVD cases reported in the
United States, the median time from yellow fever vaccination until
symptom onset is 4days (range, 118days). The case-fatality ratio for all
reported YEL-AVD cases in the United States is approximately 46%. The
incidence of YEL-AVD in the United States is 0.3 cases per 100,000
doses of vaccine administered. The rate is higher for people aged
60years, with a rate of 1.2 per 100,000 doses. The rate is even higher
for people aged 70 years.
Reactions to yellow fever vaccine are generally mild and include
headaches, muscle aches, and low-grade fevers. There have been
reports of rare but serious events following yellow fever vaccination.
These events include life-threatening allergic reaction, disease affecting
the nervous system, and disease affecting certain internal organs. Testing
can be performed to look for certain serious adverse events. Because
certain people have an increased risk of developing a serious adverse
event if vaccinated with yellow fever vaccine, vaccine is not
recommended (i.e., contraindicated) for people with:
Allergy to a vaccine component
Age <6 months
Symptomatic HIV infection or CD4+ T-lymphocytes <200/mm3
(<15% of total in children aged <6 years)
Thymus disorder associated with abnormal immune function
Primary immunodeficiencies
Malignant neoplasms
Transplantation
Immunosuppressive and immunomodulatory therapies
Some people may have an increased risk of an adverse event, but they
may benefit from receiving the vaccine. Precautions:
Age 6 to 8 months
Age 60 years
Asymptomatic HIV infection and CD4+ T-lymphocytes 200 to 499/
mm3 (15-24% of total in children aged<6 years)
Pregnancy
Breastfeeding
2.3) Booster doses of the vaccine
In February 2015, the CDC Advisory Committee on Immunization
Practices (ACIP) approved a new recommendation that a single dose of
yellow fever vaccine provides long-lasting protection and is adequate for
most travelers. The updated recommendations also identify specific
groups of travelers who should receive additional doses and others for
whom additional doses may be considered including:
Woman who were pregnant when first vaccinated
Persons who received a hematopoietic stem cell transplant following
their last dose of yellow fever vaccine
Persons who are HIV-infected
Travelers who received yellow fever vaccine at least 10 years
previously and who will be in a higher-risk setting based on season,
location, activities, and duration of their travel
Laboratory workers who routinely handle wild-type yellow fever virus
The official ACIP recommendations were published on June 19, 2015. All
current ACIP yellow fever vaccine recommendations can be found on the
ACIP website.
Although ACIP no longer recommends booster doses of yellow fever
vaccine for most travelers, clinicians and travelers should review the entry
requirements for destination countries because changes to the
International Health Regulations (IHR) have not yet been fully
implemented. In 2014, the World Health Organization adopted the
recommendation to remove the 10-year booster dose requirement from
the IHR as of June 2016. Once this change is instituted, a completed
International Certificate of Vaccination or Prophylaxis will be valid for the
lifetime of the vaccine. Some countries have already adopted this change,
which is noted under the yellow fever vaccine requirements on each
countrys destination page . However, it is uncertain when and if all
countries with yellow fever vaccination requirements will adopt this
change.

3) Transmission of Yellow Fever Virus

Yellow fever virus is an RNA virus that belongs to the genus Flavivirus. It
is related to West Nile, St. Louis encephalitis, and Japanese encephalitis
viruses. Yellow fever virusis transmitted to people primarily through the
bite of infected Aedes or Haemagogus species mosquitoes. Mosquitoes
acquire the virus by feeding on infected primates (human or non-human)
and then can transmit the virus to other primates (human or non-human).
People infected withyellow fever virusare infectious to mosquitoes
(referred to as being "viremic") shortly before the onset of fever and up to
5 days after onset.
Yellow fever virushas three transmission cycles: jungle (sylvatic), inter
mediate (savannah), and urban.
The jungle (sylvatic) cycle involves transmission of the virus
between non-human primates (e.g., monkeys) and mosquito
species found in the forest canopy. The virus is transmitted by
mosquitoes from monkeys to humans when humans are visiting or
working in the jungle.
In Africa, an intermediate (savannah) cycle exists that involves
transmission ofvirus from mosquitoes to humans living or working in
jungle border areas. In this cycle, the virus can be transmitted from
monkey to human or from human to human via mosquitoes.
The urban cycle involves transmission of the virus between humans
and urban mosquitoes, primarily Aedes aegypti. The virus is usually
brought to the urban setting by a viremic human who was infected in
the jungle or savannah.

4) Symptoms and Treatment

Symptoms
The majority of persons infected with yellow fever virus have no
 illness or only mild illness.
In persons who develop symptoms, the incubation period (time from
infection until illness) is typically 36 days.
The initial symptoms include sudden onset of fever, chills, severe
headache, back pain, general body aches, nausea, and vomiting,
fatigue, and weakness. Most persons improve after the initial
presentation.
After a brief remission of hours to a day, roughly 15% of cases
progress to develop a more severe form of the disease. The severe
form is characterized by high fever, jaundice, bleeding, and
eventually shock and failure of multiple organs.

Treatment
No specific treatments have been found to benefit patients with
yellow fever. Whenever possible, yellow fever patients should be
hospitalized for supportive care and close observation.
Treatment is symptomatic. Rest, fluids, and use of pain relievers
and medication to reduce fever may relieve symptoms of aching and
fever.
Care should be taken to avoid certain medications, such as aspirin
or other nonsteroidal anti-inflammatory drugs (e.g. ibuprofen,
naproxen), which may increase the risk of bleeding.
Yellow fever patients should be protected from further mosquito
exposure (staying indoors and/or under a mosquito net) for up to 5
days after the onset of fever. This way, yellow fever virus in their
bloodstream will be unavailable to uninfected mosquitoes, thus
breaking the transmission cycle and reducing risk to the persons
around them.

Outcome
The majority of infected persons will be asymptomatic or have mild
disease with complete recovery.
In persons who become symptomatic but recover, weakness and
fatigue may last several months.
Among those who develop severe disease, 2050% may die.
Those who recover from yellow fever generally have lasting
immunity against subsequent infection.

5) Areas with Risk of Yellow Fever Virus Transmission

in South America
6) Clinical features, laboratory Evaluation & Diagnosis
In its mildest form, yellow fever is a self-limited infection characterized by
sudden onset of fever and headache without other symptoms. Other
patients experience an abrupt onset of a high fever (up to 104F [40C]),
chills, severe headache, generalized myalgias, lumbosacral pain,
anorexia, nausea, vomiting, and dizziness. The patient appears acutely ill,
and examination might demonstrate bradycardia in relation to the elevated
body temperature (Faget's sign). The patient is usually viremic during this
period, which lasts for approximately 3 days. Many patients have an
uneventful recovery, but in approximately 15% of infected persons, the
illness recurs in more severe form within 48 hours following the viremic
period. Symptoms include fever, nausea, vomiting, epigastric pain,
jaundice, renal insufficiency, and cardiovascular instability. Viremia
generally is absent during this phase of symptom recrudescence. A
bleeding diathesis can occur, with hematemesis, melena, metrorrhagia,
hematuria, petechiae, ecchymoses, epistaxis, and oozing blood from the
gingiva and needle-puncture sites. Physical findings include scleral and
dermal icterus, hemorrhages (e.g., hematemesis, melena, petechiae,
ecchymoses), and epigastric tenderness without hepatic enlargement.
Multiple laboratory abnormalities can be observed in patients with yellow
fever; these can vary depending on the severity and stage of illness. In the
first week of the illness, leukopenia might occur; however, leukocytosis
also can occur during the second week of the disease. Bleeding
dyscrasias also can occur, together with elevated prothrombin and partial
thromboplastin times, decreased platelet count, and presence of fibrin-
split products. Hyperbilirubinemia might be present as early as the third
day but usually peaks toward the end of the first week of illness.
Elevations of serum transaminase levels occur in severe hepatorenal
disease and might remain elevated for up to 2 months after onset.
Preliminary diagnosis is based on the patient's clinical features,
vaccination status, and travel history, including destination, time of year,
and activities. Laboratory diagnosis generally is accomplished by testing
serum to detect virus-specific immunoglobulin M (IgM) and
immunoglobulin G (IgG) antibodies by serologic assays. It is important to
obtain a yellow fever vaccination history, as IgM antibodies to yellow fever
vaccine virus can persist for several years following vaccination. Serologic
cross-reactions occur with other flaviviruses (e.g., West Nile or dengue
viruses), so positive results should be confirmed with a more specific test
(e.g., plaque-reduction neutralization test). Early in the illness (during the
first 3-4 days), yellow fever virus or yellow fever virus RNA often can be
detected in the serum by virus isolation or nucleic acid amplification
testing (e.g., reverse transcription-polymerase chain reaction [RT-PCR]).
However, by the time overt symptoms are recognized, the virus or viral
RNA usually is undetectable. Therefore, negative virus isolation and RT-
PCR results cannot rule-out the diagnosis of yellow fever.
Immunohistochemical staining of formalin-fixed material can detect yellow
fever virus antigen in histopathologic specimens. Healthcare providers
should contact their state or local health department and CDC.
A presumptive diagnosis of yellow fever is often based on the patient's
clinical features, places and dates of travel (if the patient is from a non-
endemic country or area), activities, and epidemiologic history of the
location where the presumed infection occurred.
Laboratory diagnosis of yellow fever is generally accomplished by testing
of serum to detect virus-specific IgM and neutralizing antibodies.
Sometimes the virus can be found in blood samples taken early in the
illness.
In fatal cases, nucleic acid amplification, histopathology with
immunohistochemistry, and virus culture of biopsy or autopsy tissues can
also be positive. Only a few state laboratories or other specialized
laboratories, including those at CDC, are capable of doing these
specialized tests. Instructions for sending diagnostic specimens to CDCs
Arbovirus Diagnostic Laboratory can be found at CDCs Division of
Vector-Borne Diseases Arboviral Specimens submission page.
Test results are normally available 4 to 14 days after specimen receipt.
Reporting times for test results may be longer during summer months
when domestic arbovirus activity increases. Receipt of a hard copy of the
results will take at least 2 weeks after testing is completed. Initial
serological testing will be performed using IgM-capture ELISA, MIA
(Microsphere-based Immunoassay) and IgG ELISA. If the initial results
are positive, further confirmatory testing may delay the reporting of final
results. ALL RESULTS WILL BE SENT TO THE APPROPRIATE STATE
HEALTH DEPARTMENT. Notify your state health department of any
direct submissions to CDC. Find more information about laboratory testing
in suspected cases of yellow fever from the yellow fever clinical laboratory
evaluation page.

Renzo Z. Roldi
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