Yellow fever in the Americas: the growing concern about new epidemics

Yellow fever (YF) is a haemorrhagic viral disease with a high case fatality rate. It is considered a reemerging infectious disease of remarkable importance. During the last outbreaks in Brazil (2016-2017), many cases of YF emerged despite high YF vaccination coverage in some areas. However, there are many areas and populations worldwide where vaccination coverage has been low for years (e.g. Nigeria), which increases the risk of major epidemics in such areas, as would be the case in many of the American territories. Several factors, including the vast border and migratory status of Brazil, the widespread distribution of Aedes mosquitoes and the lack of efficient health policies and surveillance systems, favor this complex epidemiological scenario of reemergence. Therefore, mass vaccination of the population at risk, public health awareness and preparedness are urgently needed in this region. This opinion article describes the current global epidemiological situation of YF, focusing especially on the Americas, as well the risk and vulnerabilities in the region that would be of concern for major expansion to other countries apart from Brazil. Also, imported risk from endemic area outside of Americas (i.e. Africa) are of current concern.


Introduction
Yellow fever (YF) is a haemorrhagic viral, vector-borne disease with a high case fatality rate (CFR), spread by infected mosquitoes caused by the YF virus, an arbovirus belonging to the genus Flavivirus, family Flaviviridae. It has reappeared as a threat to global public health, evidenced by new epidemics in several countries in Africa and South America through autochthonous transmission, and in Asia with imported cases 1 . In Asia, but also Europe and North America, potential spreads beyond the borders of the endemic countries is a matter of global concern. Currently, there are around 1 billion people, from 49 endemic countries, that are considered at risk 1,2 . In this opinion article, we would like to express our concern regarding the expansion of YF in Latin America, beyond Brazil. In that country there is currently an epidemic situation, where, since the beginning of the outbreak in December 2016 up to 29 March 2017, there have been 1,987 cases of yellow fever reported (574 confirmed, 926 discarded, and 487 suspected under investigation). This included 282 deaths (187 confirmed, 24 discarded, and 71 under investigation) with a CFR of 33% among confirmed cases.

Recent outbreaks outside the Americas
Although relatively wide scale YF vaccination has been applied, a growing number of outbreaks have been documented in several African countries in the last decade [1][2][3] . The most recent outbreak occurred in Angola, resulting in 7,344 suspected cases, 962 laboratory-confirmed cases and 137 deaths (with a CFR of 14.2%), and lasting from December 2015 to October 2016 2 . In addition to spread of YF by autochthonous transmission, confirmed imported cases of YF were identified in China and Kenya 1-3 . Other countries, such as Chad, Ghana and Guinea have also reported outbreaks or sporadic cases not linked to the outbreak in Angola 1-15 . On Mar 12, 2016, the first imported case of YF was confirmed by China CDC. The patient was a 32 years old Chinese male who worked in Luanda and had fever and chills on Mar 8, 2016. He arrived to Beijing, where he was immediately hospitalized. Eleven imported cases of confirmed yellow fever occurred in China from March of 2016, prompting calls to strengthen surveillance systems at the border (http:// www.who.int/csr/don/6-april-2016-yellow-fever-china/en/) 16 .

The risk of Yellow Fever in the Americas, with a focus on Brazil
Even though no new cases have been confirmed since the last year in Angola, Africa, the global threat continues, indeed now with its epicentre in Brazil, South America. An ongoing outbreak of YF has started in Brazil since December 1, 2016. Up to February 22, 2017, a total of 1,336 cases of YF infection have been reported (292 laboratory confirmed, 920 suspected and 124 ruled out), resulting in 215 deaths (101 confirmed, 109 suspected, 5 ruled out) across six states of the country (Bahia, Espírito Santo, Minas Gerais, Rio Grande do Norte, São Paulo and Tocantins). The current CFR is 35% (from confirmed cases) and 12% (from suspected cases) 3 .
The geographical spread of the cases in Brazil has led to major concern, because cases are no longer being reported just in the jungle, but also in the most densely populated cities and states such as Minas Gerais and São Paulo. Fortunately, these regions have a long history of high YF vaccination coverage in young people (at least in urban areas), in contrast with the low vaccination rates in other major urban centres of Brazil 4 . Nevertheless, the lack of YF vaccination coverage was raised several times by the Brazilian provincial health authorities back in the early 2000s, but they were unable to reach the remote western zones of Minas Gerais.
Although the epidemiology and clinical manifestations of YF should be familiar to healthcare workers in endemic countries, where clinical manifestations can overlap with other acute viral haemorrhagic fevers and other etiologies of the febrile syndrome, a rapid spread of misinformation about this harmful disease in social media and a lack of online training for healthcare workers has been reported in the recent outbreak of 2016-2017 in the Americas 5,6 . In addition to limited health resources, this highlights that early identification could be a challenge in Latin America, as has been observed in the past with Zika and chikungunya virus outbreaks in this region, particularly in countries such as Brazil and Colombia 7,8 .
Given the current YF situation in Brazil, and the emergence of new cases in areas where YF has not occurred for several years, the Brazilian health policies have been oriented to continue efforts to detect, confirm, and adequately and timely treat cases of YF (http://portalsaude.saude.gov.br/index.php/o-ministerio/ principal/secretarias/svs/febre-amarela). To this end, health care workers should be kept up to date and trained to detect and treat cases, especially in areas of known virus circulation. Furthermore, they should also take the necessary actions to keep travelers, heading to areas where YF vaccination is mandatory, informed and vaccinated.

Conclusions
There seems to be an almost imminent risk of YF outbreaks turning into a large epidemic 9 . Unvaccinated travelers heading to the affected states in Brazil are at risk of spreading the virus in to areas where YF risk factors (human susceptibility, prevalence of competent vector, and animal reservoirs) are present. The geographic area of human cases has expanded recently to Rio de Janeiro, São Paulo, and Pará states. Ecological factors and enzootics would promote the necessary spillover that would lead to an epidemic 10-12 , and unfortunately, nothing can be done to halt the infection of non-human primates in the affected areas. Moreover, the vast border of Brazil, with 10 neighboring countries/ territories (Uruguay, Argentina, Paraguay, Bolivia, Peru, Colombia, Venezuela, Guyana, Suriname and French Guiana), the lack of efficient health policies and surveillance systems, and the distribution of Aedes vectors (as well the uncontrollable sylvatic vector species in the genus Haemagogus and Sabethes), raise the possibility of the widespread YF throughout the Americas, including the USA. The USA has suitable conditions for autochthonous cases in areas such as South Florida, where Aedes albopictus is present and has been linked to transmission of dengue virus (another flavivirus), chikungunya and possibly Zika. These entomological factors should strongly emphasize the risk of imported cases in temperate zones (i.e. Central and North Americas) during the boreal summer and Aedes spp. activity in Central and North America. It has been documented elsewhere for Dengue virus (New Mexico or Texas) and, even in the case of vectors for other diseases, such as Anopheles, the case of airport malaria in the US.
The risk of imported cases in temperate zones Mass vaccination of the at-risk population 13 , and public health awareness and preparedness is urgently needed to control the current 2016-2017 outbreak in Brazil and prevent a possible epidemic related to this deadly disease. Nevertheless, these recent outbreaks and the lack of YF vaccine stock piling (WHO) means that YF vaccine availability needs to be strategized by the countries health authorities and international community. Also, the lifelong protection of the vaccine, its innocuity and the reduction by 1/10 of the immunity dose are new and of extremely high importance for global and public health.
More studies, as well as new innovative strategies for vector control (e.g. involving community participation), early prevention (e.g. sampling in risk areas to look for asymptomatic subjects), warning and enhanced surveillance (using smart phones), are necessary in order to improve the scenario of this reemerging arboviral threat 14,15 . Mosquito biosurveillance is an important issue to control the epidemic risk. Haemagogus and Sabethes are specific for South America and have been well studied; the risk and ability of Aedes albopictus expansion to transmit the virus in the Americas needs to be assessed, and an entomological priority set up when needed (i.e. public health priority in at-risk areas).
Finally, another matter of concern that is also important to mention is the trans-border risk. Ultimately traveler's to/from endemic areas need to be covered by a mandatory international certificate of vaccination to protect the borders (trans-border risk). The long-time mystery of the absence of YF in South East Asia up to 2016 is also an issue to keep in mind for the futureparticularly in term of global risk, with new imported cases, for example those reported in China, now occurring.
Author contributions YOM, AMPB and AJRM all participated in the writing and editing of the manuscript. All authors have agreed to the final content of this opinion article.

Competing interests
No competing interests were disclosed.

Grant information
The author(s) declared that no grants were involved in supporting this work. No competing interests were disclosed.

Competing Interests:
We have read this submission. We believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. 2. Please review the punctuation of this sentence: .."In Asia, but also Europe and North America, Nevertheless, potential spreads beyond the borders of the endemic countries is a matter of global concern." RECENT OUTBREAKS 3. Because this section is referring only to information outside of Americas, I respectfully suggest modified the subtitle as: RECENT OUTBREAKS OUTSIDE OF AMERICAS THE CONCERN RAISED FROM BRAZIL In the introduction was stated.."the lack of efficient health policies", however in the development of this idea in this section there is very little (a sentence) about what are the Brazilian health policies for yellow fever or for vector-borne disease. This information could be very useful to go in deep to discussion about the "lack of efficient health policies" CONCLUSIONS Again, the statement "the lack of efficient health policies" needs a deeper discussion in the previous section to be included in the conclusions.
I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I strongly recommend to include the comments outlined above.

Are the conclusions drawn balanced and justified on the basis of the presented arguments? Yes
No competing interests were disclosed. "Angola" appears at first, also if the authors want to focus on the Americas, it will be better, in Abstract: my opinion, to have a short sentence at the end of the abstract that focus on imported risk from endemic area outside of Americas (i.e. Africa).
The authors wrote "despite high YF vaccination coverage", this is not accurate: Indeed, in many areas and populations worldwide, YF vaccination coverage is discouraging low for years (e.g. Nigeria). This needs to be clear: YF vaccine is certainly the best live attenuated vaccine among all, the less expensive and the first of its kind, consequently there is no reasons today -except politics and funding allocation -to have the people of endemic areas not yet entirely immunized with a real 100% vaccine coverage.
For the reader, CFR needs to be expressed as a number of a general historical consensus.

Introduction:
Needs also to document the historical dimension of multiple consistent re-emergence of Yellow fever since it discovery beside the excellence of the vaccine(s). While frequency and size of outbreaks are recently (a decade ago) increasing.
: China emergence needs to be more specific (i.e. risk) from where (climatic zone) Recent outbreaks these imported cases were observed. :

"Concern raised from Brazil"
From the general title or this of such chapter section, one is misleading "Americas (title) or Brazil (this section)"? I suggest something like: "From Brazilian experience, a concern of YF risk for the Americas" Line 3: "epicentre:" this needs to be more precise geographically or the sentence clearly linked to the following one, starting by "Indeed, …" Second section, line 4: "a long history of high YF vaccination coverage", I am not sure this is applicable to Minas Gerais's remote areas, at least for "long history". The lack of YF vaccination coverage was raised several times by the Brazilian provincial health authorities back in the early 2000s, unable to reach the remote western zones of the province.
Section 3, line 3, top of the page: to be politically correct we do not use anymore "Latin America" but "South America".
: Main concerns, regarding the YF risk of emergence/re-emergence, seems to be missing:

Conclusions
Vaccine: 1/ The recent outbreaks and the lack of Yellow fever vaccine stock piling (WHO). This needs to be strategized (YF vaccine availability) by the country health authorities and international community. 2/ Also the lifelong protection of the vaccine, its inocuity, and the reduction by 1/10 of the immunity dose are new and of extremely high importance (i.e. for the public & public health).
Biosurveillance needs to be stressed: Mosquito biosurveillance is an important issue to control the epidemic risk, also and specific for South America and have well Haemagogus Sabethes are studied, the risk and ability of (expansion) to transmit the virus in the Americas Aedes albopictus needs to be assessed and an entomological priority set up when needed (i.e. Public health priority in at risk areas).
Trans-border risk. Ultimately traveler's from/to endemic areas need to be covered by a mandatory international certificate of vaccination to protect the borders (trans-border risk).
The long time mystery of the absence of YFV in South East Asia can be also stressed in term of Introduction: For the reader, CFR needs to be expressed as a number of a general historical consensus.
We will explain more about the CFR historical reports.
Needs also to document the historical dimension of multiple consistent re-emergence of Yellow fever since it discovery beside the excellence of the vaccine(s). While frequency and size of outbreaks are recently (a decade ago) increasing.
Ok. We will also comment on this, according to your recommendation.
Recent outbreaks: China emergence needs to be more specific (i.e. risk) from where (climatic zone) these imported cases were observed. Ok. Now is more detailed available information about it, then we will address this in the revised version.
"Concern raised from Brazil": From the general title or this of such chapter section, one is misleading "Americas (title) or Brazil (this section)"? I suggest something like: "From Brazilian experience, a concern of YF risk for the Americas" Well, the concern is for Americas, Brazil is already with epidemics. Then, given that, we will change the title of section to "From Brazilian experience, a concern of YF risk for the Americas".
Line 3: "epicentre:" this needs to be more precise geographically or the sentence clearly linked to the following one, starting by "Indeed, …" Ok, we will correct it.
Second section, line 4: "a long history of high YF vaccination coverage", I am not sure this is applicable to Minas Gerais's remote areas, at least for "long history". The lack of YF vaccination coverage was raised several times by the Brazilian provincial health authorities back in the early 2000s, unable to reach the remote western zones of the province. Agree, we will make such clarification. Section 3, line 3, top of the page: to be politically correct we do not use anymore "Latin America" but "South America". Well, that is not really accurate, both terms are correct. But Latin America includes both Central and South America. You can consult any reference and you will realize this. South America is not exchangeable to Latin America, with this you will be excluding Central America and Mexico.
Conclusions: Main concerns, regarding the YF risk of emergence/re-emergence, seems to be missing: Vaccine: 1/ The recent outbreaks and the lack of Yellow fever vaccine stock piling (WHO). This needs to be strategized (YF vaccine availability) by the country health authorities and international community. This will be included in our new revised version.
2/ Also the lifelong protection of the vaccine, its inocuity, and the reduction by 1/10 of the immunity dose are new and of extremely high importance (i.e. for the public & public health). This too.
Biosurveillance needs to be stressed: Mosquito biosurveillance is an important issue to control the epidemic risk, also Haemagogus and Sabethes are specific for South America and have well studied, the risk and ability of Aedes albopictus (expansion) to transmit the virus in the Americas needs to be assessed and an entomological priority set up when needed (i.e. Public health priority in at risk areas).
We will add comments about this.
Trans-border risk. Ultimately traveler's from/to endemic areas need to be covered by a mandatory international certificate of vaccination to protect the borders (trans-border risk). Ok, agree. We will include comments about this.
The long time mystery of the absence of YFV in South East Asia can be also stressed in term of global risk. Ok, we will make also comments on this.