Writing Wednesday in the New England Journal of Medicine, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), said experts are concerned because the number of yellow fever cases is much higher than what’s reported in a typical year in this part of Brazil. Officials are also worried because these areas are also close to major urban centers such as Rio de Janeiro and Sao Paolo, where tens of millions of people live and where city-dwelling Aedes aegypti mosquitoes could start spreading the disease in a human-to-human cycle.

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Although there is a highly effective vaccine for yellow fever, it is not routinely given in Brazil’s major urban centers, they said. But millions of Brazilians have since been vaccinated this year as health authorities scramble to prevent the outbreak from turning into an epidemic.

Aedes aegypti are the same mosquito species that transmit Zika, dengue and chikungunya, viruses that are related to yellow fever.

“The concern now is that there are a considerable number of these jungle cases, and there’s always the possibility — although it’s very unlikely — that some of these infected people in the jungle” will travel to an urban area and spread the infection to the city-dwelling Aedes aegypti mosquitoes, Fauci said in an interview Wednesday, rather than the jungle-dwelling species that are transmitting it now.

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“This proximity raises concern that, for the first time in decades, urban transmission of yellow fever will occur in Brazil,” wrote Fauci and Catharine Paules, a colleague at NIAID.

Although it’s “highly unlikely” that there will be yellow fever outbreaks in the continental United States, the increase in domestic cases in Brazil and the frequency of international travel could lead to travel-related cases occurring in warmer parts of the United States, in the Gulf Coast states, and outbreaks in Puerto Rico and other U.S. territories, where Zika has spread explosively, primarily through infected Aedes aegypti mosquitoes.

“In light of the serious nature of this historically devastating disease, public health awareness and preparedness are critical, even for individual cases,” the authors said.

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Officials from the World Health Organization and the Centers for Disease Control and Prevention (CDC) have been monitoring the outbreak closely. Transmission continues to expand toward Brazil's Atlantic coast, with confirmed infections in the states of Minas Gerais, Sao Paulo and Espirito Santo. The entire state of Espirito Santo is considered at risk for yellow fever transmission, the WHO said this week.

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“The yellow fever outbreak in Brazil is yet another reminder of the dangers posed by mosquito-borne diseases around the world,” said Erin Staples, a medical epidemiologist at the CDC. “It’s critical that nations have the capacity to quickly detect and control these outbreaks in order to decrease the illness and death and prevent the spread to other locations.” The CDC has been working with PAHO and the WHO to provide technical assistance to Brazilian authorities.

Fauci said clinicians need to keep yellow fever on their radar in case they start seeing possible clusters of cases in areas where there are also Zika outbreaks and in possible travel-related cases. Most infectious disease clinicians haven’t ever seen a case of yellow fever, he said.

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“This is not ‘chicken little, the sky is falling,’” he said. “It’s a public health heads-up.”

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Extensive immunization campaigns, along with effective mosquito control — especially in developed countries — have reduced yellow fever cases worldwide. Localized outbreaks still occur in parts of Africa and Central and South America, accounting for an estimated 84,000 to 170,000 severe cases of disease and 29,000 to 60,000 deaths annually.

In late 2015, an outbreak of yellow fever in Angola and Congo resulted in 961 confirmed cases and 137 deaths. During that outbreak, the world’s emergency vaccine stockpile reserve was exhausted, making the outbreak more difficult to control.

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Historically, yellow fever has claimed millions of lives, including many thousands in the United States. The Philadelphia epidemic of 1793, for example, killed about 10 percent of the city’s population and prompted the federal government to flee the city, the authors noted.

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The fearsome disease starts like a common flu, with symptoms of headache, fever, muscle pain, nausea and vomiting. But in about 15 percent of patients, it develops into a more severe form, with high fever, jaundice, internal bleeding, shock, organ failure and death. Up to half of those who develop the severe form may die.

To prevent a similar occurrence during a future yellow fever outbreak in Brazil or elsewhere, the authors note that “early identification of cases and rapid implementation of public health management and prevention strategies, such as mosquito control and appropriate vaccination, are critical.”