Yellow fever could become the 5th mosquito-borne virus to hit the United States in recent years, according to experts from the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

An on-going outbreak in rural areas of Brazil has so far not involved human-to-human transmission through Aedes aegypti mosquitoes but has been spread via nonhuman forest-dwelling primates, write Infectious Disease Fellow Catharine I. Paules, MD, and NIAID Director Anthony S. Fauci, MD, in an article published online today in the New England Journal of Medicine.

However, the outbreak is near major urban areas, where yellow fever vaccine is not routinely given and might readily lead to urban human-to-human transmission.

The outbreak in the Brazilian states of Minas Gerais, Espirito Santo, and São Paulo has resulted in 234 confirmed infections and 80 confirmed deaths as of February 2017. "The high number of cases is out of proportion to the number reported in a typical year in these areas," write Dr Paules and Dr Fauci.

They also note that, as with Zika, arbovirus epidemics spread by A Aegypti can move rapidly through populations that lack immunity and can be readily spread by human travelers. Yellow fever outbreaks could occur in warmer regions of the continental United States where the mosquito is endemic as well as in some US territories (as occurred with zika in Puerto Rico following its emergence in Brazil). The arboviruses that cause dengue, West Nile, and chikungunya followed similar trajectories.

The authors note that the key to dealing with yellow fever outbreaks is to combine early identification of cases, mosquito control, and vaccination of at-risk populations. The live attenuated yellow fever vaccine still in use was developed in 1937 and provides lifetime immunity for up to 99% of recipients, but vaccine supplies have not always been adequate for dealing with sudden outbreaks.

For example, the December 2015 yellow fever outbreak in Angola and the Democratic Republic of Congo caused 961 confirmed cases of yellow fever and 137 deaths. Attempts to contain that outbreak exhausted the worldwide vaccine stockpile reserved for epidemic response, leading health authorities to decrease doses to as little as one fifth of the standard dose to conserve the dwindling vaccine supply.

Furthermore, although yellow fever claimed thousands of American lives in the eighteenth and nineteenth centuries, the disease was largely eliminated from the United States through mosquito control and better sanitation.

As most American physicians have never seen a case of yellow fever, Dr Paules and Dr Fauci provide clinical guidance on what to look for if the current outbreak leads to urban spread. As with zika virus, they recommend special attention to travelers returning from areas where there have been outbreaks. Initial diagnosis is based on clinical presentation, with later confirmation by specialized laboratory testing.

Incubation is 3 to 6 days, after which the patient may present with high fevers associated with bradycardia, leukopenia, and transaminase elevations, as well as persistent viremia.

This is typically followed by a period of remission, but within 24-48 hours up to 20% of patients progress to the intoxication stage, with high fevers, hemorrhage, severe hepatic dysfunction, jaundice, renal failure, cardiovascular abnormalities, central nervous system dysfunction, and shock. The case-fatality rate is 20% to 60% in these severely ill patients; there is no effective antiviral therapy.

"Yellow fever is the most severe arbovirus ever to circulate in the Americas, and although vaccination campaigns and vector-control efforts have eliminated it from many areas, sylvatic transmission cycles continue to occur in endemic tropical regions," the authors write.

Peter Hotez, MD, PhD, FASTMH, FAAP, dean of the National School of Tropical Medicine, professor of pediatrics and molecular & virology and microbiology, and head of the section of pediatric tropical medicine at Baylor College of Medicine in Houston, Texas, told Medscape Medical News, "Dr Paules and Dr Fauci are right to express concern about yellow fever, both in the Americas and in Angola and Democratic Republic of Congo last year.

"But it's not yellow fever alone. In the Western Hemisphere we have seen a significant and almost mysterious rise in arthropod-borne vector infections, including zika, chikungunya, dengue and yellow fever. We have also seen a parallel rise of some of these same diseases in Southern Hemisphere. In the Public Library of Science (PLoS) last year, I ascribed the rise of these vector borne infections to the 'Anthropocene' forces of climate change, human migrations, urbanization, and deforestation, as well as the shifting nature of global poverty, which I labelled blue marble health.' Yellow fever is an important part of this trend."

Dr Hotez is coeditor-in-chief of PLoS Neglected Tropical Diseases, and in 2013 warned in a blog post in that journal that US health officials should be more concerned about possible outbreaks of yellow fever in the Americas.

Dr Hotez urged at that time that yellow fever risk be evaluated in the major southern cities of the United States, including Houston, Miami, New Orleans, and Tampa. He explained that the A aegypti mosquito can be found in many areas of the southern United States. Other risk factors in those areas include high poverty rates, poor urban housing, and foci of standing water that provide potential breeding sites.

Dr Hotez also pointed out that although Max Theiler received the Nobel Prize for developing the yellow fever vaccine in 1951, almost nobody in the United States other than travelers to endemic areas gets vaccinated.

The authors and Dr Hotez have disclosed no relevant financial relationships.

NEJM. Published online March 8, 2017. Full text

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