Yellow Fever: Pathogenic Action, Symptoms And Control Strategies

Yellow Fever has two stages of sickness. The first stage is mild with symptoms of fever, muscle pain, nausea, vomiting, headache and weakness. The first stage usually lasts for 3-6 days, as that is the time the virus takes to incubate. 15-25% of people infected with first stage yellow fever progress to the second stage or so-called, the ‘toxic stage’, where 50% of people who are in the second stage die within 7-10 days. The symptoms for the second stage are visual bleeding, jaundice, kidney failure, liver failure, etc.

However, a number of steps must be completed for transmission of the mosquito-borne virus to occur:

• The virus must infect the midgut epithelium and replicate
• The virus must escape the midgut into the haemocoel and infect secondary tissues such as the salivary glands
• the critical stage for dissemination to be effective allows transmission of the virus from mosquito to susceptible host

Transmission may occur through deposition of virus-containing saliva when the mosquito feeds on the host (oral transmission)

All processes are governed by viral vectors and environmental factors.

Virus replication occurs at the site of inoculation from several species of mosquitoes of the genus Haemagogus. Most likely beginning in the dendritic cells in the epidermis, it spreads through lymphatic channels to regional lymph nodes. Through the lymph, the virus reaches other organs and then the bloodstream, seeding other tissues. Large amounts of viruses are produced in the liver, lymph nodes, and spleen and are released into the blood. During the first stage, the infection may be transmitted to blood-feeding mosquitoes.

Yellow fever is characterized by hepatic dysfunction, renal failure, coagulopathy, and shock.

Injury to hepatocytes is characterised by eosinophilic (stained) degeneration with condensed nuclear chromatin (Councilman bodies) shown in figure _. Yellow Fever causes liver cells or hepatocytes to die from apoptosis, which is the orderly process in which the cells are programmed to die, ‘a cellular death’. (https://www.khanacademy.org/science/biology/developmental-biology/apoptosis-in-development/a/apoptosis). Principally affecting the midzone of the liver lobule, hepatocytes are Fas ligand and lymphocytes infiltrating the liver mediates apoptosis. A Fas ligand is a transmembrane protein that induces apoptosis and plays an important role in the regulation of the immune system . These cells show that the immune system acted to attack the virus in its most abundant area and killing the infected hepatocytes as well as the lymphocytes. However, due to the abundance of the virus, the condensed build-up of the dead lymphocytes and dead, ballooned hepatocytes or councilman bodies in the liver eventually caused eosinophilic degeneration as well as jaundice in the toxic stages of Yellow Fever. This is again proven as in fatal cases, approximately 80% of hepatocytes undergo coagulative necrosis.

Therefore, the obstructed bile duct of the liver due to a condensed build-up of dead cells, which prevents the liver from disposing of bilirubin, causing it to leak to surrounding tissues and causes the yellow colour in the skin and eyes. The eosinophilic (stained) degeneration is also seen from the apoptosis through the ballooning hepatocytes.

Of course, all these factors together in a fatal case leads to liver failure.

A large effect of Yellow Fever is haemorrhage, which causes symptoms such as bleeding, nausea, headaches, etc. A haemorrhage results principally from a decreased synthesis of clotting factors by the failing of the liver which consequently leads to a disseminated intravascular coagulation (DIC). In a fatal situation, hemorrhagic symptoms and fatal outcomes are strongly correlated with highly elevated pro-inflammatory and anti-inflammatory cytokines. This is seen through the effects of hepatocytes when they are cleaved with apoptosis, 77 endothelial cells and their significant induction of interferon-inducible genes, 79 or activated macrophages80 may contribute. Furthermore, immune clearance attempts may exacerbate viral pathogenesis as it clogs up the blood vessels with dead cells. The hemorrhagic diathesis in yellow fever is also due to decreased synthesis of vitamin K-dependent coagulation factors by the liver, disseminated intravascular coagulation, and platelet dysfunction.

Therefore, factors such as disseminated intravascular coagulation (DIC), lack of vitamin K, pro-inflammatory and anti-inflammatory cytokines as well as others would cause excessive bleeding, inflammation, severe headaches and other haemorrhage symptoms. This explains the inflammation in the first stage of Yellow Fever and the bleeding symptoms shown in the second stage of Yellow Fever.

A late phase of Yellow Fever is characterised by circulatory shock. The underlying mechanism may be cytokine dysregulation, weak heart rate, low blood pressure, and poor organ function.

In a series of patients with fatal yellow fever, levels of proinflammatory cytokines were elevated compared with patients with non-fatal yellow fever. Patients dying of yellow fever have cerebral oedema at autopsy, most likely from the result of microvascular dysfunction. These factors that cause circulatory shock all link to organs in the body no longer functioning properly due to the viral genome invading cells. As we saw from the two factors above, all the organs depend on each other to function, so as the virus spreads, all the organs shut-down due to the change in the other organs, especially the liver (https://www.medicalnewstoday.com/articles/285954.php). Therefore, in a severe case of Yellow Fever circulatory shock is a common symptom of Yellow Fever. It is also seen that those who die of circulatory shock also have large amounts of complement-fixing antigen (NS1), which proves that when the patients died, they had a large amount of virus in their body, as NS1 is a non-structural protein of Yellow Fever.

Current and Potentially Future Control Strategies

There are many control strategies for Yellow Fever, however, vaccination is the primary and single most important measure for preventing Yellow Fever.

Before, a controlled strategy can be applied, an understanding of the transmission is needed. For Yellow Fever to be transmitted several steps must be completed for transmission of the mosquito-borne virus to occur:

• The virus must infect the midgut epithelium and replicate
• The virus must escape the midgut into the haemocoel and infect secondary tissues such as the salivary glands
• the critical stage for dissemination to be effective allows transmission of the virus from mosquito to a susceptible host

Transmission may occur through deposition of virus-containing saliva when the mosquito feeds on the host (oral transmission)

There is also a possibility that due to high levels of viremia in the late stages of Yellow Fever, a bloodborne transmission theoretically can occur via transfusion and needlesticks. Although it was thought to be theoretical, one case of perinatal transmission of wild-type YF virus has been documented from a woman who developed symptoms of YF, 3 days before giving birth. The infant tested positive for YF viral RNA and died of fulminant YF on the 12th day of life

When infected with YF virus, humans experience the highest level of viremia before the onset of the fever and for the first 3-5 days of illness and can transmit the virus to mosquitoes in this time

It should be noted that Yellow Fever cannot be passed down person to person but has to be an anthroponotic transmission.

Vaccinations are seen as the primary protective measure against Yellow Fever is because of the failure of mosquito control programmes and lack of effective antiviral measures.

Yellow Fever vaccinations are live and attenuated. Its purpose to build immunity in a human body by injecting a person with a weakened version of the virus. This introduces and stimulates the virus to your body, so it can ‘remember’ the virus without causing the disease. The antibodies will remain in the body for the duration of the life of a person, to help protect the body against future infections with the same organism, according to the data collected. This is known as active immunity (https://www.netdoctor.co.uk/medicines/infection/a8450/yellow-fever-vaccine-stamaril/).

The vaccination will prevent a fatality in those who are bitten by an Aedes or demagogues genus mosquito, however, they may have a small fever or inflammation instead, due to immune system response to a virus. However, this time instead of the virus expanding and infecting cells at an overwhelming rate for the immune system, the immune system will easily overcome the infection due to the body being vaccine with 17D, the Yellow Fever Vaccine.

Vaccinations control the spread of Yellow Fever by creating an active immunity against the viral disease.

A few days after immunisation with the live-attenuated 17D vaccine, low levels of circulating viral RNA and infectious virus are detectable (

In a vaccine, pro-inflammatory cytokines interleukin and tumour necrosis factor are released, and markers of the type I interferon response are expressed by peripheral blood cells. However, it is the humoral immunity’s T-cell and B-cell activation and rapid elicitation of the neutralizing antibodies that play a major role in host defence against Yellow Fever Virus infection. Neutralizing antibodies are used as the correlate of protection by the World Health Organisation (WHO). However, the potential importance of cell-mediated immunity in controlling primary YFV infections should not be underestimated and could be the deciding factor between life or death.

In addition, a future strategy and needed control strategy to prevent the spread and fatalities of Yellow Fever is a faster diagnosis (https://www.medicalnewstoday.com/articles/285954.php).

Currently, a new study has found that changes in white blood cells can signal an early sign of fatal yellow fever, which may lead to better diagnosis and treatment for Yellow Fever.

Prof. Messaoudi and her colleagues have discovered that the yellow fever virus replicates primarily in the liver, indicating that other organ failures that often follow in people with the disease are due to knock-on effects.

Once it gets into the liver, the yellow fever virus damages the liver cells and causes them and the immune system to release large amounts of cytokines into the bloodstream. The researchers suggest these inflammatory proteins are most likely what causes the damage to other organs.

The team also found these events in the liver are preceded by severe loss of lymphocytes, a type of white blood cell, which can be used in identifying and managing the virulence of different cases of Yellow Fever through their comparisons and organisation.

Through the state of lymphopenia, it allows us to detect any measurable changes in liver enzymes and the number of lymphocytes approximately a day or so before the changes in the liver are seen. This finding has the potential to provide an earlier clinical outcome measure of subsequent disease severity, giving doctors a better prognostic tool for offering more aggressive supportive care for these patients and potentially saving lives.

Additionally, through their studied changes in gene expression within white blood cells during the early stages of yellow fever infection – before clinical symptoms emerge and before the monkeys showed any symptoms of being sick, they also found that 3 days after infection, the virus had changed the expression of over 700 genes – many of which suppress the immune system and caused cell death due to up-regulated were highly pro-inflammatory cytokines (organ damage).

These findings (3) lead Prof. Messaoudi to the possibility that gene expression could be used as a clinical diagnostic tool for yellow fever, where a quick analysis on patients’ white blood cells can determine which infected person is at high or low risk. Through the diagnosis, degree of supportive care can be followed for all patients and change the dynamics of how aggressive the treatment needs to be.

This is a massive breakthrough for the development for a Yellow Fever cure, as currently there is only medicine to relieve the symptoms of Yellow Fever, but there is no treatment of any kind. There are only prevention methods such as vaccination, insect repellent and personal protection equipment (PPE).

Although the prevention techniques may give the average person life-long immunity to Yellow Fever, many people, especially in the infected countries who cannot afford the vaccine or simply are not aware of its dangers, so prevention measures are not effective for those who live in rural areas where it is more likely to for the virus to be transmitted.