Epidemiology and Transmission

Yellow fever, a form of hemorrhagic fever, is an acute infectious disease that is endemic in sub-Saharan Africa, Central, and South America. Yellow fever is caused by a flavivirus that is spread by the Aedes aegypti mosquito. These mosquitoes thrive, live, and breed in any standing water. Yellow fever causes 200,000 infections and 30,000 deaths every year, with nearly 90% of these occurring in Africa. Nearly a billion people live within an area of the world where the disease is commonplace.

The cause of yellow fever was not known until the turn of last century. Most of those discoveries were found due to building of the Panama Canal, during which many Americans became infected with the disease. Prior to this, the spread was increased as many people would leave the Southern hemispheres and return to mosquito dominated areas. Once the infected returned to their homes, local mosquitos could become carriers of the disease and begin to infect other humans. The last major outbreak of yellow fever within the United States was an 1888 epidemic in Jacksonville, Florida.  Assuming the disease was contagious human to human; they isolated the sick but did nothing to control the mosquito population. In the modern era, epidemics of yellow fever occur most commonly when infected people introduce the virus into heavily populated areas with high mosquito density and where most people have little or no immunity.

When a mosquito bites a human or monkey infected with yellow fever, the virus enters the mosquito’s bloodstream and settles in the salivary glands. When the infected mosquito bites another human/monkey, the virus then enters the host’s bloodstream, where it may cause an array of symptoms. In mild cases, yellow fever causes fever, headache, nausea and vomiting. But yellow fever can become more serious, causing heart, liver and kidney problems along with hemorrhaging. Up to 50 percent of people with the more severe form of yellow fever die of the disease.

Symptoms

In its mildest form, yellow fever is a self-limited infection. The incubation period for yellow fever is three to six days. Initial symptoms in the acute phase include sudden onset of fever and headache without other symptoms. After this, the infection is followed by a remission or recovery phase lasting up to 48 hours.  Many patients have an uneventful recovery, but in approximately 15% of infected persons, the illness recurs in more severe (toxic) form within 48 hours following the acute and recovery phases.

Toxic patients experience:

  • Abrupt onset of a high fever (up to 104°F [40°C]), chills and severe headache

  • Generalized myalgia and lumbosacral pains

  • Anorexia, nausea, vomiting, and dizziness

  • Bradycardia may occur in relation to the elevated body temperature (Faget’s sign)

  • Development of Adult Respiratory Distress Syndrome (ARDS)

  • Renal insufficiency and progressive failure

  • Cardiovascular instability and shock

  • Bleeding disorders with hematemesis, melena, metrorrhagia, hematuria, ecchymosis, nose bleeding and oozing from needle-puncture sites

  • Physical findings include scleral and dermal yellowing (jaundice), petechiae, bruising, and epigastric tenderness without hepatic enlargement

  • Coma or encephalitis can occur

Toxic patients may develop any or all of these symptoms.

Diagnosis

Preliminary diagnosis is based on the patient’s clinical signs and travel history, including destination, time of year, activities and vaccination status. 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.

Laboratory diagnosis of yellow fever is accomplished by serum testing for IgM enzyme-linked immunosorbent assay (ELISA), and IgG ELISA.  It can also be detected post mortem in tissue samples. Only a few specialized laboratories including those at the Center for Disease Control (CDC) are capable of performing these specialized tests.  Test results are normally available 4 to 14 days after the specimen is received, though supportive treatment should not be withheld for test results in patients with a high incident of suspicion.  The positive results are then sent to the appropriate state health department and reported to the World Health Organization (WHO). Other flaviviruses, such as West Nile, Zika and Dengue fever will also give positive results. Additional testing to definitively confirm the diagnosis of specifically yellow fever are needed, but all patients testing positive should be treated as confirmed until otherwise informed. Yellow fever RNA can only be detected very early after the onset of symptoms and is not detectable after 3-4 days. Therefore, histological staining is done to detect the yellow fever virus antigen.

 Laboratory abnormalities in yellow fever will depend on the severity and stage of illness. In the acute phase, leukopenia might occur; however, leukocytosis also can occur during the second week of the disease. Bleeding tendencies also can arise, together with elevated prothrombin and partial thromboplastin times. Decreased platelet count, and the presence of fibrin-split products result in disseminated intervascular coagulation (DIC). Hyperbilirubinemia might be present as early as the third day but usually peaks toward the end of the first week. Elevations of serum transaminase and other liver enzymes levels occur in severe disease and can remain elevated for up to 2 months after onset.

 

Treatment

No antiviral medications have proved helpful in treating yellow fever. As a result, treatment consists primarily of supportive care. Nontoxic patients can be treated through decreasing the severity of the symptoms. Aspirin and other nonsteroidal anti-inflammatory (NSAID) drugs should be avoided, as they have the potential to cause internal bleeding.

Because viremic patients bitten by mosquitoes can then transmit the virus to other mosquitos, the patient should be isolated. Most suspected cases within the US are hospitalized and observed for increasing severity of symptoms.

Treatment of toxic patients includes maintaining adequate cardiovascular status and blood pressure with vasopressors and IV fluids. Frequently, the use monitoring devices such as central venous pressure (CVP) and arterial lines are required; these also act to decrease the amount and frequency of needle sticks.  Replacing blood loss with the administration of packed cells and fresh frozen plasma is needed for those with bleeding and or symptoms of disseminated intravascular coagulation (DIC). Frequent assessment of perfusion though the evaluation of urinary output, capillary refill, and vital signs are required.

Supplemental oxygen and the potential need for intubation should be considered in patients with poor perfusion or symptoms of acute respiratory distress syndrome (ARDS). Intubated patients should receive gastric decompression and be placed on H2 receptor antagonists on proton inhibitors due to their increased risk of gastric bleeding.

Dialysis for kidney failure may need to be instituted.  Secondary infections should be treated with bacteria specific antibiotics. Steroid administration has also proven effective. Patients who survive yellow fever have acquired a lifelong immunity.

Post exposure administration of interferon-α or intravenous immunoglobulin (IVIG) for unvaccinated hospital or laboratory workers exposed to yellow fever or blood of an acutely ill patient has been proposed if administered within 24 hours. One case of transmission to a laboratory worker was confirmed without known blood contact.

Prevention

Prevention is the key to decreasing the incidence of yellow fever throughout the world. Three to four weeks prior to travel to an endemic area a person should get a yellow fever vaccine. A single dose of the yellow fever vaccine provides protection for at least 10 years. Side effects are usually mild, and may include headaches, low-grade fevers, muscle pain, fatigue and soreness at the site of injection. More significant reactions are rare. Some countries require travelers to present a valid certificate of immunization upon entry. People traveling to endemic areas should consult with an infectious disease specialist to evaluate their need and any potential contraindications while receiving the vaccine.

To reduce exposure to mosquitos, people should wear long-sleeved shirts and long pants when going into mosquito-infested areas. Housing should include screening and bed netting in high risk areas.  Applying permethrin-containing mosquito repellent to clothing, shoes, camping gear and bed netting is a good deterrent, but should not be applied to the skin.

Skin repellent products with the active ingredients DEET, IR3535 or picaridin provide long-lasting skin protection. Since these chemical repellents can be toxic, they should only be used as needed for the times outdoors. These products should not be used on the hands of young children or on infants under 2 months of age. According to the Centers for Disease Control and Prevention, oil of lemon eucalyptus, a more natural product, offers the same protection as DEET, but these products should not be used on children younger than age 3.

Though yellow fever is rarely seen in the United States, a high index of suspicion should be placed on people who have had recent travel to endemic areas. Mosquito borne viruses have been seen in the US in increasing quantities, and awareness of vector transmission and prevention through education may reduce the incidence. Since the launch of the Yellow Fever Initiative in 2006 by the World Health Organization, significant progress in combating this disease has been made in West Africa through education on transmission and vaccinations.

 

References:

https://www.cdc.gov/yellowfever/healthcareproviders/vaccine-info.html

http://www.cdc.gov/yellowfever

http://www.who.int/mediacentre/factsheets/fs100/en/