Yellow Fever Cases in Brazil Raise Concern in Latin America

Roxana Tabakman

February 07, 2018

The yellow fever epidemic that currently affects Brazil is the most severe outbreak of the last 5 decades and raises concerns for some local doctors and other countries, some of them not even neighboring the Latin American country.

Locally, the rapid dispersion is concerning because infections are not limited to the jungle or remote rural areas but are also seen in the areas surrounding the most densely populated cities of São Paulo, Minas Gerais, Espiritu Santo, Bahia, and Rio de Janeiro. The outbreak began in 2016 in Minas Gerais, where the rural adult population was not vaccinated (although children were), and it quickly spread into areas where the vaccine was not recommended.[1]

Now Brazil is considering the possibility of immunizing the entire population, a decision that is hampered by limitations in the number of doses available.

"Brazil's yellow fever epidemic worries the world and is a risk for Argentina," Dr Tomás A. Orduña, head of Tropical and Traveler's Medicine at the Infectious Disease Hospital "F. J. Muñiz," in Buenos Aires, Argentina, told Medscape Medical News.

Dr Tomás A. Orduña

"We have the vectors, Haemagogus in the jungles and Aedes aegypti in 15 provinces. For a couple of years, there has been strict surveillance of any nonspecific febrile syndrome of people who have been in risk areas, and when training doctors we have emphasized it in both the undergraduate and postgraduate classes, but the vaccinated population is minimal," he said.

The vaccine against yellow fever is included in the official vaccine schedule only in a few regions of Argentina: Misiones, north of Corrientes, east of Formosa, and Chaco, with a dose for children at 18 months and a booster when they turn 11.[2]

Recommendations for Travelers

Argentinians have the right to free vaccination if they are going to travel to areas of high transmission risk, in which case the vaccination must be prescribed individually by a doctor, according to the specific local risk.[] 2 ] Until recently, there were only three public places of free vaccination, all located in and around Buenos Aires. However, in the face of the Brazilian outbreak, these areas have expanded.[3,4]

São Paulo recently made it to the list of risk areas,[5] a decision that affects business travelers. "If you are going to make a connection in São Paulo, you do not need to get vaccinated because the airport has mosquito controls and low temperatures. But if you are going to spend a day in São Paulo, I recommend [getting vaccinated], even one night in a nearby hotel to the Guarulhos airport, because it is a potentially risky situation," Dr Orduña said.

The position of Dr Isabella Ballalai, president of the Sociedade Brasileira de Imunizações, is different. "The situation in Brazil is an outbreak of sylvatic yellow fever; our goal is to prevent the urban form," she told Medscape Medical News.

"Doctors must give each traveler an individual recommendation, evaluating the risk-benefit in each case, and knowing that the urban yellow fever is controlled. The risk is very low for one night in the city of Guarulhos for a connection," she said. "For a pregnant woman who travels to an affected area, the doctor must weigh a true risk of infection with a theoretical risk of the vaccine (because it is a live attenuated virus it can cause problems), knowing that up to now there are no issues recorded."

In the Brazilian tourist areas, there are a few risk-free areas, such as Fortaleza, Recife, and the coast (not inland) of Santa Catarina. "Salvador de Bahia, Praia do Forte, Porto Seguro are some of the most popular destinations these days, and they are already on the vaccination list."

Other countries with reported cases are Bolivia, Ecuador, Colombia, French Guiana, Suriname, and Peru. "Also for Argentina, it is recommended that those who visit the Iguazú Falls, Misiones, and Corrientes be vaccinated, although patients over 60 years of age should be evaluated to assess the risk of complications," Dr Liliana Teston, infectious disease specialist and coordinator of the Department of Epidemiology in the Center for Infectious Diseases Foundation, in Buenos Aires, Argentina, told Medscape Medical News.

Brazil and Argentina do not require vaccination at their borders. Peru is another country at risk that does not require a certificate of vaccination for incoming tourists. Colombia is at risk, and it requires a certificate for those who have spent more than 12 hours in countries with transmission risk. Costa Rica does not appear in the list of countries at risk, but it requires the certificate of vaccination if the traveler comes from countries with transmission risk.[6] People who have an increased risk for adverse effects from the vaccination should file for an official exemption with the authorities.

Severe and Difficult-to-Diagnose Disease

Yellow fever can present with a wide spectrum of manifestations, including asymptomatic, subclinical, nonspecific febrile disease, without jaundice, and the potentially fatal form, with fever, jaundice, renal failure, and hemorrhage.[7,8]

The etiologic agent of yellow fever is an arbovirus of the genus Flavivirus, an RNA virus, which replicates in the skin and lymph nodes. Its reservoirs in the sylvatic cycle are monkeys and mosquitoes of the jungle (Haemagogus and Sabethes), while in urban areas they include humans and the A aegypti mosquito. After the bite of hematophagous mosquitoes, there is an incubation period of 3 to 6 days.

The disease is characterized by three clinically evident stages: (1) infection (3 to 6 days), (2) remission (2 to 48 hours), and (3) intoxication (5 to 10 days).

During the infection stage, there is a phase of viremia, characterized by symptoms that begin abruptly, such as fever, headache, lumbar myalgias, hyporexia, nausea, vomiting, asthenia, and adynamia. Then the remission period begins, in which the symptoms subside, and the patient improves. In mild forms, the patient begins the recovery phase, which lasts 2 to 4 weeks.

However, 15% to 25% of patients present a severe form, in which the symptoms reappear. It is characterized by jaundice, epigastralgia, hemorrhagic manifestations (epistaxis, gingival hemorrhage, hematemesis, melena), and oliguria. In this phase, there is a high lethality (50%), with multiorgan failure preceded by hypotension, psychomotor agitation, stupor, and coma. The individuals who survive have a complete recovery.[8]

There is no specific treatment, and serious cases require inpatient care in the intensive care unit.[8]


What Happens in the Toxic Stage?

  • There is fatty metamorphosis and eosinophilic degeneration in the renal tubules with oliguria. Kidney failure and secondary albuminuria cause acute tubular necrosis in the advanced disease.

  • Hemorrhage and erosion of the gastric mucosa lead to hematemesis.

  • Fat infiltration in the myocardium can lead to myocarditis and arrhythmias.

  • The liver presents lobular steatosis, necrosis, apoptosis, and formation of Councilman corpuscles (degenerative eosinophilic hepatocytes).

  • The alterations of the central nervous system can be due to the metabolic disturbances.

  • The terminal shock event can be attributed to the combination of direct parenchymal damage and systemic inflammatory response.

  • Finally, circulatory shock derives from the cytokine storm, including high levels of interleukin (IL) 6, IL-1 receptor antagonist, interferon-γ inducible protein-10, and tumor necrosis factor-α.

 The disease is difficult to diagnose, especially in the early stages, because it can be confused with viral hepatitis, dengue, malaria, leptospirosis, and even poisoning. In its early stages, the virus is frequently detected in blood by reverse transcription polymerase chain reaction, but errors in identification are common given the high cross-reactivity between different viruses.[9] In the most advanced cases, it is identified by the detection of antibodies (enzyme-linked immunosorbent assay and PRINT).[10]

Vaccination Against Yellow Fever

The vaccine is considered safe, with adverse effects that lead to hospitalization for kidney, liver, or central nervous system damage in 0.4 to 0.8 per 100,000 vaccinated. The risk is higher in older individuals (age > 60 years), those with immunodeficiencies, and those with thymus disease. Children younger than 9 months are excluded from vaccination (although in epidemics and risk areas they can receive the vaccine after 6 months). Pregnant women (except during the epidemic season) and people allergic to egg protein are also excluded.

In 2013 the World Health Organization (WHO) established that one dose of the vaccine is sufficient to confer sustained lifelong protective immunity to 99% of those vaccinated within 30 days.[7] This year in Brazil, because of the shortage, a fractionated vaccine was used. Both decisions are accepted[10 ]but controversial.[11,12  ]"The second dose has no risk, but it is a waste of a vaccine that is difficult to produce," Dr Orduña said.

International Risk

The Brazilian epidemic could be the origin of transmission to countries currently free of yellow fever, such as Mexico, the United States, and other countries in the region. The fear is based on the presence of available vectors that would allow yellow fever to be imported. The distribution of A aegypti and A albopictus vectors increases the risk for their expansion to Central America and North America; in the United States, areas of specific concern are South Florida and Texas.[13]

Phylogenetic studies suggest that the yellow fever virus reached the East coast of Brazil from West Africa (with the slave trade).[14] Today, travelers and cargo on international flights are the sources of concern. In 2016, Aedes mosquitoes were captured at the Schiphol airport in the Netherlands, confirming for the first time the transportation of this vector into Europe.[15] There are 215 countries potentially suitable for the survival of A aegypti and A albopiuctus vectors. Even much of Oceania and southern Europe are appropriate for the vector.[12]

The reason for the severity of the current epidemic remains unknown, but several hypotheses have arisen.  For example, eight genetic changes were detected that could affect viral replication in the hosts, thus favoring dissemination, but this has not been proven.[13]

Currently the Centers for Disease Control and Prevention has a level 2 alert for travelers to Brazil. The agency recommends vaccination to visitors traveling to areas with a yellow fever vaccination recommendation.

This news story was originally published in the  Spanish edition of Medscape.


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