Yellow Fever Treatment & Management

There is mandated reporting to the WHO of all suspected or confirmed yellow fever cases within 24 hours of detection. Cases should also immediately be reported to the local health department.

No specific treatment exists for yellow fever; however, supportive care is critical. Severely ill patients should be treated in an intensive care setting. The required management consists of vasoactive medications, fluid resuscitation, ventilator management, and treatment of disseminated intravascular coagulation, hemorrhage, secondary infections, and renal and hepatic dysfunction. Salicylates should be avoided because of the increased risk of bleeding secondary to platelet dysfunction.

In 2001, an expert panel recommended the following common-sense recommendations (although these have never been validated in clinical studies): ^[28]

• Maintenance of nutrition and prevention of hypoglycemia
• Nasogastric suction to prevent gastric distension and aspiration
• Gastric acid suppression to prevent gastric bleeding
• Treatment of hypotension with fluid resuscitation and vasoactive drugs (dopamine)
• Administration of oxygen
• Correction of metabolic acidosis
• Treatment of bleeding with fresh frozen plasma
• Dialysis if indicated by renal failure
• Treatment of secondary bacterial infections with indicated antimicrobials

Clinical studies are ongoing, but no specific treatment is currently available. Administration of interferon-α (or possibly IVIG) would be a reasonable postexposure prophylactic treatment in an unvaccinated laboratory or hospital worker exposed to yellow fever or blood of an acutely ill (potentially viremic) patient with yellow fever if administered within 24 hours. A long list of novel small molecules have shown activity against yellow fever and other flaviviruses in vitro or in animal models, but none is currently available clinically. In studies of nonhuman primates, ribavirin treatment did not prolong survival. ^[14]

In a retrospective analysis of patients with yellow fever vaccine–associated viscerotropic disease accompanied by shock, 75% of those treated with stress-dose steroids survived, compared with 29% of those not treated with stress-dose steroids. ^[14]

Transmission prevention

Because viremic patients bitten by mosquitoes can transmit the virus to other patients, the patient should be isolated with mosquito netting in areas with potential vector mosquitoes.

Yellow fever virus is not transmitted person to person, but other infections in the differential diagnoses can be transmitted; thus, the patient should be isolated until a definitive diagnosis is made.

Adherence to universal precautions is mandatory to prevent transmission to health care workers. One case of infection of a health care worker (a phlebotomist) has been reported. However, no documented needlesticks or blood splashes explained the transmission in this case.

Treatment of yellow fever principally is symptomatic and preventative. Closely monitor patients for hypovolemia, oliguria, hypoxia, acidosis, and electrolyte imbalance. Hypotension and hypoxia may aggravate hepatic and renal injury.

Intravascular volume may decrease secondary to sequestration in the extravascular space and fluid loss through insensible losses, vomiting, and capillary leak. Invasive arterial blood pressure monitoring may be warranted.

Monitor central venous pressure, peripheral blood pressure, as well as surrogates for organ perfusion and regional blood flow (eg, capillary refill, urinary output, ScvO₂). Monitor acid-base disturbances and metabolic acidosis via arterial blood gas sampling.

Replacement of red blood cells and clotting components will be necessary to treat hemorrhage and shock. Consider vasopressor support for those patients who remain hypotensive despite volume resuscitation and further management of shock.

Patients with respiratory failure, acute respiratory distress syndrome (ARDS), or both may require endotracheal intubation and mechanical ventilation. In those cases, nasogastric suction is essential to prevent gastric distention and aspiration of gastric contents.

Other points to remember include the following:

• Renal failure may necessitate dialysis

• H2-receptor antagonists and proton pump inhibitors may be valuable in preventing gastric bleeding

• Use of cooling blankets and tepid sponging can reduce fever and, thus, oxygen consumption

• Hypothermia frequently occurs late in the disease course and is corrected with gradual rewarming

• Consider parenteral alimentation; hypoglycemia can be prevented by infusion of 10-20% glucose solution

Prevention remains the cornerstone to minimizing the risk of yellow fever. Travelers to endemic areas and local populations should be vaccinated. The currently available vaccine confers near lifelong immunity in 99% of patients. ^{[3, 29]}

In 2015, the CDC's Advisory Committee on Immunization Practices and the World Health Organization (WHO) updated recommendations that a single lifetime dose of yellow fever vaccine is sufficient for most people traveling to endemic areas (based on increasing data that prolonged immunity [upwards of 30-35 years in some studies] was noted following a single vaccination). The CDC also recommends that some high-risk groups may receive a booster dose after 10 years or an additional dose before traveling to an endemic area. ^{[30, 31]}

An additional dose is recommended for the following populations:

• Women who were pregnant (regardless of trimester) when they received their initial dose of yellow fever vaccine should receive 1 additional dose before their next travel that puts them at risk for yellow fever virus infection.
• Persons who have undergone hematopoietic stem cell transplantation after receiving a dose of yellow fever vaccine and who are sufficiently immunocompetent to be safely vaccinated should be revaccinated before their next travel that puts them at risk for yellow fever virus infection.

A booster dose is recommended for the following high-risk populations after 10 years:

• A booster dose may be given to travelers who received their last dose of 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.
• Persons who were infected with HIV when they received their last dose of yellow fever vaccine should receive a dose every 10 years.
• Travelers who plan to spend a prolonged period in endemic areas or those traveling to highly endemic areas such as rural West Africa during peak transmission season or an area with an ongoing outbreak should receive a booster dose.
• Laboratory workers who routinely handle wild-type yellow fever virus should have yellow fever virus–specific neutralizing antibody titers measured at least every 10 years to determine if they should receive additional doses of the vaccine.
• For laboratory workers who are unable to have neutralizing antibody titers measured, yellow fever vaccine should be given every 10 years as long as they remain at risk.

International Health Regulations allow countries to require proof of vaccination before allowing travelers to enter or leave. Travelers should have a completed International Certificate of Vaccination or Prophylaxis (ICVP). Only the most recent ICVP form CDC 731 complies with the International Health Regulations. For specific information regarding vaccination, see the CDC's Traveler's Health Web site. ^[22]

Preventive measures also include staying in air-conditioned or properly screened sleeping quarters and wearing protective clothing, long sleeves, and long pants. Travelers should consider using DEET (N,N -diethyl-meta-toluamide)-containing insect repellent spray.

Because of ongoing concerns for vaccination shortages, work is ongoing to develop alternate dosing, administration, or vaccine options to expand the vaccination supply. ^{[32, 33, 34, 35]} In the United States, only one vaccine is licensed by the Food and Drug Administration (FDA), YF-VAX (Sanofi-Pasteur). Manufacturing issues in the process of transitioning to a new vaccine production facility triggered YF-VAX shortages and order restrictions in 2015. Subsequently, the FDA accepted use of an alternate vaccine, Stamaril (produced in France and distributed to more than 70 countries with a similar efficacy and safety profile to YF-VAX), through an Investigational New Drug (IND) protocol in an Expanded Access Program. There are 250 US clinic sites spread throughout the country. However, vaccine recommendations for the Stamaril IND differ from YF-VAX in that breastfeeding women and children aged 6-8 months are excluded from enrollment. ^[36] Sites where Stamaril is available are listed at www.cdc.gov/travel/page/search-for-stamaril-clinics. ^[19]

In June 2016, the WHO Strategic Advisory Group of Experts on Immunization approved the use of fractional vaccine (one-fifth the standard dose) in emergency response when vaccine supplies are limited. Until long-term immunity is proven with fractional dosing, this does not meet requirements for International Health Regulations proof of vaccination; revaccination with full-dose vaccine is required, when available. ^[37] In the United States, fractional dosing is not recommended owing to limited efficacy data. ^[36]

Eradication challenges

Yellow fever will likely not be eradicated in the near future. Various mosquito species transmit the sylvatic form via nonhuman primates in the jungles and moist savannas; ^[6] this ongoing life cycle does not require humans for the spread of disease. Additionally, urbanization and deforestation have reintroduced the virus into areas of previous inactivity. New outbreaks and epidemics continue to reemerge in regions of Africa and South America previously not considered at risk.

At present, the burden of disease internationally is greater than the resources available for proper surveillance and mass vaccination. ^[8] Yellow fever also carries the potential threat of use as a bioterrorist agent; ^[1] however, other viral hemorrhagic fevers pose a greater risk because of their lack of prophylactic protection.