By Louise Corscadden, University of Leicester, UK

Most people are first introduced to yellow fever at the travel clinic; upon imminent jet-setting to a tropical destination far away, we are told we need a yellow fever vaccine. To us, yellow fever is a disease of places far away: out of sight, out of mind. However, to those in the 47 at-risk countries in South America and Africa (WHO, 2018), it is a highly lethal disease. The World Health Organization estimates that in 2013 between 84,000 and 170,000 people suffered from the severe form of the disease, with 29,000 to 60,000 dying as a result (WHO, 2018). Last year, the disease once again reared its head in Brazil in a precedence recently unseen in years.

The yellow fever virus is a member of the Flavivirus genus, along with Zika virus, West Nile virus, Dengue virus, and other viruses which can cause encephalitis (Shi, 2012). Its transmission vector is mosquitos of the Haemogogus and Aedes genuses which spread the disease through three types of transmission cycles:

• Syvatic (jungle yellow fever): Non-human primates acquire the disease via the mosquitos which spread it from primate to primate. Human forest workers can then acquire the disease from mosquitos.
• Intermediate: Commonly seen in multi-village outbreaks in Africa, mosquitos can transmit the virus between non-human primates and humans.
• Urban yellow fever: Large outbreaks in heavily-populated areas occur due to Aedes aegypti mosquito transmission. Populations are particularly at risk due to lack of previous exposure and low vaccination uptake (WHO, 2018).

Once infected, most people do not experience symptoms for the incubation period of 3-6 days. Most of those infected experience non-specific symptoms of muscle ache, headache, fever, and nausea for a few days. The name “yellow fever” refers to the small percentage of sufferers who further experience a severe phase of the disease 24 hours after apparent recovery. Patients experience jaundice through liver damage with a high fever, abdominal pain, vomiting, and haemorrhage from the mouth and eyes. Half of those who enter this phase die within 10 days (WHO, 2018).

Currently, Brazil is expecting a large outbreak of yellow fever. As of late 2017, 107 human cases of yellow fever were reported in the state of Minas Gerais, resulting in 40 deaths (Watts, 2018). Despite the Brazillian government administering 3.5 million yellow fever vaccines within the region and a declaration from health minister Ricardo Barro that the outbreak was over, the disease returned with a vengeance this year. Between July 2017 and March 2018, 1098 cases with 340 deaths were reported (Phillips, 2018). Calls for increased vaccination uptake have so far been only partially fulfilled; of the 21 million people within the state of Minas Gerais, up to half are vaccinated against the disease. Increased demand for the vaccine has left Brazil scrambling to keep up, with patients waiting up to 7 hours for a shot or not being unable to receive any vaccination whatsoever (U.S., 2018). The WHO reports that Brazil requested 3.5 million doses of the yellow fever vaccine from its emergency stockpile (WHO, 2018).

Currently in the throes of the yellow fever outbreak, Dr Anna S. Levin is a coordinator for infection control at Hospital das Clinicas for the Faculty of Medicine at the University of São Paulo (FMUSP) (Imt.usp.br, 2016). Here she provides her knowledge of the current outbreak and her experiences of the infection.

What is the origin of this latest outbreak?

“The disease was sylvatic until now. This means that the mosquitoes [of the species] Haemagogus that transmitted yellow fever were sylvatic and the only people affected until now were people who had contact with forests and rural areas, for work reasons or pleasure (hikers etc.). The epidemic involves mainly monkeys and the species mostly affected was the [Brown Howler monkey] Alouatta guariba (a very common species) with a mortality of almost 100%. Other primates are also affected such as the marmosets but with lower mortality.”

“The reasons for this monkey epidemic being so large in Brazil is a cause for debate. Some believe that it was due to the ecological disaster that occurred in Mariana in the state of Minas Gerais. A dam that carried toxic mud originated from mining burst in 2015 and polluted a huge area and rivers. With this, the population of fish was largely affected and the possible result may have been the increase in mosquito populations. Global warming may also play a role in increasing vector population”

What is the city of São Paulo doing to combat the spread of yellow fever?

“The city is focusing on vaccination. The main concern is the urbanization of yellow fever [as the disease is currently between the sylvatic and intermediate types]. The most obvious way this could occur is by sick people infecting the urban vector [the mosquito species] Aedes aegypti which is very common in the city. If this happens, the epidemic will be almost uncontrollable. Another possibility is the urbanization of the Haemagogus [specie] which is a possibility as larvae have been found in abandoned tires.”

How has the outbreak affected vaccination protocols in the state of São Paulo?

“The main discussion on vaccination strategy involves the decision on what population should be priority as there is a shortage of vaccines. The WHO guidelines recommend focusing on the cities to avoid urbanization of the disease, but the state of São Paulo Health department has followed the deaths of monkeys in the forests and closely followed the spread of the monkey epidemic. Contrary to the WHO [recommendations], the vaccination [uptake] in São Paulo has targeted rural populations in areas where the monkey epidemic is expected to hit next.”

How are the government increasing vaccine uptake despite the increase in demand and is this enough to curb the outbreak?

“To increase vaccine coverage, the government started to use one-fifth of the usual dose which is effective for at least a year, probably 8 years. With this it will be possible to increase coverage involving the entire population of the state [of São Paulo] (approximately 40 million). Unfortunately, the scare is over for the moment and influenza seems to be on the radar so I’m not sure that [vaccine] coverage will be very high by the time the warm weather comes. At present I believe [vaccine coverage of the State of São Paulo] is around 50%.”

Why has vaccine uptake not curbed the outbreak?

“Unfortunately herd immunity does not work in our outbreak as the epidemic is not human but involves non-human primates. The vaccination target should be 100%, which is virtually unachievable. As yellow fever is seasonal, we have had no new cases in May but unless vaccination coverage improves, we expect the epidemic to continue in November or December, when summer starts.”

Alike to the Ebola outbreak of 2013, have your observations of this outbreak changed your perception on the documented mortality rates and symptoms of yellow fever?  

“From December until April our hospital was flooded with yellow fever cases. The severe cases are terrible. The median time between hospitalization and death was 3 days, and mortality was 63%. This consumed a huge part of our budget, blocked elective hospitalizations and surgeries, and caused a huge physical and emotional stress on our healthcare workers.

Also, we observed that severe yellow fever is not like the disease that is described in books. It does not look like other cases of fulminant hepatitis [severe impairment and necrosis of the liver]. The symptoms are non-specific such as fever and malaise. The patients are not jaundiced. They evolve rapidly to renal failure, bleeding, shock, seizures, coma, and death without ever becoming yellow.”

What do you think is the future of this disease? Could global warming and other ecological factors increase the regions in which the mosquito vectors could survive in?

“Global warming may play a role in increasing vector populations. So I don’t know if we could make a prediction of where the disease is going (or other diseases, for that matter). However, the experience in Brazil shows that surveillance of monkey deaths can predict the spread of yellow fever quite accurately and allow for action to be taken before the epidemic hits each area.”

From Dr Levin’s interview, we see similar characteristics of this outbreak to the Ebola outbreak of 2014 in east Africa, the symptoms of yellow fever seem to differ from the previously documented natural history of the disease. Unfortunately, the mortality rate of Dr Levin’s patients is higher at 63%  than the 50% projected by the WHO (Who.int, 2018) and the time between progression from severe disease to death seems remarkably quick at 3 days compared to 10 days. The progression is so quick that the patients don’t ever present the characteristic symptom of the disease – yellowing due to jaundice.

Dr Levin has provided us with a harrowing first-hand account of the outbreak in São Paulo. Diseases of destinations far away may seem a mere conversation topic or the mild inconvenience of an extra trip to the travel clinic; however, for millions globally, they mean a very real risk of death. I’d like to thank Dr Levin for her great insight into the details of this outbreak, its unique potential origin, and the severe consequences it has on infrastructure, the Brazillian health system, and human life.

Further reading:

• Imt.usp.br. (2016). Anna Sara Levin, PhD |. [online] Available at: http://www.imt.usp.br/pesquisadores/anna-sara-levin/ [Accessed 11 Jun. 2018].
• U.S. (2018). Brazilians rush to get yellow fever vaccinations amid fatal cases. [online] Available at: http://www.reuters.com/article/us-health-yellowfever-brazil/brazilians-rush-to-get-yellow-fever-vaccinations-amid-fatal-cases-idUSKBN1F62RI [Accessed 6 Jun. 2018].
• Rayur.com. (2016). Yellow Fever : Definition, Causes, Symptoms, Diagnosis, Prevent and Treatment | Rayur. [online] Available at: http://www.rayur.com/yellow-fever-definition-causes-symptoms-diagnosis-prevent-and-treatment.html [Accessed 11 Jun. 2018].
• Shi, P. (2012). Molecular virology and control of flaviviruses. Norfolk: Caister Academic Press.
• Watts, J. (2018). Brazil on high alert as yellow fever threatens major cities. [online] the Guardian. Available at: http://www.theguardian.com/world/2017/feb/02/brazil-yellow-fever-outbreak-vaccination-espirito-santo [Accessed 4 Jun. 2018].
• World Health Organization. (2018). Yellow fever. [online] Available at: http://www.who.int/en/news-room/fact-sheets/detail/yellow-fever [Accessed 4 Jun. 2018].
• World Health Organization. (2018). WHO dispatched 3.5 million doses of yellow fever vaccine for outbreak response in Brazil. [online] Available at: http://www.who.int/csr/disease/yellowfev/vaccination-in-Brazil/en/ [Accessed 6 Jun. 2018].
• World Health Organization. (2018). ​Lower doses of yellow fever vaccine could be used in emergencies. [online] Available at: http://www.who.int/news-room/detail/17-06-2016–lower-doses-of-yellow-fever-vaccine-could-be-used-in-emergencies [Accessed 6 Jun. 2018].
• Who.int. (2018). WHO | WHO Report on Global Surveillance of Epidemic-prone Infectious Diseases – Yellow fever. [online] Available at: http://www.who.int/csr/resources/publications/yellowfev/CSR_ISR_2000_1/en/ [Accessed 6 Jun. 2018].

About me

The multitudes of people were not wrong when they told me that the PhD would “fly by”. Upon entering my second year, I am left with 1.5 years to go. The topic of my work is how air pollution affects bacterial behaviour. Before taking my PhD position at the University of Leicester, I completed a Master’s degree in Medical Microbiology at the London School of Hygiene and Tropical Medicine and a Bsc in Biomedical Sciences at St George’s University of London. When not in the lab, I can be found cooking up a storm in the kitchen or sewing something outrageous. I can be contacted on Twitter via my email address, lc378@leciester.ac.uk.