Yellow Fever

Yellow fever is an acute viral illness that affects both humans and non-human primates/apes. It is transmitted by mosquitoes and is characterized by fever, jaundice (yellowing of the skin and eyes), proteinuria (presence of excess protein in urine), hemorrhagic manifestations (bleeding tendencies), and a relatively short seroconversion time-frame.

• Yellow fever is caused by a small group B arbovirus.
• Virologically, the yellow fever virus is classified as a Flavivirus within the Flaviviridae family.
• The virus is enclosed within an enveloped virus particle, typically measuring between 35 to 50 nanometers in diameter.
• It possesses a single-stranded infectious RNA genome.

• Epidemics of yellow fever have been documented as far back as the 16th century.
• The virus was likely introduced during the era of the slave trade, primarily through Caribbean ports.
• Epidemic and endemic forms of the disease occur in Africa and South America.
• Historical medical reports suggest that yellow fever persisted in Europe and North America until around 1900.
• Humans and non-human primates serve as the hosts for the disease, with infected mosquitoes acting as disease amplifiers, facilitating a higher rate of mosquito infection (note that mosquitoes do not bite each other).
• Once a mosquito becomes infected, it remains infected for life, typically several weeks, and thus serves as the true extra-human reservoir of the infection.
• After being bitten by an infected mosquito, both humans and primates develop viremia (presence of the virus in the blood) after approximately 3-6 days, becoming sources of spread through fresh mosquito bites.
• The yellow fever virus replicates in the gut of the mosquito and then migrates to the mosquito's salivary glands, making it ready for transmission to the next human host through mosquito bites, similar to how malaria is transmitted.
• Yellow fever-associated mosquitoes are known to be frequently active during the day, which is especially concerning for individuals such as loggers working outdoors.
• The mosquitoes involved in yellow fever transmission include:
  • Aedes aegypti;
  • Aedes africanus;
  • Haemogogus;
  • Aedes simpsoni.

Cycles of Spread

Two cycles of yellow fever spread are recognized:

1. Urban Yellow Fever Cycle:
   • From an affected human host to Aedes aegypti mosquitoes and then to a new human host.
2. Jungle (Yellow Fever) Cycle:
   • From an affected monkey/ape host to jungle mosquitoes, such as Aedes africanus in Africa or Haemogogus spp., and then to a new non-human primate (monkey/ape).
3. Peri-Urban Cycle:
   • Involves "anchored" Aedes simpsonii mosquitoes, which act as a link host. They bite peri-urban monkeys that raid farms for bananas and are also capable of biting rural humans.

More on Epidemiology

• The classic form of the disease occurs in epidemic forms.
• Epidemics have been recorded for ages, occurring when the virus is suddenly introduced into an environment that supports the proliferation and abundance of Aedes mosquito species, resulting in urban yellow fever in human populations and jungle yellow fever in primate populations.
• Epidemics occur in human populations with low levels of relevant immunization (low seropositivity).
• Endemic yellow fever occurs sporadically, especially in some moist savannah populations of Africa, where detectable seropositivity may reach up to 50% of the population.
• Jungle yellow fever is enzootic in jungle primates in the Amazon forest of South America, in river basins such as Magdalena, Orinoco, and Catatumbo.
• Sporadic human cases of yellow fever occur in such endemic areas, with the last reported epidemic dating back to 1942.
• Geographical restrictions play a role in disease occurrence.
• The occurrence of the disease is closely related to the entomological characteristics of the mosquito vectors, including rainfall and the abundance of standing water that supports mosquito breeding.
• Similar to malaria, yellow fever is geographically restricted to the region between 15 degrees North and 10 degrees South of the equator, as suggested by serological studies since the 1930s.
• In West African populations such as Nigeria, Burkina Faso, and Ghana, yellow fever occurrence varies from sporadic isolated cases to the advent of wild or severe epidemics, with attack rates of up to about 50% or more and case fatality ranging from as low as 5% to about 50% or more, particularly when severe cases requiring hospitalization are considered.
• During epidemics, it is important to note that the highest morbidity and mortality occur among infants and children because most adults are immune to the disease.

Yellow fever is associated with specific pathological changes, including:

• Coagulative Necrosis of Hepatocytes: This occurs in the midzone of the liver lobule, with a notable sparing of periportal cells and central veins.
• Eosinophilic Necrosis of Hepatocytes: This results in the appearance of Councilman's bodies, which are characteristic cellular changes.
• Microvascular Fatty Changes: These alterations are observed in the liver.
• Minimal Inflammation: There is generally minimal inflammation, and the normal cytoarchitecture of the liver is only slightly disrupted. Liver cirrhosis is rare in cases of yellow fever.
• Myocardial Fiber Degeneration: Yellow fever can lead to degeneration of myocardial fibers and fatty infiltration of the heart muscle.
• Brain Involvement: Brain-related symptoms may include edema and the presence of petechial hemorrhagic lesions.

• Inapparent or Asymptomatic Infection: Many cases of yellow fever are either inapparent or asymptomatic. Mild infections often present as non-specific dengue-like febrile illnesses.
• Incubation Period: The incubation period in humans is typically 3-6 days. This is the minimum time required for a significant viremia to develop, making the next mosquito bite capable of transmitting the virus.
• Biphasic Illness: Yellow fever is characterized by two distinct phases:
• Early Stage (3-5 days):
  • Resembles malaria or dengue fever.
  • Characterized by:
  • Abrupt onset of high fever.
  • Severe headache.
  • Severe lumbar/back pain.
  • Agitation, anxiety, flushed face, and congested mucosal surfaces, especially in light-skinned populations.
  • Proteinuria may occur at this stage, but oliguria is unusual.
• Interval of Deceptive Remission:
  • Fever subsides, and there is a subjective feeling of improvement.
  • Most mild cases resolve at this stage, but a few progress to the next stage.
• Stage of Severe Disease:
  • Resurgence of fever associated with vomiting.
  • Essentially hemorrhagic manifestations, including melaena (bloody stool) and haematemesis (vomiting blood) from the gastrointestinal tract. This is referred to as "El vomito negro" in Spanish-speaking South American countries.
  • Hepatic involvement with the advent of moderate to severe hepatocellular jaundice and derangement of liver function test (LFT) parameters.
  • Renal involvement leading to oliguria (scanty urine) or anuria (absence of urine).
  • Temperature-pulse dissociation (Faget's Sign) possibly due to myocardial involvement in the widespread hemorrhagic lesions.
  • Dehydration, hypotension, and abdominal pain.
  • Worsening hepatic derangement deepens jaundice and leads to hepatic failure with attendant symptoms.
  • Corresponding worsening of renal involvement results in renal failure with oliguria, massive proteinuria, and hematuria.
  • Other symptoms may include hypoglycemia, altered mental state with delirium, or coma.
• Typically, symptoms worsen progressively over 7-10 days from the onset of the disease, with death occurring over the same period.
• A proportion of patients may improve with supportive care, leading to a gradual reduction in jaundice, resolution of fever, and other symptoms.
• Fatality in yellow fever cases is usually attributed to renal failure or myocardial damage.

• Clinical: Diagnosis can be easier for the epidemic presentation compared to sporadic cases.
• Virus Isolation: Yellow fever virus can be isolated in specific tissue culture lines.
• Rapid Diagnostic Tests: These include:
• Detection of virus-specific IgM via ELISA (Enzyme-Linked Immunosorbent Assay).
• Direct detection of viral antigen.
• Nuclear Amplification Tests, particularly PCR (Polymerase Chain Reaction).
• Serological Identification: Diagnosis can be confirmed by detecting a 4-fold rise in YF IgG using methods like HI (Hemagglutination Inhibition), CF (Complement Fixation), or NI (Neutralization Index).
• Post Mortem Histopathology of the Liver: This involves the identification of specific histopathological changes caused by the virus infection, including:
• Councilman's Bodies: Acidophilic areas of hyaline necrosis in hepatocytes.
• Midzonal Necrosis: Necrosis in the midzone of the liver lobule with little or no cytoarchitectural distortion and no evidence of cirrhotic changes.
• Light Microscopy: Patchy focal degeneration of the liver cords, giving a "salt and pepper appearance" of liver cord degeneration.

• Mild/Moderate disease:
• Viral:
• Viral hepatitis;
• Influenza;
• Dengue fever and dengue-like diseases like West Nile & Chikungunya virus infection;
• Non-viral:
• Malaria;
• Enteric (Typhoid) fever;
• Leptospirosis, especially due to Leptospira icterohaemorrhagica;
• Sepsis, with or without underlying Sickle Cell Disease;
• Toxic hepatitides, e.g. due to carbon tetrachloride ingestion/poisoning;
• Severe Disease:
• Severe viral hepatitis with or without liver failure;
• Other haemorrhagic fevers;

• Supportive treatment:
• Isolation and nursing under mosquito nets, preferably in a mosquito-free environment, which is crucial for breaking virus transmission.
• Vitamin K/multivitamin supplements, dietary modifications (low fat, low protein, and high carb), and other supportive treatment for acute or imminent liver failure.
• Dulcolax suppository for reducing liver load of GI bacterial toxins.
• Avoidance of potentially hepatotoxic medications.
• Whole blood or blood product transfusion as needed.
• In severe life-threatening cases:
• Heamo- or peritoneal dialysis, especially in those with oliguria/anuria (concomitant renal insufficiency).
• Possible exchange blood transfusion.
• Possible charcoal haemoperfusion.
• Serial LFTs and adequate follow-up.

• Vaccine-based:
• Yellow fever vaccination is a component of the regular NPI schedule in children.
• It requires renewal every 10 years.
• The lyophilized 17D vaccine type, prepared from chick embryos and using the Asibi strain of the virus, is much safer than the alternative Dakar or French strain of the virus. The latter may be followed by neurological complications like post-vaccination encephalitis.
• Non-vaccine related measures:
• Mosquito control measures to reduce the risk of bites from the relevant mosquitoes, including the use of mosquito repellent cream and other protective measures for loggers and individuals at risk of exposure.