the yellow fever virus

A woman with a moderate case of yellow fever complained of "a sudden onset of fever, headache, general malaise, and body pain." 1 In 15% of the patients presented, the acute form of yellow fever occurs. “fever, nausea, vomiting, epigastric pain, jaundice, renal insufficiency, and cardiovascular instability” are symptoms of this stage of the disease. The key findings of the physical examination of yellow fever are “fever, jaundice, relative bradycardia for the degree of fever, conjunctival injection, and skin flushing.”3

Lab Findings

The laboratory diagnosis of yellow fever is usually a tough task especially in the early stages of the disease. A physician must, therefore, perform a preliminary diagnosis before any lab work. This diagnosis would be based on an assessment of the symptoms exhibited by the patient, the patient’s travel history and activities, and whether or not the patient is vaccinated. Serological assays are usually used to diagnose yellow fever by detecting virus- specific IgM and IgG.

Signature Signs

The signature signs of yellow fever are jaundice and the combination of fever, headache, and general malaise.

Description of the Infectious Agent

“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 Members of the yellow fever virus group can be distinguished from each other on the basis of their genetic make-up. The group 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. As such the yellow fever virus has a cellular tropism for hepatocytes. 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.”4 In the 19th century, there were numerous outbreaks in the United States. In the Spanish- American war, many American soldiers succumbed to the illness. This prompted the military to form the Reed Yellow Fever Commission that eventually proved that yellow fever is vector-borne.

Epidemiology

“Forty-seven countries in Africa (34) and Central and South America (13) are either endemic for or have regions that are endemic for yellow fever.”2 In some cases, unvaccinated travelers who are infected bring disease to non-endemic regions. This has led to epidemics in Europe and North America in the past. The transmission of yellow fever virus among human populations is effected by mosquito vectors primarily the species Aedes and Haemagogus. The cases of yellow fever in endemic areas usually vary based on the season. “Most cases occur between the end of the rainy and the dry season which is between July and October in West Africa and January to March in South America.”7 Brazil has been the victim of arboviral outbreaks over the past decade. The first cases in the current Brazilian “yellow fever outbreak were reported in Minas Gerais in 2016.”

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. 3(p.12) 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 the small proportion whose infection transforms to mild disease, the most common symptoms 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 too many body organs, and characteristic symptoms include “hepatic dysfunction, renal failure, coagulopathy, and shock.”9 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. “Death due to yellow fever is preceded by cytokine dysregulation with subsequent cardiovascular shock and multi- organ failure.”10 “50 percent of the patients who enter the toxic phase of yellow fever die within 7- 10 days.”11 Individuals who recover from yellow fever are usually gain life- long immunity and have no long- term sequelae.12

Treatment

“There is no primary treatment for yellow fever. As such, secondary supportive care based on the patient’s symptoms is common.”13 Individuals who are infected with the virus and gain complete recovery gain life-long immunity against the virus. The prevention of yellow fever is achieved through vaccination.14 “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.”15 There have been attempts to produce an inactivated vaccine for the disease of late. This has led to the formulation of “XRX 001” is an inactivated yellow fever virus vaccine that is currently in the clinical trial phase.

Discussion Questions

What are the other Viruses of Medical Importance Transmitted by Mosquitoes?

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 and zika virus.”16 Alphaviruses which belong to the family Togaviridae are also spread by mosquito vectors. Chikungunya virus is one of the pathogenic alphaviruses.

What is a Live- Attenuated Vaccine?

“Live-attenuated vaccines are disease-preventing formulations that consist of infectious particles that have been weakened under laboratory conditions.”17 They stimulate the body to elicit an immune response against the pathogen without causing the associated disease.

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.

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.