Yellow Fever

Etiology

The virus is an RNA virus of the genus Flavivirus, closely related to the viruses that cause West Nile, St. Louis, and Japanese encephalitis. Tree-hole breeding mosquitoes, such as Aedes aegypti and Haemagogous species, transmit yellow fever during the rainy season. The yellow fever virus has three distinct transmission cycles: jungle, intermediate, and urban. The jungle cycle involves transmission between non-human primates (monkeys) and mosquitoes. Humans are infected through infected mosquito bites while visiting or working in the jungle. The intermediate cycle occurs in the African savannah and involves humans who live or work in jungle border areas. Transmission may be between monkeys and humans or humans via mosquito vectors. The urban cycle involves a viremic human who contracted the virus in either the jungle or intermediate cycle who then returns to an urban area. Humans develop significant viremia to infect mosquitoes, which can then transmit the virus to other humans in urban areas. Person to person or primate to human transmission has not been reported without the involvement of a mosquito vector. [4][5]

Epidemiology

Vaccination has decreased worldwide epidemics of yellow fever, but the infection has reemerged in many parts of Africa and South America. No one is immune from yellow fever, and it occurs in people of all ages and races. The highest mortality rates are reported in infants and the elderly, who often have depressed immune systems. yellow fever is very rare in the United States. Most cases are diagnosed in unvaccinated travelers to sub-Saharan Africa or South America. While most people develop a self-limited infection, those who develop severe disease.[6]

Pathophysiology

The incubation period is 3 to 6 days. Once acquired, the virus quickly spreads to multiple organs in the body. The liver is the most important organ affected by yellow fever. It produces profound jaundice due to liver damage. The kidneys also undergo similar pathological alterations and can lead to acute renal failure. When the upper gastrointestinal (GI) tract is involved, the gastric acid mixed with blood produces what is known as black vomit. Central nervous system (CNS) features include cerebral edema and hemorrhage. Encephalopathy is also a common feature of yellow fever.[7][8]

History and Physical

The diagnosis requires a thorough travel history and record of immunization. Patients may present with headache, malaise, jaundice, and myalgias with severe back pain commonly reported.

The incubation period is 3-7 days, with most individuals having mild flu like illness. About 15% of cases have severe symptoms including chills, low back pain, headache, and fever.

There is a period of remission which may last 24-48 hours. This may be followed by a return of symptoms and marked intoxication. During this stage, the hepatorenal disease is common and carries a high mortality.

A physical exam may reveal the Faget sign or pulse fever dissociation, facial flushing, and conjunctival injection. During the most toxic phase, patients develop jaundice, dark urine, and vomiting. Bleeding may occur from mucous membranes and in the gastrointestinal tract. Symptoms may mimic those of malaria, leptospirosis, viral hepatitis, other hemorrhagic fevers, dengue, and other flavivirus infections.

Evaluation

Rapid detection methods include the detection of yellow fever antigen using monoclonal enzyme immunoassay in serum specimens and detection of viral genome sequences using polymerase chain reaction (PCR) assay. Yellow fever can be diagnosed using ELISA and serology titers of antibodies. Other investigations depend on what organ is involved. If there is evidence of altered mentation, a lumbar puncture and a CT scan are performed. Blood work may reveal leukopenia with elevated transaminase levels. Neutropenia is common during the first week of the infection.

If the liver is involved, the coagulation profile may be abnormal. Elevation in creatinine, hypoglycemia and metabolic acidosis are strongly associated with a very poor prognosis.

Most yellow fever specific testing can be done at the CDC, but reports will be sent to the state health department. When sending blood samples directly to the CDC, the health department should be informed.[3]

A chest x-ray is done in patients with respiratory distress because of the pulmonary edema. ECG may identify prolonged QT and PR intervals. Arrhythmias are common when the myocardium is affected.

Treatment / Management

Yellow fever is a reportable infection. Once the virus is contracted, symptoms develop after 3 to 6 days. There is no specific treatment, but severe cases require aggressive supportive care and hydration. Patients should be managed in the intensive care unit (ICU) and closely monitored for disseminated intravascular coagulation (DIC), hemorrhage, kidney, and liver dysfunction. Coagulopathy is managed with fresh frozen plasma, and renal failure may require dialysis. Even though yellow fever is not transmitted from person to person, isolation of the individual should be undertaken until the diagnosis is confirmed. Universal precautions are required when looking after patients with yellow fever although person-person transmission of the virus is unlikely. Infected patients should avoid mosquitoes, as they may transmit the virus to mosquitoes, which can serve as vectors for infection other patients.

Since there is no effective treatment or vaccine, prevention is critical.  This is best accomplished by avoiding mosquito bites entirely. Even very short periods outdoors can lead to exposure to mosquito bites, so people should wear proper protective clothing. This protection includes long sleeves, long pants, socks, and closed-toe shoes. Pant legs can be tucked into socks to prevent bites to exposed ankles. Transmission is common during the warmer months, and mosquitoes may bite through very thin clothing, so treating clothing with repellents containing permethrin, DEET, oil of lemon eucalyptus, or other EPA-registered insect repellants will reduce this risk. Permethrin should not be applied directly to the skin, but when applied to clothing, it provides protection even after the clothing is washed. Transmission is most frequent when mosquitoes feed, between dawn and dusk, so outdoor activities during this period should be avoided. However, one of the mosquitos responsible for transmitting the virus, Aedes Aegypty, feeds during the daytime; so there is no safe time during the day for a traveler without repellent and wearing protective clothing. Travelers should sleep in air-conditioned spaces or use mosquito nets or screens to prevent bites during sleep. Standing water is a breeding ground for mosquitoes, so flower pots, buckets, and other containers should be drained. Children’s wading pools should be emptied and stored on their sides, and tire swings should have holes drilled into the bottom to allow trapped water to drain.

There is a safe and highly effective live-attenuated vaccine available to prevent yellow fever. A single dose confers lifelong immunity and is effective within 30 days for 99% of patients. Patients with relative contraindications to live attenuated vaccine who plan to travel to endemic areas should review the recommendations for vaccination prior to travel.[9][10][11]

Differential Diagnosis

The differential diagnosis of yellow fever is broad and makes a careful travel history important. It includes:

• Viral hemorrhagic fevers
• Viral hepatitis
• Malaria
• Lassa fever
• Ebola virus
• Typhoid fever
• Dengue fever
• Disseminated Intravascular Coagulation
• Louse-borne relapsing fever
• West Nile virus encephalitis
• Japanese encephalitis
• Herpes simplex encephalitis
• Eastern and Western equine encephalitis
• Venezuelan Equine encephalitis
• Enterovirus meningitis
• Mycoplasma meningitis
• Cytomegalovirus infection in immunocompromised host
• Tuberculous meningitis
• Nipah virus infection
• Rocky Mountain spotted fever
• Fungal meningitis
• Leptospirosis
• Neurocysticercosis
• Amebic meningoencephalitis 

Prognosis

Most cases are subclinical or mildly symptomatic with an excellent prognosis. About 15% of symptomatic patients will develop severe disease. Most will recover, but after a bout of yellow fever, full recovery may take weeks or months. In most cases, there is a reversal of the liver and renal dysfunction. Death occurs in 30% to 50% of patients with severe disease. All travelers to endemic areas should be vaccinated if they are candidates for the live attenuated vaccine.

Death often occurs within 2 weeks during the toxic phase of the infection. Unvaccinated travelers to endemic areas are at high risk for developing symptomatic disease compared to the natives, who have acquired immunity. Rare cases of neurologic and viscerotropic disease have been reported following vaccination.

Complications

• Multiorgan failure
• ARDS
• Sepsis
• Respiratory failure
• Myocarditis
• Encephalitis
• Hemorrhage
• DIC