Infectious Disease and Microbiology - Yellow Fever

BASICS

Description

Yellow fever is an acute mosquito-borne viral infection caused by the yellow fever virus. Clinical illness ranges from an asymptomatic or mild febrile syndrome to a severe systemic disease characterized by jaundice, hepatic injury, hemorrhage, renal dysfunction, shock, and multiorgan failure.

The term “yellow” refers to the jaundice that develops in severe disease.

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EPIDEMIOLOGY

Yellow fever occurs primarily in tropical regions of:

• Sub-Saharan Africa

• Tropical South America

Transmission occurs mainly in areas located approximately between 15° north and 15° south of the equator.

The infection may occur as:

• Sporadic cases

• Local outbreaks

• Large epidemics

The true incidence is substantially higher than the number of reported cases because many infections are mild, unrecognized, or occur in areas with limited surveillance.

Historically, Africa has accounted for the majority of cases and deaths.

Travel-associated risk varies according to:

• Destination

• Season

• Vaccination status

• Mosquito exposure

• Local outbreak activity

Transmission has traditionally been highest:

• In parts of West Africa during the rainy season

• In parts of Brazil and South America during periods of increased mosquito activity

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RISK FACTORS

Major risk factors include:

• Residence in or travel to an endemic region

• Lack of yellow fever vaccination

• Mosquito exposure

• Travel during periods of increased mosquito activity

• Outdoor activities without appropriate mosquito precautions

• Travel to areas experiencing an outbreak

Unvaccinated travelers entering endemic regions are at greatest risk.

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ETIOLOGY

Yellow fever is caused by:

Yellow fever virus

The virus is:

• An enveloped RNA virus

• A member of the Flaviviridae family

• Related to other flaviviruses such as dengue, Zika, West Nile, and Japanese encephalitis viruses

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TRANSMISSION

Yellow fever is transmitted through the bite of infected mosquitoes.

Important mosquito vectors include:

• Aedes species

• Haemagogus species in the Americas

Humans and nonhuman primates participate in transmission cycles.

Three epidemiologic transmission patterns are recognized:

1. Sylvatic or jungle cycle

The virus circulates between mosquitoes and nonhuman primates.

Humans become infected when they enter forested environments.

2. Intermediate or savannah cycle

Occurs mainly in Africa.

Mosquitoes transmit infection between humans and nonhuman primates in areas between jungle and urban environments.

3. Urban cycle

The virus is transmitted from:

Human → Aedes aegypti mosquito → Human

This cycle can produce large urban outbreaks.

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PATHOPHYSIOLOGY

After an infected mosquito bite, the virus initially replicates in local tissues and regional lymph nodes.

Viremia subsequently develops and the virus disseminates through the bloodstream.

Important organs affected include:

• Liver

• Kidneys

• Heart

• Adrenal glands

• Spleen

Severe hepatic injury produces:

• Jaundice

• Impaired clotting-factor synthesis

• Coagulopathy

Hemorrhage is promoted by:

• Thrombocytopenia

• Platelet dysfunction

• Reduced hepatic production of coagulation factors

• Disseminated intravascular coagulation in severe disease

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INCUBATION PERIOD

The incubation period is generally:

3–6 days

Symptoms usually begin abruptly.

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CLINICAL COURSE

Yellow fever traditionally progresses through three clinical phases:

1. Infection phase

2. Remission phase

3. Intoxication phase

Not every patient progresses through all three phases.

Most infections are mild or asymptomatic.

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INFECTION PHASE

The illness usually begins suddenly with:

• High fever

• Chills

• Severe headache

• Myalgias

• Back pain

• Malaise

• Prostration

• Nausea

• Vomiting

Patients may also develop:

• Photophobia

• Arthralgia

• Loss of appetite

This phase usually lasts approximately 3–4 days.

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REMISSION PHASE

After several days of fever, symptoms may temporarily improve.

The patient may become:

• Afebrile

• Less symptomatic

• Apparently recovering

This remission may last:

• Several hours

• Up to approximately 1–2 days

Most patients recover during this stage.

A minority, however, progress to severe disease.

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INTOXICATION PHASE

Patients who enter the toxic phase become severely ill.

Fever returns and systemic organ dysfunction develops.

Important manifestations include:

• Jaundice

• Severe hepatic dysfunction

• Renal failure

• Hemorrhage

• Hypotension

• Shock

• Myocarditis

• Encephalopathy

This is the most dangerous phase of yellow fever.

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HEMORRHAGIC MANIFESTATIONS

Bleeding may occur from:

• Gums

• Nose

• Gastrointestinal tract

• Venipuncture sites

• Other mucosal surfaces

Clinical manifestations include:

• Petechiae

• Purpura

• Hematemesis

• Melena

• Hematochezia

Vomiting of dark blood has historically been called:

“Black vomit”

This is a classic manifestation of severe yellow fever.

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HEPATIC MANIFESTATIONS

Severe liver involvement produces:

• Jaundice

• Markedly elevated aminotransferases

• Coagulopathy

• Hepatic dysfunction

A useful clue is that AST may become markedly elevated, sometimes exceeding ALT because of both hepatic and extrahepatic tissue injury.

Severe hepatic failure is associated with poor prognosis.

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RENAL MANIFESTATIONS

Renal involvement may cause:

• Oliguria

• Acute kidney injury

• Azotemia

• Proteinuria or albuminuria

Severe patients may require renal replacement therapy.

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CARDIAC INVOLVEMENT

Myocarditis may occur.

Possible manifestations include:

• Bradycardia

• Arrhythmias

• ECG abnormalities

• Reduced cardiac function

• Cardiovascular collapse

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RELATIVE BRADYCARDIA

A classic clinical finding is:

High fever + unexpectedly slow pulse

This is called:

Faget sign

or

pulse-temperature dissociation.

It is suggestive but not specific for yellow fever.

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NEUROLOGIC MANIFESTATIONS

Severe or late disease can cause:

• Confusion

• Agitation

• Delirium

• Seizures

• Encephalopathy

• Coma

Neurologic abnormalities generally indicate severe systemic illness.

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PHYSICAL EXAMINATION

Possible findings include:

• Fever

• Relative bradycardia

• Conjunctival injection

• Jaundice

• Abdominal tenderness

• Hepatomegaly

• Petechiae

• Purpura

• Mucosal bleeding

• Gastrointestinal bleeding

• Hypotension

• Signs of shock

Severe cases may progress to:

• Acute respiratory distress syndrome

• Multiorgan failure

• Coma

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DIAGNOSIS

Diagnosis requires consideration of:

Compatible illness + epidemiologic exposure

Important questions include:

• Recent travel

• Residence in an endemic area

• Vaccination status

• Mosquito exposure

• Local yellow fever outbreaks

• Timing of illness after travel

Laboratory confirmation is especially important because many infections can resemble yellow fever.

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LABORATORY FINDINGS

Common nonspecific findings include:

• Leukopenia

• Thrombocytopenia

• Elevated AST and ALT

• Elevated bilirubin

• Prolonged coagulation studies

• Evidence of DIC

• Metabolic acidosis

• Elevated creatinine

• Azotemia

• Proteinuria or albuminuria

Severe thrombocytopenia and hepatic dysfunction increase the risk of hemorrhage.

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PCR

During the early viremic phase, yellow fever viral RNA may be detected by:

RT-PCR

PCR is most useful early in illness while viremia is present.

Availability may be limited to specialized or public-health laboratories.

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SEROLOGY

Serologic diagnosis commonly relies on detection of:

Yellow fever-specific IgM antibodies

IgM can be detected using assays such as:

ELISA

Interpretation may be complicated by cross-reactivity with other flaviviruses, including:

• Dengue

• Zika

• West Nile virus

• Japanese encephalitis virus

Previous flavivirus vaccination may also complicate serologic interpretation.

Confirmation may require specialized neutralization testing.

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TISSUE TESTING

In fatal or diagnostically difficult cases, viral antigen can be demonstrated by:

• Immunohistochemistry

• Molecular testing

Possible tissues include:

• Liver

• Kidney

• Myocardium

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LIVER BIOPSY

Liver biopsy should generally be avoided during acute severe yellow fever because of the major risk of:

Fatal hemorrhage

This is an important clinical point.

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PATHOLOGY

Characteristic hepatic abnormalities include:

• Hepatocyte apoptosis

• Steatosis

• Midzonal hepatic necrosis

Classic eosinophilic apoptotic hepatocytes are known as:

Councilman bodies

The midzonal pattern of hepatic injury is a characteristic pathologic feature of yellow fever.

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ECG FINDINGS

Possible ECG abnormalities include:

• Sinus bradycardia

• ST-T abnormalities

• Other changes associated with myocarditis

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DIFFERENTIAL DIAGNOSIS

Yellow fever can resemble many tropical and systemic infections.

Important differential diagnoses include:

• Dengue

• Severe malaria

• Leptospirosis

• Viral hepatitis

• Typhoid fever

• Ebola virus disease

• Marburg virus disease

• Lassa fever

• Rift Valley fever

• Crimean-Congo hemorrhagic fever

• South American viral hemorrhagic fevers

• Other causes of acute hepatic failure

Travel history is essential for narrowing the differential.

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TREATMENT

There is currently no established specific antiviral therapy for yellow fever.

Treatment is therefore:

SUPPORTIVE

Patients with severe disease require careful management of organ dysfunction.

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SUPPORTIVE CARE

Important measures include:

• Fluid resuscitation

• Electrolyte correction

• Oxygen support

• Hemodynamic monitoring

• Treatment of hypoglycemia

• Correction of metabolic acidosis

• Renal support

• Management of hemorrhage

• Mechanical ventilation when necessary

Severely ill patients should receive intensive-care management.

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SHOCK

Treatment may require:

• Careful intravenous fluid resuscitation

• Vasopressors when hypotension persists

• Monitoring of urine output

• Correction of acid-base abnormalities

• Treatment of concurrent organ failure

Fluid therapy must be balanced carefully because capillary leak and organ dysfunction can predispose to pulmonary edema.

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COAGULOPATHY

Significant bleeding or severe coagulation abnormalities may require:

• Fresh frozen plasma

• Other blood products when clinically indicated

• Vitamin K in selected patients

Management should be guided by active bleeding and coagulation studies.

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RENAL FAILURE

Severe acute kidney injury may require:

Hemodialysis or another form of renal replacement therapy.

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RESPIRATORY FAILURE

Patients who develop:

• Severe hypoxemia

• ARDS

• Respiratory failure

may require:

• Endotracheal intubation

• Mechanical ventilation

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MEDICATION PRECAUTIONS

Avoid medications that increase bleeding risk.

In particular, avoid:

• Aspirin

• Other salicylates

• NSAIDs when significant hemorrhagic risk exists

Acetaminophen may also require caution in severe hepatic injury because of potential hepatotoxicity.

Medication selection should therefore be individualized in patients with hepatic dysfunction.

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ADMISSION

Hospitalization is generally appropriate for patients with suspected clinically significant yellow fever, particularly outside endemic settings.

Urgent admission is required when there is:

• Jaundice

• Hemorrhage

• Hypotension

• Renal dysfunction

• Altered mental status

• Respiratory compromise

• Severe vomiting

• Evidence of multiorgan disease

Severe cases require ICU care.

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PREVENTION

Prevention relies on two major strategies:

1. Vaccination

2. Mosquito-bite avoidance

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YELLOW FEVER VACCINE

The yellow fever vaccine is a:

Live attenuated 17D vaccine

It is highly effective.

A single dose produces protective immunity in the great majority of recipients.

Protection generally develops within approximately:

10 days

Current international guidance recognizes that a single dose provides long-lasting protection for most people.

Routine booster vaccination every 10 years is no longer required for most individuals, although additional doses may be recommended in selected circumstances.

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INTERNATIONAL CERTIFICATE OF VACCINATION

Some countries require proof of yellow fever vaccination for:

• Entry from endemic countries

• Travel through high-risk areas

• Prevention of importation into regions capable of sustaining transmission

The International Certificate of Vaccination or Prophylaxis generally becomes valid:

10 days after primary vaccination

Under current International Health Regulations, the certificate is generally considered valid for the lifetime of the vaccinated person.

Travelers should verify the current entry requirements of their destination before travel.

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MOSQUITO-BITE PREVENTION

Travelers should use:

• EPA- or locally approved insect repellents

• Long sleeves

• Long trousers

• Permethrin-treated clothing or equipment when appropriate

• Window screens

• Air conditioning

• Mosquito nets where needed

Mosquito precautions remain important even after vaccination because mosquitoes transmit many diseases other than yellow fever.

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VACCINE ADVERSE EFFECTS

Most vaccine reactions are mild.

Common reactions include:

• Headache

• Myalgia

• Low-grade fever

• Local injection-site discomfort

Serious reactions are extremely rare.

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YELLOW FEVER VACCINE-ASSOCIATED NEUROLOGIC DISEASE

Rare neurologic complications include:

• Encephalitis

• Meningoencephalitis

• Guillain-Barré-like syndromes

• Other neurologic syndromes

Symptoms generally develop within days to several weeks following vaccination.

The risk is very low but is higher in certain age groups.

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YELLOW FEVER VACCINE-ASSOCIATED VISCEROTROPIC DISEASE

This is an extremely rare but potentially fatal complication in which the vaccine strain produces an illness resembling severe wild-type yellow fever.

Features may include:

• High fever

• Hypotension

• Liver injury

• Thrombocytopenia

• Respiratory failure

• Multiorgan dysfunction

Risk is increased in certain patients, including:

• Older adults

• Individuals with significant thymus disorders

Because of its severity, vaccination should be based on careful risk-benefit assessment when risk factors are present.

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VACCINE CONTRAINDICATIONS AND PRECAUTIONS

Because yellow fever vaccine is live attenuated, caution is required in patients with significant immune dysfunction.

Contraindications or major precautions may include:

• Severe immunosuppression

• Certain thymus disorders

• Severe allergy to vaccine components

• Infancy below the recommended vaccination age

• Pregnancy in situations where exposure risk is low

Decisions should be individualized according to:

Risk of yellow fever exposure vs risk of vaccination.

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HIV

People living with HIV require individualized assessment.

Vaccination may be considered in selected patients who:

• Are clinically stable

• Do not have severe immunosuppression

• Have adequate CD4 counts

Severely immunocompromised patients generally should not receive a live yellow fever vaccine.

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PREGNANCY

Pregnancy is generally considered a precaution rather than an absolute contraindication when yellow fever exposure is significant.

If travel to a high-risk area can be postponed, postponement may be preferred.

If travel cannot be avoided and the risk of yellow fever is substantial, vaccination may be considered after individualized risk-benefit assessment.

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PROGNOSIS

Most infected individuals either remain asymptomatic or recover from the initial febrile illness.

Patients who progress to the intoxication phase have a substantially worse prognosis.

Mortality in severe yellow fever may reach approximately:

20–50%

Death usually results from:

• Shock

• Hepatic failure

• Renal failure

• Hemorrhage

• Multiorgan dysfunction

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IMMUNITY AFTER INFECTION

Survivors generally develop:

Strong, long-lasting immunity

Recurrent yellow fever after natural infection is extremely unusual.

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COMPLICATIONS

Important complications include:

• Fulminant hepatitis

• Severe jaundice

• Coagulopathy

• DIC

• Gastrointestinal hemorrhage

• Acute kidney injury

• Myocarditis

• Arrhythmias

• Shock

• ARDS

• Encephalopathy

• Seizures

• Multiorgan failure

Secondary bacterial infections may complicate prolonged severe illness.

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HIGH-YIELD CLINICAL PATTERN

Traveler from tropical Africa or South America

+

Fever

+

Jaundice

+

Hemorrhage

+

Renal dysfunction

→ Think yellow fever

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HIGH-YIELD DISEASE COURSE

Initial fever and myalgias

↓

Temporary improvement

↓

Return of fever + jaundice + hemorrhage + organ failure

→ Intoxication phase of yellow fever

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HIGH-YIELD PHYSICAL SIGN

High fever + relative bradycardia

→ Faget sign

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HIGH-YIELD PATHOLOGY

Midzonal hepatic necrosis

+

Councilman bodies

→ Characteristic of yellow fever

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HIGH-YIELD DIAGNOSTIC APPROACH

Early illness:

→ RT-PCR

Later illness:

→ Yellow fever IgM serology

Remember:

Flavivirus serology can cross-react.

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HIGH-YIELD PREVENTION

Most effective preventive measure:

→ Yellow fever vaccination

Additional essential measure:

→ Mosquito-bite prevention

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EXAM ESSENTIALS

Causative agent:

→ Yellow fever virus

Virus family:

→ Flaviviridae

Genome:

→ RNA

Vector:

→ Mosquito

Major urban vector:

→ Aedes aegypti

Major endemic regions:

→ Sub-Saharan Africa and tropical South America

Incubation period:

→ Approximately 3–6 days

Classic severe manifestations:

→ Fever + jaundice + hemorrhage

Characteristic pulse finding:

→ Relative bradycardia / Faget sign

Characteristic liver pathology:

→ Midzonal necrosis

Characteristic apoptotic hepatocytes:

→ Councilman bodies

Diagnostic test during viremia:

→ RT-PCR

Important later diagnostic test:

→ IgM serology

Specific antiviral therapy:

→ None established

Main treatment:

→ Supportive care

Major prevention:

→ Live attenuated yellow fever vaccine

Vaccine type:

→ 17D live attenuated vaccine

Time for primary vaccine certificate to become valid:

→ 10 days

Routine 10-year booster for most people:

→ No longer required

Severe-stage mortality:

→ Approximately 20–50%

Major complications:

→ Hepatic failure, hemorrhage, renal failure, shock, ARDS, multiorgan failure