Yellow Fever Virus

The mild type of yellow fever

The mild type of yellow fever is characterized by “a rapid onset of fever, headache, general malaise, and body pain.” 1 In 15% of the patients presented, the acute form of yellow fever occurs. During this stage of the disease, symptoms include “fever, fatigue, vomiting, epigastric discomfort, jaundice, renal insufficiency, and cardiovascular instability.” 2 The lethal type of yellow fever is distinguished by hemorrhagic symptoms that progress to organ failure. Key Physical Exam Details (PE)

In the case of yellow fever, the key findings of the physical examination are “fever, jaundice, relative bradycardia for the degree of fever, conjunctival injection, and skin flushing.”

Lab Findings

The laboratory diagnosis of yellow fever is usually a tough task especially in the early stages of the disease. As such, the physician in question must first make a preliminary diagnosis based on the symptoms exhibited by the patient, the patient’s travel history and activities, and whether or not the patient is vaccinated. A variety of abnormalities in routine lab tests are observed in patients with yellow fever. These include leukopenia, decreased platelet count, and hyperbilirubinemia. Serological assays are usually used to diagnose yellow fever by detecting virus- specific IgM and IgG. A positive result is then confirmed through serologic cross reactions with related viruses such as dengue virus. In the early phases of infection, diagnosis can be achieved by the identification of viral genetic material- RNA- by RT- PCR. This method is only useful in the early stages since viral RNA cannot be detected once the infection enters the acute phase.

Signature Signs

Fever, headache, and general malaise

Jaundice

Description of the Yellow Fever Virus

“The yellow fever virus belongs to family Flaviviridae, genus Flavivirus. Its genetic material is positive- sense single- stranded RNA which is contained in genomes which are linear and non- segmented.”4 Yellow fever virus has seven genotypes which differ in the nucleotide sequences of the 3’ non- coding region.5 The virus’s primary target once it infects a human being is the liver. However, it can also replicate in the kidneys, heart, and lungs.6 “Yellow fever virus was the first virus to be proven to be pathogenic to human beings in 1927.”7

Epidemiology

“Forty-seven countries in Africa (34) and Central and South America (14) are either endemic for, or have regions that are endemic for yellow fever with the burden of yellow fever, based on African data, in 2013 being 84,000- 170,000 severe cases and 29,000- 60,000 deaths.”2 Travelers are implicated for bringing the disease to non- endemic countries especially after visiting endemic countries without any prior vaccination. In the past, this has led to epidemics in Europe and North America. The transmission of yellow fever virus among human populations is effected by mosquito vectors. The species of mosquitoes involved, in this case, are Aedes and Haemagogus. The vectors acquire yellow fever virus from infected primates which could be from primates “human or non- human” and then transmit the infectious particles to other primates “human or non- human” through a bite on the skin. “There are three distinct transmission cycles for yellow fever virus. The jungle/ sylvatic cycle involves relevant mosquito species and non- human primates in the jungle while the intermediate/ Savannah cycle is all about the transmission of yellow fever virus from infected vectors to human beings living in areas around the forest.”8 The urban cycle, on the other hand, involves the transmission of the virus between human beings infected in the other cycles and urban mosquitoes. The urban mosquitoes, which are mainly Aedes aegypti, are involved in this cycle. The cases of yellow fever in endemic areas usually vary based on the season. “Most cases occur between the end of the rainy season and the dry season which is between July and October in West Africa and January to March in South America.”9 Brazil has been the victim of arboviral outbreaks over the past decade. The yellow fever outbreak in the country was first reported in Minas Gerais state in 2016 and has since spread out to the surrounding states in the region that include Rio de Janeiro, Espirito Santo, and Sao Paulo.10

Pathogenesis

Yellow fever virus is introduced to the human body by an infected mosquito bite which could either be by a mosquito of the genus Aedes or Haemagogus. The female mosquito is responsible for transmission of the virus with it disseminating 1,000- 10,000 infectious particles through the skin when feeding on human blood. The yellow fever virus starts replication at the site of the bite before spreading to the rest of the body through the lymphatic system. Through the lymph, and later the bloodstream, the viral particles are able to reach organs such as the liver and spleen where large amounts of the virus are produced. The incubation period of yellow fever virus is normally between 3 and 6 days. Most infected individuals do not develop associated symptoms of the disease. However, for those who develop the symptoms, the most common are “fever, headache, myalgia, general malaise, nausea, and vomiting.”1 The symptoms usually subside after 3- 4 days in the vast majority of cases. Progression to the acute phase of yellow fever is observed in approximately 15 percent of the cases. This phase is particularly damaging to many body organs, and characteristic symptoms include “hepatic dysfunction, renal failure, coagulopathy, and shock.”11 The degeneration of eosinophils is a salient feature of injury observed in hepatocytes of infected liver tissue. The death of these cells is usually attributed to programmed cell death. Changes in the function of the glomerulus after the infection of the kidneys is responsible for the classic albuminuria that is associated with yellow fever. The accumulation of wastes in the body due to multiple organ failure leads toxic shock. Hemorrhaging symptoms have also been reported in the toxic phase of yellow fever. “Death due to yellow fever is preceded by cytokine dysregulation with subsequent cardiovascular shock and multi- organ failure.”12 “50 percent of the patients who enter the toxic phase of yellow fever die within 7- 10 days.”13 Individuals who recover from yellow fever are usually gain life- long immunity and have no long- term sequelae.14

Treatment

“There is no primary treatment for yellow fever. As such, secondary supportive care based on the patient’s symptoms is common.”15 Complete care, especially in the latter stages of the disease, requires admission into an intensive care facility. Recovery after infection with the virus makes one immune for life. The prevention of yellow fever is achieved through vaccination. “Vaccination is advisable for adults and children over age 9 months who are traveling to or living in countries with a known risk of yellow fever.”16 “YF 17D, which is a live-attenuated vaccine, has been used in the prevention of yellow fever around the world for more than six decades.”17

Discussion Questions

What other pathogenic viruses are caused by mosquito vectors?

Most viruses in the Flavivirus genus are spread by mosquito vectors. They have emerged as serious threats to public health around the world. They include “dengue virus, zika virus, West Nile virus, and Japanese encephalitis virus.” The diseases associated with these viruses have increased in incidence and geographical range since the turn of the century.18 Alphaviruses which belong to the family Togaviridae are also spread by mosquito vectors. Medically important viruses in this genus include “Chikungunya virus, Ross River virus, and Semliki forest virus.”

What is a live- attenuated vaccine?

“Live attenuated vaccines basically consist of pathogens that have been weakened under laboratory conditions.”19 They stimulate the body to elicit an immune response against the pathogen without causing the associated disease. Examples of live attenuated vaccines are BCG, oral polio vaccine, yellow fever, rotavirus, and measles. The unpredictability of the organisms used in the vaccines has led safety concerns among members of the public over the years.

References

Centers for Disease Control and Prevention. Yellow Fever: Clinical and Laboratory Evaluation. https://www.cdc.gov/yellowfever/healthcareproviders/healthcareproviders-clinlabeval.html. Published August 21, 2015. Accessed August 30, 2017.

World Health Organization. Yellow Fever. http://www.who.int/mediacentre/factsheets/fs100/en/. Published May 16, 2016. Accessed August 30, 2017.

Monath TP. Yellow fever: An Update. The Lancet Infectious Diseases. 2001; 1(1), 11- 20. https://doi.org/10.1016/S1473-3099(01)00016-0. Accessed August 30, 2017.

Stock NK, Laraway H, Faye O, Diallo M, Niedrig M, Sall AA. Biological and Phylogenetic Characteristics of Yellow Fever Virus Lineages from West Africa. Journal of Virology. 2013; 87(5), 2895- 2907. doi:10.1128/JVI.01116-12. Accessed August 30, 2017.

Mutebi JP, Rijnbrand RC, Wang H, Ryman KD, Wang E, Fulop LD, Titball R, Barret AD. Genetic relationships and evolution of genotypes of yellow fever virus and other members of the yellow fever virus group within the Flavivirus genus based on the 3’ noncoding region. Journal of Virology. 2004; 78(18), 9652- 9665. doi:10.1128/JVI.78.18.9652-9665.2004. Accessed August 30, 2017.

Fernandez- Garcia MD, Meertens L, Chazal M, Hafirassou ML, Dejarnac O, Zamborlini A, Despres P, Sauvonnet N, Arenzana- Seisdedos F, Jouvenet N, Amara A. Vaccine and wild- type strains of yellow fever virus engage distinct entry mechanisms and differentially stimulate antiviral immune responses. mBio. 2016; 7(1), 1- 15. doi: 10.1128/mBio.01956-15. Accessed August 30, 2017.

Stock NK, Laraway H, Faye O, Diallo M, Niedrig M, Sall AA. Biological and phylogenetic characteristics of yellow fever virus lineages from West Africa. Journal of Virology. 2013;87(5), 2895-907. doi: 10.1128/JVI.01116-12. Accessed August 30, 2017.

Gubler DJ. The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle? Comparative Immunology, Microbiology and Infectious Diseases. 2004; 27(5), 319- 330. https://doi.org/10.1016/j.cimid.2004.03.013. Accessed August 30, 2017.

Fisman D. Seasonality of viral infections: mechanisms and unknowns. Clinical Microbiology and Infection. 2012; 18(10), 946- 954. https://doi.org/10.1111/j.1469-0691.2012.03968.x. Accessed August 30, 2017.

Centers for Disease Control and Prevention. Yellow Fever in Brazil. https://wwwnc.cdc.gov/travel/notices/alert/yellow-fever-brazil. Published July 24, 2017. Accessed August 30, 2017.

Monath TP, Barrett AD. Pathogenesis and pathophysiology of yellow fever. Advances in Virus Research. 2003; 60, 343- 395. https://www.ncbi.nlm.nih.gov/pubmed/14689698. Accessed August 30, 2017.

Vasconcelos PF, Costa ZG, Travassos Da Rosa ES, Luna E, Rodrigues SG, Barros VL, Dias JP, Monteiro HA, Oliva OF, Vasconcelos HB, Oliveira RC, Sousa MR, Barbosa Da Silva J, Cruz AC, Martins EC, Travassos Da Rosa JF. Epidemic of jungle yellow fever in Brazil, 2000: implications of climatic alterations in disease spread. Journal of Medical Virology. 2001; 65(3), 598- 604. PMID:11596099. Accessed August 30, 2017.

Barrett AD, Higgs S. Yellow fever: a disease that has yet to be conquered. Annual Review of Entomology. 2007; 52, 209- 229. https://doi.org/10.1146/annurev.ento.52.110405.091454. Accessed August 30, 2017.

Coulange BH, Benabdelmoumen G, Gergely A, Goujon C, Pelicot M, Poujol P, Consigny PH. Long- term persistence of yellow fever neutralizing antibodies in elderly persons. Bulletin De La Societe De Pathologie Exotique. 2011; 104(4), 260- 265. doi: 10.1007/s13149-011-0135-7. Accessed August 30, 2017.

Reiter P. Yellow fever and dengue: a threat to Europe. Euro Surveillance. 2010; 15(10), 19509. http://www.eurosurveillance.org/images/dynamic/ee/v15n10/art19509.pdf. Accessed August 30, 2017.

WebMD. Yellow Fever. http://www.webmd.com/a-to-z-guides/yellow-fever-symptoms-treatment#2. Published July 13, 2017. Accessed August 30, 2017.

Monath TP. Treatment of yellow fever. Antiviral Research. 2008; 78(1), 116- 124. https://doi.org/10.1016/j.antiviral.2007.10.009. Accessed August 30, 2017.

Mackenzie JS, Gubler DJ, Petersen LR. Emerging Flaviviruses: the spread and resurgence of Japanese encephalitis, West Nile, and dengue viruses. Nature Medicine. 2004; 10(12), 98- 109. DOI:10.1038/nm1144. Accessed August 30, 2017.

Minor PD. Live attenuated vaccines: historical successes and current challenges. Virology. 2015; 479, 379- 392. https://doi.org/10.1016/j.virol.2015.03.032. Accessed August 30, 2017.