Clinical Topics
Yellow Fever
Yellow Fever is a disease of much historical significance. It is first described in early Mayan records dating from 1648. The virus most likely originated in Africa and was exported to the new world as a result of the slave trade. The term yellow fever was first used during an epidemic in Barbados in 1750. During the eighteenth century it was recognized as a major human disease. In the United States, major epidemics occurred in the large port cities. In 1793, it is estimated that 10% of the population of Philadelphia succumbed to yellow fever. Thomas Jefferson stated that "yellow fever will discourage the growth of great cities in our nation." In 1802, Napoleon and 25,000 of his troops descended upon Haiti and only 3,000 survived the wrath of yellow fever. It was this event that convinced France to sell the Louisiana Territory to the United States. Napoleon felt it was a wasteland laden with disease and pestilence. The last outbreak of yellow fever in the USA occurred in New Orleans in 1905, resulting in 8,399 cases and 908 deaths.(1)
In 1881, Carlos J. Finlay, a Cuban physician, suggested that yellow fever was carried by a mosquito. In 1900, the United States, faced with annual epidemics that threatened the Mississippi valley and because the disease was seriously interfering with the construction of the Panama Canal, appointed an Army Investigative Board to study whether or not there was a mosquito/disease relationship. The Board consisted of Drs. Reed, Carrol, Agramonte and Lazear. During the course of this investigation, mostly done in Cuba, Carrol and Lazear allowed themselves to be bitten by mosquitoes which had previously fed on patients with yellow fever. Both men contracted the disease and Lazear died. In 1903 the board concluded that yellow fever was transmitted by the Aedes aegypti mosquito.(2) In 1927, in Africa, the virus was first identified. This led to a race for the development of a vaccine. In 1932 the French neurotropic vaccine was developed, but it was discontinued in 1982 because of cases of encephalitis followed vaccination. The 17D vaccination was developed by the Americans in 1936 and is still currently used today.
Epidemiology
Yellow Fever is now found only in Sub-Saharan Africa, the Amazonian region of South America, and occasionally in Trinidad. Africa accounts for around 90% of the cases. Yellow fever is grossly underreported due to unrecognized cases, unavailability of laboratory facilities to make the diagnosis, and poor surveillance. The WHO estimates that there are 200,000 cases a year with 30,000 deaths.(3) Yellow fever appears to be on the rise due to deforestation, urbanization, and the increases of global travel.
Life Cycle
The vector is the Aedes aegypti or Haemagogus mosquito. Vertical transmission occurs when the virus is passed on to the mosquito's ovum. This is advantageous for continuation of the life cycle during the dry season when the eggs may lay dormant. When the rainy season returns, the eggs hatch, allowing the virus to carry on. Horizontal transmission occurs when either an animal (typically monkeys) or humans are infected by the mosquito.
There are several different transmission cycles in yellow fever: sylvatic, intermediate, and urban. All three occur in Africa, but only sylvatic and urban occur in South America. Sylvatic (or jungle ) yellow fever occurs in tropical rainforests where monkeys are infected. Here humans are accidentally infected as a result of entering the forest. Intermediate yellow fever occurs in the humid or semi-humid savannahs of Africa where small epidemics occur in villages. Here mosquitoes infect both monkeys and humans at this zone of emergence. Urban yellow fever can occur in large epidemics where the virus is passed from human to human via the mosquito.
Pathology
Yellow Fever is the prototype of the flavivirus family. It is a small (40-60nm) single stranded RNA virus. There are several different genotypes of the virus, which vary based upon the geographic region. Lymphoid cells are the principal targets for early replication. During the viremia the Kupffer cells are seeded causing direct viral damage to the liver. The pathological findings of yellow fever in the liver are midzonal necrosis and Councilman bodies (eosinophilic intranuclear inclusions). It is not uncommon for damage also to occur to the kidneys and heart. Bleeding is the result of a hemorrhagic diathesis.
Clinical Presentation
The incubation period is usually 3 – 6 days, then symptoms of fever, malaise, headache, photophobia, nausea, vomiting, and irritability may occur. Physical examination at this time reveals a patient who is febrile, toxic in appearance and who has hyperemic skin, injected conjunctiva, coated tongue, and epigastric or hepatic tenderness. Faget's sign may be present, a relative bradycardia with a fever. After 3 to 5 days, either the patient recovers or goes onto the next stage of fulminate disease.
In fulminate disease there is significant hepatic injury with jaundice occurring, hence the name "yellow fever." Renal failure is not uncommon. A hemorrhagic diathesis may occur causing of epistaxis, oozing at the gums, petechiae, eccymosis, hematemesis: ("black vomit"), melena, hematuria, thrombocytopenia, and disseminated intravascular coagulation. Myocarditis, encephalopathy, and shock may also ensue. The case fatality rate is from 20% – 50%. If one survives, a full recovery can be expected.
The differential diagnosis of yellow fever includes leptospirosis, relapsing fever, malaria, typhoid, viral hepatitis (especially hepatitis E), Q fever, and other viral hemorrhagic fevers.
Diagnosis
The diagnosis of yellow fever can be very difficult in isolated cases; when epidemics occur physicians are vigilant to the disease and the diagnosis is generally made. In the tropics, the diagnosis is often a clinical one. A liver biopsy can be done looking for the pathological changes. However, the biopsy findings are not absolute and do not exclude the possible diagnosis. Moreover, liver biopsies in yellow fever can be associated with massive hemorrhage. In developed nations there are specialized laboratories that can assist in the diagnosis. In such facilities the diagnosis can be made by viral cultures, PCR, or preferably from ELISA tests looking for the IgM rise during acute infection.(4)
Treatment and Prevention
Treatment for yellow fever is supportive in nature. Preventive measures are several fold and include vector control, surveillance, and immunization. The 17D yellow fever vaccination is the only strain available. It is a live, attenuated vaccine and has several contraindications including: children under 9 months of age, pregnancy, and immunosuppression. The vaccine can only be administered by a designated yellow fever center. The vaccination dose is 0.5 ml given SC in the upper arm. Travelers should receive the vaccination at least 10 days prior to departure for effective immunity. International regulations require a booster every 10 years to enter or depart from endemic yellow fever regions.
Bibliography
Monath TP. Yellow Fever: A medically neglected disease. Report on a seminar. Reviews Infect Dis 1987;9(1):165
Cahill KM, O'Brien W. Tropical Medicine A Clinical Text. Mount Salus Press, Dublin ,1989, p104-105
World Health Organization, Yellow Fever Fact Sheet, WHO Fact Sheets 1999 August, #100
Guerrant RL, Walker DH, Weller PF. Tropical Infectious Diseases. Churchill Livingstone. Philadelphia 1999, p 1262
Q & A: Traveling Children
At the recent American Society of Tropical Medicine and Hygiene meeting in Houston, Texas, information about controversial issues affecting children was presented by three experts in pediatric travel medicine, Sheila Mackell, Karl Neumann and John Christenson. The material they presented is useful in formulating responses to common clinical questions. The meeting was chaired by Phil Fischer, who provide this summary of some of their discussions.
- Is mefloquine safe in children who have had a febrile seizure?
Mefloquine alters the seizure threshold. Consequently, travelers with seizure disorders are usually advised to use a prophylactic agent other than mefloquine. More than one percent of young children have simple febrile seizures (convulsions associated with fever in the absence of underlying pathology of the central nervous system) but do not go on to manifest epilepsy with a persistent risk of recurrent convulsive episodes. To date, there have not been reports of mefloquine-related seizures in individuals with histories of simple febrile seizures. Thus, mefloquine can probably be safety used in children who have had simple febrile seizures. An alternative chemoprophylactic agent would be used in children with histories of prolonged, focal, or recurrent seizures and in children who have had neurologic deficits associated with their seizures. - Should infants be retrained in safety seats on airplanes?
Data are limited, but anecdotal reports suggest that one serious injury or death might be prevented every 2 years by the universal in-flight use of infant restraints. Commonly used car seats, however, are not particularly designed to protect babies from the sorts of jarring forces that occur with turbulence and air crashes. Also, there is concern that the ticket cost of using airplane seats for infants in their restraints would prompt some families to travel by automobile rather than by airplane; car travel is linked to greater accident risk and death per mile than is air travel. Further study and the development of airplane-specific restraining seats can continue, and some families can use infant car seats on airplanes for the potential, yet costly, benefit they offer. Mandating universal use of infant restraints, however, is not currently appropriate. - When antibiotic therapy is indicated for the treatment of a child with traveler's diarrhea, which agent should be used?
The organisms causing traveler's diarrhea seem to be the same in children as in adults, and many of those germs are resistant to cotrimoxazole (trimethoprim-sulfamethoxazole). Thus, cotrimoxazole is no longer the antimicrobial of choice for traveling children with diarrhea. Azithromycin is effective against the common pathogens, is well-tolerated, and is available in a child-friendly liquid formulation. An alternative antibiotic, ciprofloxacin, is commonly used in adults but is not approved in some countries for pediatric use due to concerns about skeletal toxicity in experimental animals. Thousands of children, however, have used ciprofloxacin for serious infectious conditions and have not experienced untoward outcomes. Ciprofloxacin can be used for traveler's diarrhea in children, especially when other effective agents are not available.
