Summary of Emergent Infectious Disease: Yellow ...

Summary of Emergent Infectious Disease: Yellow Fever Focus John W. Cross, Ph.D.a 10 March 2017 Table of Contents World Health Organization (WHO)...............................................................................................................1 Pan American Health Organization (PAHO)..................................................................................................3 News and Feature Articles..........................................................................................................................3 Peer Reviewed Literature.............................................................................................................................5 In early 2017 Brazil reported a significant human epidemic of yellow fever, beginning in its State of Minas Gerais. The epidemic is believed to be of sylvatic origin, since it is paralleled by a epizootic that has caused massive fatalities among native monkeys. This summary focuses on the Brazilian outbreak, and updates the Yellow Fever Focus Summary released 30 January of this year.

World Health Organization (WHO) •

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02-24-2017 Disease outbreak news: Yellow fever – Brazil. From 1 December 2016 to 22 February 2017, 1336 cases of yellow fever (292 confirmed, 920 suspected, and 124 discarded), including 215 deaths (101 confirmed, 109 suspected, 5 discarded), have been detected in six states (Bahia, Espírito Santo, Minas Gerais, Rio Grande do Norte, São Paulo, and Tocantins). The estimated case fatality rate is 35% for confirmed cases and 12% for suspected cases. To date, the majority (86%) of the confirmed cases are men and of which, approximately 81% are aged between 21 and 60 years. From 1 December 2016 to 22 February 2017, a total of 883 epizootics of non-human primates (NHP) have been reported, of which 337 were confirmed for yellow fever by laboratory confirmation or epidemiological link. Epizootics have been reported from the Federal District and in Alagoas, Bahia, Goiás, Espírito Santo, Mato Grosso do Sul, Minas Gerais, Paraná, Pernambuco, Rio Grande do Norte, Rio Grande do Sul, Santa Catarina, São Paulo, Sergipe, and Tocantins. 01-27-2017 Disease outbreak news: Yellow fever – Brazil. On 24 January 2017, Brazil’s International Health Regulations (IHR) National Focal Point (NFP) provided the Pan American Health Organization/World Health Organization (PAHO/WHO) with an update on the yellow fever situation. The geographical distribution of confirmed yellow fever human cases is expanding and includes, in addition to Minas Gerais State, the States of Espírito Santo and São Paulo. In addition, Bahia State reported 6 yellow fever human cases under investigation. Espírito Santo State, an area that was previously not considered at risk for yellow fever, confirmed its first autochthonous human case of yellow fever since 1940. The case is a 44-year-old male from the municipality of Ibatiba. São Paulo State, reported three laboratory-confirmed cases of human yellow fever, all of whom died. In Minas Gerais State, as of 24 January, a total of 404 cases (66 confirmed, 337 suspected and 1 discarded), including 84 deaths (37 among confirmed cases and 47 among suspected with a case fatality rate of 56% and 14%, respectively) were reported. The total number of suspected and confirmed a

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Summary of Emergent Infectious Disease, 10 March 2017 © John W. Cross, 2017.

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yellow fever cases reported is the highest reported nationwide since 2000. Among the 66 confirmed cases from Minas Gerais State, 88% are male and 45% have not been vaccinated against yellow fever (the vaccination status of the remaining 55% is unknown or not available). Additionally, a large number of epizootics among non-human primates (NHP) were reported in the States of São Paulo (247 epizootics, including 3 confirmed for yellow fever) and Espírito Santo (367 epizootics). In Espírito Santo State, epizootics have been confirmed for yellow fever in Irupia and Colatina municipalities.. Public health response: Brazilian health authorities, at the federal, state, and municipal levels, are implementing several measures to respond to the outbreak, including: In addition to the 650,000 doses of yellow fever vaccine distributed across the country as part of the routine supply of the National Vaccination Calendar in January 2017, the Ministry of Health of Brazil has sent 4.2 million doses of yellow fever vaccines to the States of Bahia (400,000), Espírito Santo (1 million), Minas Gerais (2.4 million), and Rio de Janeiro (350,000).... 01-13-2017 Disease outbreak news: Yellow fever – Brazil. On 6 January 2017, the Brazil Ministry of Health (MoH) reported 12 suspected cases of yellow fever from six municipalities in the state of Minas Gerais. On the same day, the Brazil IHR National Focal Point (NFP) informed PAHO/WHO that the 12 cases are male, residing in rural areas, and have an average age of approximately 37 years (range: 7–53 years). The first of these cases had onset of symptoms on 18 December 2016. Samples from the cases were sent to the State Reference Laboratory (the Ezequiel Dias Foundation) for differential diagnosis, including dengue, hantavirus, leptospirosis, malaria, Rocky Mountain spotted fever, and viral hepatitis (A, B, C, D, and E). Results are pending. On 12 January, the Brazil IHR NFP provided an update on the event informing that a total of 110 suspected cases, including 30 deaths. Figure 1: Confirmed cases and deaths from yellow fever in Brazil, 2017 (Graphics by the author from WHO reports).


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Pan American Health Organization (PAHO) Epidemiological Alerts and Updates •

01-09-2017 Situation summary in the Americas. Since epidemiological week (EW) 1 to EW 7 of 2017, Brazil, Colombia, Peru, and the Plurinational State of Bolivia, have reported suspected and confirmed yellow fever cases. The situation summary includes detailed statistical information on the epidemic in Brazil and recommendations for diagnosis of the disease. Figure 2: eographic distribution of reported human yellow fever cases and yellow fever epizootics, Brazil, up to 24 February 2017.

News and Feature Articles •

03-08-2017 Yellow fever outbreak in Brazil worries U.S. officials. (Lena H. Sun, Washington Post) Top infectious disease experts are warning about a rapidly spreading outbreak of deadly yellow fever in Brazil that could hit parts of the United States. ...The outbreak in Brazil has been underway since December, mostly in rural areas in the southeastern part of the country. It’s taking place primarily in jungle areas, where forest-dwelling mosquitoes are spreading the virus mainly to monkeys. But an increasing number of people also have been infected, making it Brazil's worst yellow fever outbreak among humans in decades. ...Anthony Fauci, director of the [NIAID], said experts are concerned because the number of yellow fever cases is much higher than what’s reported in a typical year.... these areas are also close to Summary of Emergent Infectious Disease, 10 March 2017 © John W. Cross, 2017.

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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. [The] highly effective vaccine for yellow fever...is not routinely given in Brazil’s major urban centers.... But millions of Brazilians have since been vaccinated this year.... [See: Paules CI, Fauci AS. Yellow fever: Once again on the radar screen in the Americas, and NIAID, Yellow Fever in the Americas. Current Outbreak Warrants Close Watch.] 02-21-2017 Emergency Alert Due to Yellow Fever Issued for 64 Cities in Brazil. Officials declared emergency situation in 64 cities in Minas Gerais and are sending millions of extra doses of vaccines to three states days before Carnival. (Lise Alves, The Rio Times) SÃO PAULO, BRAZIL – The federal government of Brazil has issued emergency situations for 63 cities in Minas Gerais and one in Espirito Santo due to the outbreak of yellow fever. Since the beginning of the year authorities have confirmed 44 people died of the disease and over seventy other suspected deaths are being investigated. Federal officials are sending extra doses of yellow fever vaccines to the affected area in fear that the virus may spread during the great flux of tourists coming into the affected areas due to the Carnival festivities. In total, 12.8 million extra doses were sent…. 02-17-2017 Brazil's Expanding Yellow Fever Outbreak Started With Monkeys. ( Jason Beaubien, NPR) The first sign of trouble was the monkeys dropping dead in the forest. Then people started getting sick and dying, too. Brazil is in the midst of its worst yellow fever outbreak since the 1940s, when the country started mass vaccination and mosquito eradication campaigns…. The first cases in this current outbreak were detected in December among men living in rural parts of the Brazilian state of Minas Gerais, an agricultural region just north of Sao Paulo and Rio de Janeiro…. Most of these cases are sylvatic or "jungle" cases in which a person who's working in or visiting a forest is bitten by an infected mosquito.... Human outbreaks tend to follow larger outbreaks among primates in the jungle…. Public health officials say there's the potential for yellow fever to spread like wildfire if it takes hold in a place that has Aedes aegypti mosquitoes and where vaccination rates are low. Unfortunately that's the case throughout much of the tropics of this hemisphere…. 02-15-2017 Yellow fever outbreak in Congo declared over. (CBC) The World Health Organization has declared an end to the yellow fever outbreak that killed about 400 people in Congo and Angola, calling it "one of the largest and most challenging" in recent years. The outbreak, first detected in Angola in late 2015, caused 965 confirmed cases and thousands of suspected cases in both countries, the WHO said in a statement Tuesday. Neither country has reported a new confirmed case in the past six months…. The global health agency said more than 30 million people were vaccinated in emergency campaigns to control the outbreak in the two neighbouring countries, which have among the world's weakest health systems. "This unprecedented response exhausted the global stockpile of yellow fever vaccines several times," the WHO statement said…. 02-01-2017 Brazil: Yellow fever outbreak grows, CDC issues travel notice. (Robert Hermann, Outbreak News Today) The number of confirmed yellow fever cases in the Brazil outbreak, which began in December 2016, has grown to 149, including 52 confirmed fatalities, according to the Brazilian Health Ministry today…. Five states report suspected/confirmed yellow fever cases–Minas Gerais, Espírito Santo, Bahia, São Paulo and Tocantins. Minas Gerais accounts for nine out every 10 confirmed yellow fever cases in the country. ...one infectious disease specialist believes the outbreak may have peaked…. The outbreak, the largest in Brazil since 2000, has prompted the US Centers for Disease Control and Prevention (CDC) to issue a travel notice for travelers….


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Peer Reviewed Literature Paules CI, Fauci AS. Yellow Fever — Once Again on the Radar Screen in the Americas. N Engl J Med. 2017 Mar 8. doi: 10.1056/NEJMp1702172. [Epub ahead of print] PubMed PMID: 28273000. [Perspective] “...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 most recent outbreak in Brazil highlights this phenomenon. If the current outbreak leads to urban spread through A. aegypti mosquitoes, clinicians should adopt a high index of suspicion for yellow fever, particularly in travelers returning from affected regions. As with all potentially reemerging infectious diseases, public health awareness and preparedness are essential to prevent a resurgence of this historical threat.” Bagcchi S. Looking back at yellow fever in Angola. Lancet Infect Dis. 2017 Mar;17(3):269-270. doi: 10.1016/S1473-3099(17)30064-6. PubMed PMID: 28244394. [Commentary] Morales MA, et al. Detection of the mosquito-borne flaviviruses, West Nile, Dengue, Saint Louis Encephalitis, Ilheus, Bussuquara, and Yellow Fever in free-ranging black howlers (Alouatta caraya) of Northeastern Argentina. PLoS Negl Trop Dis. 2017 Feb 10;11(2):e0005351. doi: 10.1371/journal.pntd.0005351. PubMed PMID: 28187130. “Non-human primates can act as important hosts in the natural cycle of flaviviruses... From July-August 2010, we conducted serological and molecular surveys in free-ranging black howlers (Alouatta caraya) captured in northeastern Argentina...for antibodies to WNV, SLEV, YFV, DENV (serotypes 1 and 3), ILHV, and BSQV. Virus genome detection was performed using generic reverse transcription (RT)-nested PCR to identify flaviviruses in 51 antibody-negative animals. Seventy animals had antibodies for one or more flaviviruses for a total antibody prevalence of 64.8% (70/108). Monotypic (13/70, 19%) and heterotypic (27/70, 39%) patterns were differentiated. Specific neutralizing antibodies against WNV, SLEV, DENV-1, DENV-3, ILHV, and BSQV were found. Unexpectedly, the highest flavivirus antibody prevalence detected was to WNV with 9 (8.33%) monotypic responses. All samples tested by (RT)-nested PCR were negative for viral genome. This is the first detection of WNV-specific antibodies in black howlers from Argentina and the first report in free-ranging non-human primates from Latin-American countries. Given that no animals had specific neutralizing antibodies to YFV, our results suggest that the study population remains susceptible to YFV. Monitoring of these agents should be strengthened to detect the establishment of sylvatic cycles of flaviviruses in America and evaluate risks to wildlife and human health.” Dyer O. Yellow fever stalks Brazil in Zika's wake. BMJ. 2017 Feb 8;356:j707. doi: 10.1136/bmj.j707. PubMed PMID: 28179231. [Perspective] Marlow MA, et al. Notes from the Field: Knowledge, Attitudes, and Practices Regarding Yellow Fever Vaccination Among Men During an Outbreak - Luanda, Angola, 2016. MMWR Morb Mortal Wkly Rep. 2017 Feb 3;66(4):117-118. doi: 10.15585/mmwr.mm6604a6. PubMed PMID: 28151922. “...A rapid assessment to identify and address potential barriers to vaccination among men was designed, using a knowledge, attitudes, and practices survey…. These results highlight several Summary of Emergent Infectious Disease, 10 March 2017 © John W. Cross, 2017.

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challenges. Most vaccine campaigns target children and women; although this yellow fever campaign needed to reach men, it was not well adapted to their needs. Men could not access vaccination posts during working hours, and those who did experienced long lines because persons from nontargeted municipalities sought vaccination. Lack of information caused many men to fear the vaccine, believing persons had died from the vaccine or that vaccines were fake. Some men did not understand whether the vaccine provided prevention or treatment....” Pacca CC, et al. Thiosemicarbazones and Phthalyl-Thiazoles compounds exert antiviral activity against yellow fever virus and Saint Louis encephalitis virus. Biomed Pharmacother. 2017 Mar;87:381-387. doi: 10.1016/j.biopha.2016.12.112. PubMed PMID: 28068627. “...The genus Flavivirus, such as Yellow Fever Virus (YFV) and Saint Louis Encephalitis Virus (SLEV), are important pathogens…. There is no specific antiviral drugs for these viruses, only supporting treatment that can alleviate symptoms and prevent complications. Here, we evaluated the potential anti-YFV and SLEV activity of a series of thiosemicarbazones and phthalyl-thiazoles. Plaque reduction assay, flow cytometry, immunofluorescence and cellular viability were used to test the compounds in vitro. Treated cells showed efficient inhibition of the viral replication at concentrations that presented minimal toxicity to cells. The assays showed that phthalyl-thiazole and phenoxymethyl-thiosemicarbazone reduced 60% of YFV replication and 75% of SLEV replication.” Li Y, Yang Z. Adaptive Diversification between Yellow Fever Virus West African and South American Lineages: A Genome-Wide Study. Am J Trop Med Hyg. 2017 Jan 2. pii: 16-0698. doi: 10.4269/ajtmh.160698. [Epub ahead of print] PubMed PMID: 28044043. “Yellow fever virus (YFV)...phylogenies indicate that the isolates collected from West Africa, East and Central Africa, and South America cluster into different lineages and the virus spread into the Americas from Africa. ...we performed a genome-wide evolutionary study on the West African and South American lineages of YFV. Our results reveal that adaptive genetic diversification has occurred on viral nonstructural protein 5 (NS5), which is crucially required for viral genome replication, in the early epidemic phase of these currently circulating lineages. Furthermore, major amino acid changes relevant to the adaptive diversification generally cluster in different structural regions of NS5 in a lineage-specific manner. These results suggest that YFV has experienced adaptive diversification…” Wilder-Smith A, Monath TP. Responding to the threat of urban yellow fever outbreaks. Lancet Infect Dis. 2017 Mar;17(3):248-250. Doi: 10.1016/S1473-3099(16)30588-6. PubMed PMID: 28017560. [Commentary] Alencar J, et al. Diversity of yellow fever mosquito vectors in the Atlantic Forest of Rio de Janeiro, Brazil. Rev Soc Bras Med Trop. 2016 May-Jun;49(3):351-6. doi: 10.1590/0037-8682-0438-2015. PubMed PMID: 27384833. “...Mosquitoes were collected using ovitraps in three sampling sites in the Atlantic Forest in the State of Rio de Janeiro, Brazil. We collected 2,162 Culicidae specimens. Haemagogus janthinomys and Haemagogus leucocelaenus, both sylvatic yellow fever virus vectors, were the most common species found....”


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