Yellow fever in Brazil: thoughts and hypotheses on the emergence in previously free areas

This article describes and discusses factors associated to the reemergence of yellow fever and its transmission dynamics in the states of São Paulo (Southeastern Brazil) and Rio Grande do Sul (Southern) during 2008 and 2009. The following factors have played a pivotal role for the reemergence of yellow fever in these areas: large susceptible human population; high prevalence of vectors and primary hosts (non-human primates); favorable climate conditions, especially increased rainfall; emergence of a new genetic lineage; and circulation of people and/or monkeys infected by virus. There is a need for an effective surveillance program to prevent the reemergence of yellow fever in other Brazilian states. DESCRIPTORS: Yellow Fever, epidemiology. Disease Outbreaks. Epidemiologic Factors. Zoonoses. Communicable Diseases, Emerging. Epidemiologic Surveillance.


3With t
e introduction of yellow fever 17D vaccine in the late 1930s 14 and campaigns for the eradication of Aedes aegypti mosquito, urban epidemics of yellow fever have dropped dramatically and outbreaks have been confi ned to wilderness areas with transmission mostly by Haemagogus janthinomys in the Americas and Aedes africanus in Africa. 22Despite that, it is estimated that 200,000 cases of yellow fever occur annually with 30,000 deaths, and underreporting of cases is the rule rather than the exception. 9e basic question concerning yellow fever in Brazil and other endemic countries is: why are there still so many cases despite the fact that a low-cost, effective vaccine has been available for more than 70 years?Other puzzling issues should be addressed, particularly in Brazil: a) recent occurrence of epidemics and epizootics in areas in which there were no cases for decades (Figure ); b) the reasons why viral spread is repeating the same path as in the 1940s and moving towards the coast; and c) why this is a reemerging disease despite improved surveillance, easy access to vaccine and recent environmental changes with high rates of deforestation.These are challenging issues as many factors are involved and they are addressed in the present article.


YELLOW FEVER PARADIGMS


Periodic epizootic outbreaks

Historically, epizootic outbreaks have been reported in Brazil (and in other endemic countries as well) from time to time.These outbreaks vary from region to region.In the 1940s (Figure ), there was a sequential shift of yellow fever virus (YFV) from Central-West Brazil (state of Mato Grosso) to the coast with the disease being reported in the Northeast (state of Bahia), Southeast (states of Minas Gerais, Espírito Santo, and São Paulo), and the Southern. 13In the Amazon region and in other endemic areas in Brazil, epizootic outbreaks have been reported every fi ve to seven years. 18This periodicity is likely due to renewal of non-human primate populations essential for viral amplifi cation, which does not occur with vector population alone (Haemagogus and Sabethes mosquitoes) even considering the possibility of transovarial or vertical transmission.

A goo

oiás (Central-West Brazil).Th
most recent epizootics and epidemics of yellow fever in Goiás occurred in 1972-1973, 1980, 1988, 2000, and 2007-2008. 11,15,17,18 These occurrences INTRODUCTION are part of a paradigm in which yellow fever virus periodically spreads via epizootic outbreaks to continuous and contiguous areas, following the movements of nonhuman primates and natural watercourses. 7,8,13wever, the same is not expected in unaffected areas.Yellow fever virus is usually introduced by probably one of two ways.First, people who are viremic or in an incubation period go to areas with high population densities of vectors/transmitters and vertebrate hosts.Once the virus is established in the area, an explosive viral transmission via vectors occurs among non-human primates without natural immunity, resulting in an almost total elimination of these monkey populations, which has bee

demonstrated
n a molecular study with more than 70 strains of yellow fever virus isolated in Brazil 20 and in the recent epidemic registered in the states of Rio Grande do Sul and São Paulo. 12Indeed, molecular analysis showed that yellow fever virus isolates from Marajó island in the Northern state of Pará 16 were identical to yellow fever viral strains found in Goiás and Bahia. 15Since these two areas where infection probably occurred were more than 2,000 km apart (Figure ), viral spread through monkeys is not possible, and only viremic humans with oligosymptomatic or even asymptomatic infections could have carried these yellow fever virus strains. 20other way is illegal traffi c of wild animals.Animal traffi ckers are known to use illegal roads or means that are generally of more diffi cult access, which might lead to the introduction of the virus into areas where, when conditions are favorable, natural zoonotic transmission cycle may occur.


Favorable climate conditions

Although it is diffi cult to measure and evaluate the impact of climate conditions on the onset and magnitude of an outbreak or zoonotic epidemic of yellow fever, a study conducted in the state of Goiás during the 2000 epidemic showed that climate conditions played a crucial role in determining its magnitude. 15A 10-year survey of offi cial data recorded between 1991 and 2000 by the Instituto Nacional de Meteorologia (INMET -National Institute of Meteorology) showed that temperatures increased and rainfall index was much higher in 2000 than the average for 1990 to 1999.This suggests that increased rainfall favored mosquito proliferation and high temperatures promoted viral spread and transm

sion. 15


Wildlife vectors o
yellow fever

There are two major mosquito vectors for zoonotic yellow fever in Brazil nowadays, Hg. janthinomys and Hg.leucocelaenus. 18,19The former is the main vector of yellow fever in endemic areas (where vaccine is  recommended) and in the state of São Paulo; [3][4][5]13 but it has not been found in southern Brazil. It s a mosquito with strict host specifi city for wild animals, indicating that virus transmission occurs within or near forested areas.The latter has a more broad host range; it sometimes leaves the forest and can be found at ground level in areas surrounding woods or forested groves common in southern Brazil.6 In 2001 YFV was isolated from Hg. leucocelaenus during an epizootic outbr

k in the mission areas in the Sou
hern state of Rio Grande do Sul, 40 years after the last report of yellow fever in this region.1,10,19 More recently, during the 2008 and 2009 outbreaks, it was commonly captured infected in the municipalities of Rio Grande do Sul and São Paulo, where human cases and epizootic cases in monkeys (Alouatta caraya) were reported.2,12 These fi ndings support the hypothesis that this species plays a role in yellow fever transmission in Brazilian southern areas, especially due to absence of Hg. janthinomys.


Non-human primates

Monkeys are the primary vertebrate hosts of YFV and play an important role in the amplifi cation of viral transmission.A single viremic monkey can be an infection source for tens or hundreds of mosquito vectors, greatly increasing the rate of disease transmission.Since Haemogogus species preferably feed on primates, their role in the infection of mosquito vectors, including minimal infection rate, can be measured and is a very important marker of mosquito infection. 21


ON THE REEMERGENCE OF YELLOW FEVER IN SOUTHERN BRAZIL


Susceptible population

Yellow fever vaccination in Rio Grande do Sul (since 2001) and

o Paulo are carried
out only in districts where epizootic outbreaks occurred and in adjacent municipalities within a safety margin.Hence, most human population susceptible to the virus has not been vaccinated.It suggests that the circulating of YFV among susceptible human population can increase the risk of arbovirus transmission to humans, and especially to monkeys, as it was observed in the states of Rio Grande do Sul in 2008 and Sao Paulo in 2009.Following the traumatic events of these la

ms should be in place.
Large populations of vectors and primary hosts

High population densities of yellow fever vectors and their primary hosts were certainly present in Rio Grande do Sul and São Paulo states.This was evidenced especially in Southern Brazil, where dozens of outbreaks were confi rmed by specifi c examination of mosquitoes and howler monkeys found dead, sick, or captured in transmission areas.Considering that each viremic monkey can infect hundreds of mosquitoes, it is easy to understand the dynamics of viral transmission in Rio Grande do Sul: as epizootics occurred, several howler monkeys died, and hundreds, perhaps thousands, of Hg. leucocel

nus became infected, leading to epizootic maint
nance, including through transovarial transmission. 8As the virus was carried by humans and/or viremic monkeys and spread to other areas, new cases and epizootics were reported.Interestingly, this pattern supports the transmission paradigm in epizootic outbreaks.

The respect for animals, particularly howler monkeys, caused this population of animals to greatly increase in the South, creating favorable conditions to the maintenance of a native transmission cycle of yellow fever.The reintroduction of YFV in 2000 in the Rio Grande do Sul was probably due a silent cycle. 19It is therefore possible that during the years that preceded the most recent outbreak, an intense viral multiplication in vectors had been going on, which was crucial for viral spread among vectors.This fact was pivotal for the explosion of yellow fever transmission in Rio Grande do Sul and São Paulo states.


Favorable climate conditi ns

There have been recently major climate changes especially in the state of Rio Grande do Sul, resulting in intense and prolonged conditions alternating between rainfall and drought.A detailed study of humidity, temperature, and rainfall patterns is imperative to explore whether there were unusual conditions during the years with yellow fever case reports.Nevertheless, it is likely that recent climate alterations may have signifi cantly contributed to the reemergence of yellow fever in that state.A comparison between Goiás 15 and Rio Grande do Sul 2 show that the epizootics and occurrence of cases were very similar;

herefore it seems likely that
climate factors have also played an important role in transmission.


Emergence of a new viral lineage

In the 2008-2009 epidemic in Rio Grande do Sul 2 and São Paulo, 12 a new viral lineage (genotype 1E) emerged from the previously described lineage genotype 1D. 20Molecular evidence indicates that the emergence of this new genetic lineage follows a pattern described for several viruses with a "boom-and-bust cycle," where the current lineage originates from the previous lineage and replaces it. 23Lineage 1D, which has emerged and circulated in Brazil since 1998 in the state of Pará (Northern Brazil), caused yellow fever epidemics until 2007. 15,16,19,20It later gave rise to lineage 1E, which replaced it, as reporte

by Sousa et al 12 and Cardoso et
l. 2


Circulation of yellow fever virus and viremic people

The circulation of YFV and people movement within affected states, mostly in Rio Grande do Sul state, allows us to partially understand the virus circulation dynamics.The virus found in both states is identical.People movement and infected monkey traffi cking is a compelling explanation for yellow fever reemergence in areas that have been unaffected by viral circulation for more than 40 years and that are about 1,000 km away from each other.


FINAL CONSIDERATIONS

A combination of fi ve factors is likely to be associated with the reemergence of yellow fever in southern and so

heastern Brazil (recent epizootics and epidemics): ex
osure of a susceptible human population; high density of vectors and primary hosts (non-human primates); favorable climate conditions, especially increased rainfall; emergence of a new genetic lineage; and circulation of people and/or infected monkeys.There is a need for an effective surveillance program to prevent the reemergence of yellow fever in other Brazilian states.

BFigure .
.
Figure.Map of Brazil showing epizootic outbreaks in the 193