Introduction
Background
Yellow fever was first recognized in an outbreak occurring in the New World in 1648. It is a member of the flavivirus family (group B arbovirus). The Flavivirus genus is composed of more than 68 arthropod transmitted viruses, of which 30 are known to cause human disease. Other flaviviral infections include dengue, Japanese encephalitis, and tick-borne encephalitis. It is important to consider this group of viruses in the clinical differential of CNS infection, hemorrhagic fever, and acute febrile illnesses with arthropathy.
It is surmised that the yellow fever virus most likely was introduced by slave-trading vessels from West Africa infested with Aedes aegypti (mosquito), with similar outbreaks occurring in port cities in the New World and in Europe. Sanitation measures, such as piped water, greatly diminished the transmission of the disease. The viral cause of yellow fever was not discovered until after 1928, which led to Theiler's discovery of the attenuated 17D vaccine strain in the 1930s that earned him a Nobel Prize.
Despite the effectiveness of this vaccine, outbreaks continue to recur periodically because of the fragmentary vaccine implementation in many areas.
Pathophysiology
The pathophysiology of yellow fever infection was largely inferred from vaccine studies in rhesus monkeys using the attenuated 17D vaccine. After inoculation in rhesus monkeys, the virus replicated initially in local lymph nodes, followed by blood-borne spread and subsequent replication mostly occurring in regional lymph tissue, spleen, and bone marrow followed by the liver, lung, and adrenal glands.
The liver and kidneys demonstrate the greatest degree of pathologic changes. Hemorrhage and erosion of the gastric mucosa lead to hematemesis popularly known as "black vomit." Hepatocellular damage is characterized by lobular necrosis with the subsequent formation of Councilman bodies. Albuminuria and renal insufficiency evolve secondary to the prerenal component of yellow fever, ultimately leading to acute tubular necrosis with advanced disease. Fatty infiltration of the myocardium, including the conduction system, can lead to myocarditis and arrhythmias.
CNS findings can be attributed to cerebral edema and hemorrhages compounded on metabolic disturbances. The bleeding diathesis of this disease can be attributed to reduced hepatic synthesis of clotting factors, thrombocytopenia, and platelet dysfunction. The terminal event of shock can be attributed to a combination of direct parenchymal damage and a systemic inflammatory response.
Frequency
United States
The last epidemic of yellow fever in North America occurred in New Orleans in 1905 during which more than 3000 cases were met with 452 deaths. Because Aedes aegypti (see Physical) now has reinfested the southeastern United States, autochthonous transmission in the United States is possible.
International
Yellow fever transmission predominately occurs in areas of sub-Saharan Africa and South America 15° north and 10° south of the equator. It has never been documented in Asia. Yellow fever epidemics were dominant in Africa from 1986-1991, with close to 20,000 cases and 6000 deaths. This is considered to be grossly underestimated because of underreporting. These epidemics commonly include 30-1000 cases and have fatality ratios of 20-50%. In areas of West Africa, 200,000 endemic cases may occur annually. In South America, an annual mean of 100 cases has been reported for the last 25 years. These cases predominate from January to March among males aged 15- 45 years who work outdoors in agriculture and forestry. The last outbreak in the western hemisphere occurred in 1954 in Trinidad. Yellow fever's range continues to expand, now including areas in which it previously was believed to be eradicated (eg, eastern and southern African countries).
In South America, sporadic infections occur almost exclusively in forestry and agricultural workers from exposure in or near the forests. In Africa, the virus is transmitted in 3 geographic regions: West and Central Africa savanna zones during the rainy season, urban locations and villages in Africa, and, to a lesser extent, the jungle regions.
Mortality/Morbidity
Yellow fever ranges in severity from a self-limited infection to hemorrhagic fever that carries a 50% mortality rate. Fatality rates are higher in the young. Early appearance of jaundice (day 3) indicates a poor prognosis. Transaminase elevations reflect the degree of hepatic injury and are prognostic. Individuals who survive the toxic phase may experience renal failure. Convalescence with symptoms of weakness and fatigue may last up to 3 months.
Sex
Jungle yellow fever is most common among healthy young males as a result of occupational risk.
Clinical
History
To arrive at a diagnosis, consider the patient's clinical features and their places and dates of travel, including the epidemiologic history of the places visited, immunizations, and activities.
- An incubation period of 3-6 days indicates that travelers may be viremic before demonstrating symptoms.
- Clinical symptoms manifest in 1 in 20 partially immune patients and 1 in 5 immunologically naïve patients.
- Initial symptoms, listed below, correspond to the viremic phase (period of infection) and are followed by a transient (up to 24 h) remission.
- Fever and chills
- Severe headache
- Back pain
- Myalgia
- Nausea
- Prostration
- The toxic phase (ie, period of intoxication) of yellow fever develops as the fever returns.
- Clinical symptoms include high fever, headache, lumbosacral back pain, nausea, vomiting, abdominal pain, and somnolence.
- Hepatic-induced coagulopathy produces hemorrhagic manifestations, including the characteristic black vomit (hematemesis), epistaxis, gum bleeding, and petechial and purpuric hemorrhages.
- Systemic manifestations include deepening jaundice and albuminuria.
- In the late stages of disease hypotension, shock, metabolic acidosis, acute tubular necrosis, myocardial dysfunction, and arrhythmia dominate the picture.
- Confusion, seizure, and coma distinguish the late CNS manifestations of the disease. Death usually follows within 7-10 days of onset.
- Secondary bacterial infections are frequent complications in patients who survive the critical period of illness.
Physical
- Altered mental status
- Fever
- Relative bradycardia (Faget sign)
- Conjunctival injection
- Other physical findings such as jaundice occur as disease progresses
Causes
- Two types of yellow fever exist, the jungle type and the urban type.
- In jungle yellow fever, Haemagogus mosquitoes in South America and Aedes africanus in Africa acquire the disease from monkeys, which serve as hosts for the virus.
- Mosquitoes then bite and infect humans, usually young men engaged in forestry or agricultural activities.
- This results in sporadic outbreaks in South America and Africa.
- In urban yellow fever, humans serve as viremic hosts and the disease is spread between humans by the domestic mosquito vector, A aegypti.
- Because of widespread control of this vector in the 1930s, urban yellow fever has become uncommon.
- However, these mosquitoes recently reinvaded South America; thus, the potential for transmission exists.
- In jungle yellow fever, Haemagogus mosquitoes in South America and Aedes africanus in Africa acquire the disease from monkeys, which serve as hosts for the virus.
More on Yellow Fever |
 Overview: Yellow Fever |
| Differential Diagnoses & Workup: Yellow Fever |
| Treatment & Medication: Yellow Fever |
| Follow-up: Yellow Fever |
| References |
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References
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Stephen EL, Sammons ML, Pannier WL, et al. Effect of a nuclease-resistant derivative of polyriboinosinic- polyribocytidylic acid complex on yellow fever in rhesus monkeys (Macaca mulatta). J Infect Dis. Jul 1977;136(1):122-6. [Medline].
Tsai, Theodore. Flaviviruses (Yellow Fever, Dengue, Dengue Hemorrhagic Fever, Japanese Encephalitis, St. Louis Encephalitis, Tick-Borne Encephalitis). Principles and Practice of Infectious Diseases. 2:1714-1733.
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Further Reading
Keywords
Flavivirus, Aedes aegypti, group B arbovirus, Theiler, attenuated 17D vaccine, yellow fever, flaviviral infections, dengue, Japanese encephalitis, tick-borne encephalitis, CNS infection, hemorrhagic fever, acute febrile illnesses with arthropathy
