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Yellow Fever On The Rise: 

What Is It?   
Is There A Cure? 
How Do I Prevent It? 

Yellow fever is caused by the yellow fever virus (YFV), also called Flavivirus. The virus is transmitted by female mosquitos, who pick it up from monkeys or other humans, then delivers it to a new human when they bite and suck blood. The disease cannot be spread from person to person.

CAUSES - IN DETAIL
Yellow fever is caused by a virus that is spread by the Aedes aegypti mosquito. These mosquitoes thrive in and near human habitations where they breed in even the cleanest water. Most cases of yellow fever occur in sub-Saharan Africa and tropical South America.

Humans and monkeys are most commonly infected with the yellow fever virus. Mosquitoes transmit the virus back and forth between monkeys, humans or both.

When a mosquito bites a human or a monkey infected with yellow fever, the virus enters the mosquito's bloodstream and circulates before settling in the salivary glands. When the infected mosquito bites another monkey or human, the virus then enters the host's bloodstream, where it may cause illness.

SYMPTOMS
During the first three to six days after you've contracted yellow fever — the incubation period — you won't experience any signs or symptoms. After this, the infection enters an acute phase and then, in some cases, a toxic phase that can be life-threatening.

Acute phase
Once the infection enters the acute phase, you may experience signs and symptoms including:


  1. Fever
  2. Headache
  3. Muscle aches, particularly in your back and knees
  4. Sensitivity to light
  5. Nausea, vomiting or both
  6. Loss of appetite
  7. Dizziness
  8. Red eyes, face or tongue
  9. These signs and symptoms usually improve and are gone within several days.


Toxic phase
Although signs and symptoms may disappear for a day or two following the acute phase, some people with acute yellow fever then enter a toxic phase. During the toxic phase, acute signs and symptoms return and more-severe and life-threatening ones also appear. These can include:


  1. Yellowing of your skin and the whites of your eyes (jaundice)
  2. Abdominal pain and vomiting, sometimes of blood
  3. Decreased urination
  4. Bleeding from your nose, mouth and eyes
  5. Slow heart rate (bradycardia)
  6. Liver and kidney failure
  7. Brain dysfunction, including delirium, seizures and coma
  8. The toxic phase of yellow fever can be fatal.


When to see a doctor Before travel
Four weeks or more before your trip, make an appointment to see your doctor if you're traveling to an area in which yellow fever is known to occur so that you discuss whether you need the yellow fever vaccine.

If you have less than four weeks to prepare, call your doctor anyway. Ideally, you'll be able to be vaccinated at least three to four weeks before traveling to an area where yellow fever occurs to give the vaccine time to work. Your doctor will help you determine whether you need vaccinations and can provide general guidance on protecting your health while abroad.

After travel
Seek emergency medical care if you've recently traveled to a region where yellow fever is known to occur and you develop signs or symptoms of the toxic phase of the disease.
Call your doctor if you develop mild symptoms, after traveling to a region where yellow fever occurs.


DEFINITIONS
Yellow fever is a viral infection spread by a particular type of mosquito. The infection is most common in areas of Africa and South America, affecting travelers to and residents of those areas.

In mild cases, yellow fever causes fever, headache, nausea and vomiting. But yellow fever can become more serious, causing heart, liver and kidney problems along with bleeding (hemorrhaging). Up to 50 percent of people with the more severe form of yellow fever die of the disease.

There's no specific treatment for yellow fever. But getting a yellow fever vaccine before traveling to an area in which the virus is known to exist can protect you from the disease.


RISK FACTORS
You may be at risk of the disease if you travel to an area where mosquitoes continue to carry the yellow fever virus. These areas include sub-Saharan Africa and tropical South America.

Even if there aren't current reports of infected humans in these areas, it doesn't mean you're risk-free. It's possible that local populations have been vaccinated and are protected from the disease, or that cases of yellow fever just haven't been detected and officially reported.

If you're planning on traveling to these areas, you can protect yourself by getting a yellow fever vaccine at least several weeks before traveling.

Anyone can be infected with the yellow fever virus, but older adults are at greater risk of getting seriously ill.

COMPLICATIONS
Yellow fever results in death for 20 to 50 percent of those who develop severe disease. Complications during the toxic phase of a yellow fever infection include kidney and liver failure, jaundice, delirium, and coma.

People who survive the infection recover gradually over a period of several weeks to months, usually without significant organ damage. During this time a person may experience fatigue and jaundice. Other complications include secondary bacterial infections, such as pneumonia or blood infections.

PREPARING FOR YOUR APPOINTMENT
Call your doctor if you've recently returned from travel abroad and develop mild symptoms similar to those that occur with yellow fever. If your symptoms are severe, go to an emergency room or call 911 or your local emergency number.

Here's some information to help you get ready, and know what to expect from your doctor.

Information to gather in advance

Symptom history. Write down any symptoms you've been experiencing and for how long.
Recent exposure to possible sources of infection. Be sure to describe international trips in detail, including the countries you visited and the dates, as well as any contact you may have had with mosquitoes.

Medical history. Make a list of your key medical information, including other conditions for which you're being treated and any medications, vitamins or supplements you're taking. Your doctor will also need to know your vaccination history.

Questions to ask your doctor. Write down your questions in advance so that you can make the most of your time with your doctor.

The list below suggests questions to raise with your doctor about yellow fever. Don't hesitate to ask more questions during your appointment.


  1. What's the most likely cause of my symptoms?
  2. Are there any other possible causes for my symptoms?
  3. What kinds of tests do I need?
  4. Are treatments available to help me recover?
  5. How long do you expect a full recovery will take?
  6. When can I return to work or school?
  7. Am I at risk of any long-term complications from yellow fever?
  8. What to expect from your doctor


Your doctor is likely to ask you a number of questions. Being ready to answer them may reserve time to go over any points you want to talk about in-depth. Your doctor may ask:


  1. What are your symptoms?
  2. When did you first begin experiencing symptoms?
  3. Have your symptoms seemed to be getting better or worse?
  4. Did your symptoms briefly get better and then come back?
  5. Have you recently traveled abroad? Where?
  6. Were you exposed to mosquitoes while traveling?
  7. Did you update your vaccinations before traveling?
  8. Are you being treated for any other medical conditions?
  9. Are you taking any medications?



TESTS AND DIAGNOSIS
Diagnosing yellow fever based on signs and symptoms can be difficult because early in its course, the infection can be easily confused with malaria, typhoid, dengue fever and other viral hemorrhagic fevers.

To diagnose your condition, your doctor will likely:


  1. Ask questions about your medical and travel history
  2. Collect a blood sample for testing
  3. If you have yellow fever, your blood may reveal the virus itself. If not, blood tests also can detect antibodies and other substances specific to the virus.


TREATMENT AND DRUGS
No antiviral medications have proved helpful in treating yellow fever. As a result, treatment consists primarily of supportive care in a hospital. This includes providing fluids and oxygen, maintaining adequate blood pressure, replacing blood loss, providing dialysis for kidney failure, and treating any other infections that develop. Some people receive transfusions of plasma to replace blood proteins that improve clotting.

If you have yellow fever, your doctor will likely recommend that you stay inside, away from mosquitoes, to avoid transmitting the disease to others. Once you've have yellow fever, you'll be immune to the disease for the rest of your life.

PREVENTION
A safe and highly effective vaccine prevents yellow fever. Yellow fever is known to be present in sub-Saharan Africa and parts of South America. If you live in one of these areas, talk to your doctor about whether you need the yellow fever vaccine. If you plan to travel in these areas, talk with your doctor at least 10 days, but preferably three to four weeks, before your trip begins. Some countries require travelers to present a valid certificate of immunization upon entry.

A single dose of the yellow fever vaccine provides protection for at least 10 years. Side effects are usually mild, lasting five to 10 days, and may include headaches, low-grade fevers, muscle pain, fatigue and soreness at the site of injection. More-significant reactions — such as developing a syndrome similar to actual yellow fever, inflammation of the brain (encephalitis) or death — can occur, most often in infants and older adults. The vaccine is considered safest for those between the ages of 9 months and 60 years.

Talk to your doctor about whether the yellow fever vaccine is appropriate if your child is younger than 9 months, if you have a weakened immune system (immunocompromised), or if you're older than 60 years.

Mosquito protection

In addition to getting the vaccine, you can help protect yourself against yellow fever by protecting yourself against mosquitoes.

To reduce your exposure to mosquitoes:

  1. Avoid unnecessary outdoor activity when mosquitoes are most active.
  2. Wear long-sleeved shirts and long pants when you go into mosquito-infested areas.
  3. Stay in air-conditioned or well-screened housing.
  4. If your accommodations don't have good window screens or air-conditioning, use bed nets. Nets that have been pre-treated with insecticide offer additional protection.


To ward off mosquitoes with repellent, use both of the following:

Nonskin repellent. Apply permethrin-containing mosquito repellent to your clothing, shoes, camping gear and bed netting. You can buy some articles of clothing and gear pre-treated with permethrin. Permethrin is not intended for use on your skin.

Skin repellent. Products with the active ingredients DEET, IR3535 or picaridin provide long-lasting skin protection. Choose the concentration based on the hours of protection you need. In general, higher concentrations last longer.

Keep in mind that chemical repellents can be toxic, and use only the amount needed for the time you'll be outdoors. Don't use DEET on the hands of young children or on infants under 2 months of age. Instead, cover your infant's stroller or playpen with mosquito netting when outside.

According to the Centers for Disease Control and Prevention, oil of lemon eucalyptus, a more natural product, offers the same protection as DEET when used in similar concentrations. But these products should not be used on children younger than age 3.

http://www.mayoclinic.org/diseases-conditions/yellow-fever/basics/causes/con-20032263




SUGGESTED QUESTIONS FOR DISCUSSION

  1. The 12th century Spanish rabbi, doctor, and philosopher Moses Maimonides said "May I never see in the patient anything but a fellow creature in pain." What did Maimonides understand about his obligations to his patients?
  2. What is informed consent? What types of information and interactions should researchers give to volunteers to ensure that the volunteers are truly informed?
  3. What are the pros and cons of paying people to participate in clinical trials? Do payments corrupt or compromise "volunteerism?"
  4. Consider this quote from Claude Bernard: "The principle of medical morality consists then in never performing on man an experiment which would be harmful to him in any degree whatsoever though the result may be of great interest to science, that is, of benefit to save the health of others." What are the rights of individuals in a society? What are the rights of the society?
  5. If an individual living in a given society wishes to benefit from the medical research carried out by that society, does the individual have an obligation to participate in research? In what circumstances would an individual place the benefits of medical research to society above the benefits to herself or himself?
  6. Were the yellow fever experiments exacting too large a personal price from subjects?
  7. In the past, people with infectious diseases were quarantined. Why is this practice not common any more? What are the issues raised by quarantine in a democratic society?
  8. Consider 'autonomy' for soldiers. Is it possible for soldiers to truly volunteer? What problems might be created by the hierarchical structure of the military?
  9. Colonel Arthur Anderson, M.D., Chief of the Department of Clinical Pathology and Office of Human Use and Ethics at the Army Medical Research Institute of Infectious Diseases at Fort Detrick, Maryland, says "Civilians have autonomy. Medical volunteers in the army are given autonomy when they sign a consent form. The extra risk for medical volunteers (in addition to those inherent in the experiment) is that, after they participate in a trial, they could become medically unqualified (to serve in the army)." Discuss how the problems and issues associated with volunteering differ for civilians and soldiers.
  10. From 1954 through 1974, the U.S. Army used members of the Seventh-Day Adventist Church as medical volunteers. The church does not approve of combat but does believe in community service. Through collaborative agreements hammered out by the leaders of the church and the military, some 2300 volunteers participated in about 150 experiments. Only two people ever lodged complaints that they had been harmed as a result of their participation. Today, the army still has a small number of medical volunteers, called MRVs (medical research volunteers), who work in labs and occasionally volunteer to participate in clinical trials. Their only obligation is to attend information sessions for upcoming experiments; they never have to participate in a study. What might be reasons that soldiers agree to join studies? Why might they decide not to? Why would soldiers volunteer for this type of duty?


Topics for Discussion/Written Assessment

  1. How do mosquitoes transmit diseases?
  2. What other infectious agents do mosquitoes transmit besides the yellow fever agent?
  3. What is the "second host" for an infectious organism? What is the "natural history" of an infectious disease?
  4. Paul De Kruif wrote about Walter Reed's yellow fever experiments in his book The Microbe Hunters.
  5. "Walter Reed let it be known to the American soldiers in Cuba that there was another war on, a war for the saving of men-were there men who would volunteer? Before the ink was dry on the announcements Private Kissenger of Ohio stepped into his office, and with him came (civilian clerk) John J. Moran?"You can try it on us, sir!" they told him. Walter Reed was a thoroughly conscientious man. "But, men, do you realize the danger?" And he told them of the headaches and the hiccups and the black vomit. ..."We volunteer solely for the cause of humanity and in the interest of science." Then Walter Reed told them of ? the handsome sum they would get ? "The one condition on which we volunteer, sir," (they) said, "is that we get no compensation for it." ? Then great days came to Reed and Carroll and Agramonte-for, if they weren't exactly overrun with young Americans who were ready to throw away their lives in the interest of science-and for humanity, still there were ignorant people, just come to Cuba from Spain, who could very well use two hundred dollars. ? "Spanish immigrants," or I could call them Man 1, 2, 3, and 4-just as microbe hunters often mark animals: "Rabbit 1, 2, 3, and 4-" anyway ? they earned their two hundred dollars ? If they hadn't been ignorant immigrants-hardly more intelligent than animals, you might say-they might have been bored, because nothing had happened to them excepting the stabs of silver-striped she-mosquitoes ? " (pages 296-297).
  6. Comment on DeKruif's style of writing about the various 'players'-Reed, the soldiers, and the Spanish immigrants. How respectful was he of each group?
  7. How voluntary is the 'consent' likely to be of prisoners who agree to be in clinical trials? In 1951, Dr. Albert Kligman treated some patients for athlete's foot at Pennsylvania's Holmesburg prison. At the time, the prison housed some 1200 prisoners. "I began to go to the prison regularly," said Kligman, "although I had no authorization. It was years before the authorities knew that I was conducting various studies on prisoner volunteers. Things were simpler then. Informed consent was unheard of. No one asked me what I was doing. It was a wonderful time." Kligman was studying how various agents (including probably LSD, sunscreens, dyes, and isotopes) affected, protected, and/or penetrated the skin. "All I saw before me were acres of skin. It was like a farmer seeing a fertile field for the first time." What happens when the subjects of experiments are objectified in the way that Kligman objectified the prisoners? Kligman continued his experiments at Holmesburg for 30 years. Said one volunteer: "Many (prisoners) compromised the experiments" (by taking the soaked patches off their skin when they went to their cells). "Those doctors were running a game on us, so we ran a game on them." What was wrong with Kligman's approach? How reliable are the data, considering that the prisoners were not interested in compliance?
  8. What reasons would you give for volunteering for medical research? What reasons would you give for not volunteering?
  9. Have you ever participated in medical research? If so, what was the experiment and what happened? Design an experiment in which you would be willing to be a subject.
  10. When the members of the yellow fever commission decided to experiment on themselves, what reasoning and principles guided their decisions?
  11. What are the steps in the review process for medical experimentation?
  12. Should self experimentation be subjected to the same review process as experiments on others? Why?
  13. When volunteers agree to participate in a study, they are asked to sign a consent form, which outlines the purpose, design, risks and benefits, and possible outcomes of the experiment. What responsibilities do researchers have to make sure that volunteers are truly informed about the experiment? How can they find out if the subjects really understand what they are volunteering to do?

Extension Questions for Further Investigation

  1. Is self experimentation a good or bad idea? Why? What about experiments on lab workers, nurses, doctors, and others who are familiar with the experiments? What are the advantages of using those who are knowledgable about the studies? What are the disadvantages?
  2. What other examples of self experiments can you find? What happened in each case? From your research, what advantages and disadvantages do you see in self experimentation?
  3. What other infectious agents do mosquitoes transmit besides the agent that causes yellow fever?
  4. Sometimes transmission of a disease-causing agent by an insect vector involves a second host. What organisms are transmitted this way? What diseases do they cause? What happens to the agent of disease in each host animal?
  5. What are Koch's Postulates? How do Koch's Postulates prove that a given organism causes a given disease?
  6. In what areas of the world is yellow fever still a problem?
  7. Why was yellow fever endemic in Cuba but not present at all 90 miles north in the United States?
  8. What are the differences between diseases that are endemic and those that are epidemic?
  9. Walter Reed never actually participated in the yellow fever studies, even though he had agreed to along with his colleagues. Find out what Reed was doing when the others were being bitten by mosquitoes.
  10. In 1999, U.S. Air Force Major Sonnie Bates refused to be vaccinated against anthrax. Bates cited a rise in unusual symptoms and illnesses (bone and joint pain, memory loss, thyroid damage, liver damage, cysts around the heart, autoimmunity) in members of his squadron after they began taking the shots. Anthrax is a deadly disease that is considered a likely component of biological weaponry. By 2000, Bates was facing a court martial. Examine the subsequent events in the case.
  11. Tuberculosis has become a major public health problem in recent years. Under what circumstances, if any, would it be appropriate to quarantine those with the disease who do not agree to take their medicines and therefore are endangering the health of others?
  12. Under what circumstances, if any, would you find it appropriate to waive the informed consent requirements in a clinical trial?

Topics for Teacher Preparation

  1. How mosquitoes transmit the agents of disease
  2. Informed consent
  3. Host animal
  4. Insect vector
  5. Rights of volunteers in medical experiments
  6. Cause of yellow fever
  7. Endemic disease
  8. Epidemic disease

https://highschoolbioethics.georgetown.edu/units/cases/unit3_5.html


The Yellow Fever Vaccine: A History

After failed attempts at producing bacteria-based vaccines, the discovery of a viral agent causing yellow fever and its isolation in monkeys opened new avenues of research. Subsequent advances were the attenuation of the virus in mice and later in tissue culture; the creation of the seed lot system to avoid spontaneous mutations; the ability to produce the vaccine on a large scale in eggs; and the removal of dangerous contaminants. An important person in the story is Max Theiler, who was Professor of Epidemiology and Public Health at Yale from 1964-67, and whose work on virus attenuation created the modern vaccine and earned him the Nobel Prize.

Keywords: yellow fever, vaccine, history, cell culture, Theiler

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892770/


VACCINE

YELLOW FEVER VACCINE
YF-VAX® 

DESCRIPTION 
YF-VAX®, Yellow Fever Vaccine, for subcutaneous use, is prepared by culturing the 17D-204 strain of yellow fever virus in living avian leukosis virus-free (ALV-free) chicken embryos. The vaccine contains sorbitol and gelatin as a stabilizer, is lyophilized, and is hermetically sealed under nitrogen. No preservative is added. The vaccine must be reconstituted immediately before use with the sterile diluent provided (Sodium Chloride Injection USP – contains no preservative). YF-VAX vaccine is formulated to contain not less than 4.74 log10 plaque forming units (PFU) per 0.5 mL dose throughout the life of the product. YF-VAX vaccine is a slight pink-brown suspension after reconstitution.

http://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM142831.pdf

http://www.biomedcentral.com/1471-2334/14/391

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