YELLOW FEVER

YELLOW FEVER

Current Diagnosis

• Yellow fever is a historically important mosquito-borne Flavivirus with high morbidity and mortality.

• Travel to yellow fever–endemic areas in Sub-Saharan Africa and tropical Central and South America is the essential risk factor.

• Symptoms may include abrupt onset of fever, relative bradycardia, headache, and, if severe, jaundice, hemorrhage, and multiorgan failure.

•   Diagnosis is with viral culture and serologic tests.

• Although infectious disease experts consider it improbable that yellow fever outbreaks will return to the continental United States, this reemerging disease is threatening to become more prevalent and deadly in tropical South America and Africa. Travel-related cases should be anticipated in the United States and its territories, as well as the possibility of brief episodes of local dissemination in areas bordering the Gulf of Mexico, where the vector, the Aedes aegypti mosquito, can be found.

Current Therapy

• Prevention is key and accomplished by vaccination and mosquito avoidance and control.

•   Supportive care is the only treatment.

Epidemiology

Yellow fever is one of the great epidemic diseases of tropical Africa and the Americas. It receives its appellation “yellow” from the symptom of jaundice, which appears in severe disease, and it is caused by an RNA virus, specifically a Flavivirus (a family name derived from yellow fever, with flavus Latin for yellow), that is held in natural reservoirs by forest monkeys and spread to people via mosquitoes. The disease, termed an acute hemorrhagic fever, infects humans, all species of monkeys, and certain other small mammals and is transmitted among its hosts by several species of mosquitoes.

There are three types of yellow fever infection: urban, jungle, and intermediate. In urban or classical yellow fever, human-to-human spread occurs by the bite of the A. aegypti mosquito, which breeds in urban unpolluted water and bites principally in the daytime.

Reinvasion of this mosquito in Central and South America has occurred beginning in the 1970s owing to increases in breeding sites resulting from urbanization and the collapse of vector control efforts. In jungle or sylvatic yellow fever, which was first recognized in 1933, the disease is perpetuated by enzootic infection of mammalians, usually monkeys, disseminated by several different mosquitoes: in South America via the Haemagogus and Sabethes spp.; in East Africa via Ae. africanus; and in West Africa via a variety of species of Aedes.

Human infection arises by jungle exposure to these mosquitoes. In intermediate or savannah yellow fever, which commonly occurs in Africa, the virus disseminates from mosquitoes to humans residing or working in areas bordering jungles. This cycle also involves spread of the virus from monkey to human or from human to human via the bite of a mosquito.

Yellow fever, also termed Yellow Jack, the Saffron Scourge, fievre jaune, Bronze John, and Black Vomit (the Spanish name is vómito negro), is the deadliest arthropod virus ever to emerge in the Americas. Both the molecular taxonomic research of viral strains and the annals of history reveal an African origin. Most authorities assert it was introduced to the new world by A. aegypti–infested slave ships voyaging from West Africa, with its first recognition in the Americas occurring in Yucatan, Mexico, in 1648 (although research suggests the disease was present in the Americas as early as 1498). Over the next two and a half centuries, yellow fever erupted with regularity in American and European port cities, with hundreds of thousands of deaths, earning the virus deserved recognition as one of the worst plagues the world had ever seen. Two of the most significant North American epidemics occurred in Philadelphia in 1793 and in the Mississippi Valley in 1878. American epidemics were the result of the introduction of the mosquito vector and infected humans along routes of trade, especially sea and river ports and rail lines, with particular virulence associated with the Gulf region where A. aegypti resided.

Early attempts at control focused on quarantine and sanitary measures. The devastation associated with American epidemics was an important impetus in the nation’s early public health and sanitation movements for the creation of city, state, and national boards of health.

Although two 19th-century physicians, Josiah Nott and Carlos Juan Finlay, suggested the mosquito was the infectious agent for yellow fever, it was not until 1900 that the work of the U.S. Army Commission in Cuba under Major Walter Reed established that the vector of the urban form of this disease was the A. aegypti mosquito, with its viral cause not established until after 1928. Max Theiler developed an attenuated vaccine strain in 1937, which was recognized with a Nobel Prize. In what is recognized as one of the most successful campaigns in history against infectious disease, mosquito eradication and control efforts and this vaccine effectively controlled and eliminated urban yellow fever in the Americas and the West Indies, with the last large outbreak occurring in the continental United States in New Orleans in 1905. However, the disease persisted in its jungle form in forest areas in Africa and South America. Vaccine administration remains incomplete in endemic areas and outbreaks periodically recur. As well, mosquito eradication efforts in both the Americas and Africa have recently slackened, with the resulting resurgence of A. aegypti into nearly all of the tropical American countries, placing this region at extraordinary risk for urban outbreaks. Also, while only travel-related cases have been documented in Asia, theoretic anthroponotic dissemination could also take place there in the many areas where the urban vector resides.

Official statistics suggest the incidence of yellow fever fluctuates, with 90% of the 200,000 annual cases reported in Africa. However, authorities warn that these statistics considerably underestimate (owing to underreporting) the true magnitude of epidemics, which field studies estimate as 50 times greater. A frightening prospect associated with failing mosquito control in urban habitats is the potential reemergence of yellow fever similar to the recent rapid resurgence of dengue, which is also transmitted by the vector A. aegypti. Experts contend that one of the most profound mysteries of tropical medicine is that this dangerous virus has not emerged more frequently where a susceptible, unimmunized human population and the vector density coexist. However, since the 1980s, a resurgence of yellow fever has been seen across South America and Africa, which augurs potential risk for the United States. While yellow fever outbreaks remain unlikely in the Unites States, travel-related cases should be expected, as well as the possibility of brief urban cycle transmission in the American Southeast.

The 2015–2017 outbreaks in Brazil and Africa portend ominously that yellow fever appears to be moving from its typical rural setting toward urban areas. A large urban outbreak in Angola, which began in December 2015 and subsequently spread to the Democratic Republic of the Congo, resulted in 961 confirmed cases and 137 deaths and included multiple travel-related cases appearing in nonendemic areas internationally such as China. The outbreak in Brazil was first recognized in December 2016, with more than 1500 cases and 241 deaths noted as of March 9, 2017.

In response to yellow fever’s reemergence in Africa, the World Health Organization (WHO) launched the Yellow Fever Initiative in 2006, vaccinating in mass campaigns more than 105 million people in West Africa and attempting to secure a global vaccine supply.

Yellow fever remains the most dangerous arbovirus ever to inhabit the Western Hemisphere. Despite ongoing vaccination and mosquito control efforts in endemic areas, sylvatic and intermediate transmission cycles persist and appear to be expanding toward urban spread. Public health leaders encourage clinicians to utilize heightened suspicion and awareness for the virus, especially among travelers to tropical areas. Recent yellow fever outbreaks underscore boldly the potential threat this disease poses for the international community.

Risk Factors

Travel to yellow fever–endemic areas in Sub-Saharan Africa and tropical Central and South America, between the 15th parallel north and the 15th parallel south, is the essential risk factor.

Pathophysiology

Yellow fever virus has three types or cycles of transmission: urban, jungle (sylvatic), and intermediate (savannah). In urban yellow fever, the virus is spread by the bite of an A. aegypti mosquito infected about 2 weeks previously by feeding on a person with viremia. In jungle (sylvatic) yellow fever, the virus is transmitted by various forest canopy mosquitoes that acquire it from wild primates and then disseminate it to humans who are visiting or working in the jungle.

Incidence of the disease is highest during months of peak temperature, rainfall, and humidity in South America and during the late rainy and early dry seasons in Africa. In the intermediate (savannah) cycle, which is most common in Africa, transmission of the virus to humans results from humans living or working in jungle border areas, with the virus spread from monkey to human or from human to human by mosquitoes. Humans infected with the virus are infectious to mosquitoes (what is termed being “viremic”) shortly before the onset of illness and up to 5 days after onset. Yellow fever is not transmissible by contact, only via a vector’s bite.

Prevention

Yellow fever is a mosquito-borne infection that can be prevented by mosquito avoidance and vaccination. Recovery from yellow fever imparts lifelong immunity against the virus.

Mosquito control is an essential component of any strategy to prevent the spread of yellow fever. Before the development of the vaccine and after the mosquito was proven as the vector, eliminating mosquito-breeding sites and decreasing exposure to A. aegypti mosquitoes proved successful in ending yellow fever outbreaks in North America and also in the building of the Panama Canal. Today, it remains critical not only to reduce the number of mosquitoes through larvicides and insecticides but also to limit mosquito bites through the use of house screening, mosquito netting, the wearing of protective attire, and the use of insect repellants such as diethyltoluamide (DEET). During jungle outbreaks, mosquito elimination is impractical and evacuation is essential until individuals are immunized and mosquitoes controlled. To prevent further mosquito transmission during outbreaks, infected patients should be isolated in well-screened rooms sprayed with insecticides.

Immunization is the most effective and reliable way to prevent yellow fever in areas in which it is endemic. Live attenuated yellow fever virus vaccine (17D strain) (YF-VAX) should be given (0.5 mL subcutaneously every 10 years) at least 10 days before travel to endemic areas in Africa and Central and South America. A single dose of vaccine gives greater than or equal to 99% protection and confers lifelong immunity. (Although required by some countries, a booster dose of the vaccine is not medically needed.) Although infection is uncommon in most of the endemic areas, vaccination is legally required for entry into many of these countries. The typically well- tolerated vaccine is contraindicated in pregnant women, in individuals with concurrent febrile illness or compromised immunity, and in infants younger than 6 months. If infants aged 6 to 8 months cannot avoid travel to a high-risk location, parents should discuss immunization with their physician since the vaccine is usually not offered until the age of 9 months. In the United States, the vaccine is given only at US Public Health Service–authorized Yellow Fever Vaccination Centers. The International Certificate of Vaccination is valid for 10 years from 10 days after immunization or immediately after reimmunization.

Clinical Manifestations

Yellow fever is characterized by the swift onset of fever, rigors, myalgias, headache, nausea, and vomiting. With an incubation period lasting 3 to 6 days, the illness is typically biphasic, with a two-stage course during which the pulse slows and kidney involvement occurs along with bleeding disorders. Between 5% and 50% of the cases are so mild they are inapparent. In those cases recognized, the pulse is usually rapid initially but by the second day becomes slow for the degree of fever (Faget sign). A tendency to bleed may be seen early in the disease. Often, the face is flushed, with facial edema and conjunctival injection. Restlessness, irritability, and leukopenia are also common. In most cases, this initial period of mild infection resolves after 1 to 3 days, occasionally longer, and the illness concludes with rapid recovery and no sequelae. However, approximately 15% of those infected progress further into the moderate to severe phases. In these cases, the falling fever and remission of symptoms 2 to 5 days after onset are only transitory, and a deadly phase soon begins with renewal of malignant symptoms.

This stage of the illness, called intoxication, is marked by the fever returning, and although the pulse remains slow, the blood pressure drops with resultant renal failure. The flushed face is replaced by a dusky pallor, with swollen, bleeding gums and a pronounced hemorrhagic tendency with telltale black vomit (one of the disease’s monikers and classic symptoms) and melena. The skin and eyes may appear yellow (jaundice), the symptom that gave rise to the disease’s popular name. (However, this jaundice is generally a symptom of convalescence more than acute disease.) Liver and renal failure (which may progress to acute tubular necrosis) and epigastric tenderness with hematemesis and gastrointestinal hemorrhage often occur. There may be oliguria, albuminuria, disseminated intravascular coagulopathy, backache, dizziness, ecchymoses, myocarditis, agitated delirium, intractable hiccups, seizures, coma, and multiple organ failure. During recovery, bacterial superinfections, particularly pneumonia, may occur.

In terminal cases, death usually transpires within 7 days of onset and is rare beyond 10 days of illness. In patients with intoxication (malignant yellow fever), a 20% to 50% mortality may be seen, with survival depending on the quality of supportive management. At autopsy, the kidneys, liver, heart, and spleen appear to be the organs most impacted by the disease.

Diagnosis

Yellow fever is suspected in patients in endemic areas or returning from them if they develop classic clinical features such as sudden fever with relative bradycardia and jaundice. Mild infection often escapes recognition by the patient or clinician. Complete blood count, urinalysis, liver function tests, coagulation studies, viral blood cultures, and serologic tests should be done. Leukopenia with relative neutropenia is common, as are thrombocytopenia, prolonged clotting, and increased prothrombin time. Bilirubin and aminotransferase levels may be elevated acutely and for several months. Albuminuria, which occurs in 90% of patients, may reach 20 g/L. This finding helps differentiate yellow fever from viral hepatitis. In malignant yellow fever, hypoglycemia and hyperkalemia may occur terminally.

Diagnosis is confirmed by viral culture, serology, the identification of viral antigens and virus-specific immunoglobulin M (IgM) and neutralizing antibodies in serum by several rapid diagnostic methods, or detecting characteristic midzonal hepatocyte necrosis at autopsy.

Suspected or confirmed cases must be quarantined and health departments notified. Needle biopsy of the liver during illness is contraindicated because of high risk of hemorrhage.

Differential Diagnosis

Mild yellow fever appears clinically like a broad expanse of other infections presenting with similar symptoms, including dengue, viral hepatitis, malaria, typhus, Q fever, typhoid, Rift Valley fever, leptospirosis, drug-induced syndromes, and toxic causes. Yellow fever may be distinguished from malaria by the findings of conjunctival suffusion or relative bradycardia. The other viral hemorrhagic fevers, which include dengue, Lassa fever, Marburg disease, Ebola, Crimean- Congo hemorrhagic fever, and Bolivian and Argentine hemorrhagic fevers, usually present without jaundice. As well, albuminuria is a reliable hallmark of yellow fever that allows its differentiation from other causes of viral hepatitis.

Treatment

Since no antiviral therapy is currently available, treatment is supportive, focused on aggressive symptom management designed to correct the acid-base imbalance and electrolyte abnormalities caused by emesis, heart failure, and renal derangements. Placement in an intensive care unit is recommended. Transfusions of blood, fresh- frozen plasma, and vitamin K1 may be utilized with hemorrhagic symptoms. As well, a proton pump inhibitor, H2 blocker, and sucralfate (Carafate)1 can be helpful as prophylaxis for gastrointestinal bleeding and should be considered in all hospitalized patients.

Antipyretics, oxygen, vasopressors, and IV hydration may also be helpful. Avoidance of sedatives and drugs metabolized hepatically is prudent, and medication dosing should be adjusted in the face of declining renal function. Antibiotic therapy for secondary bacterial sepsis is often necessary during the recovery period. Owing to the increased risk of bleeding, avoidance of aspirin and other nonsteroidal antiinflammatory drugs, such as naproxen and ibuprofen, is recommended.

Complications

The majority of those infected with yellow fever will be asymptomatic or experience only mild disease with total recovery. The mortality rates in tropical America range from 45% to 75%, compared with less than 30% in Africa. This difference suggests genetic factors play a role in the course of the illness, as well as the viral strain. The convalescence of a yellow fever patient is usually prolonged and varies from patient to patient. Although uncommon, late death (weeks after the acute illness) can occur as a result of cardiac complications or renal failure. Profound asthenia and fatigue usually last for 1 to 2 weeks, but in some cases can last many months. Jaundice and the elevation of liver enzymes have been known to last an extended period (several months) during convalescence. Survival of an attack imparts lifelong immunity against subsequent infection.

References

1.     Bennett J.E., Dolin R., Blaser M. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: Elsevier Saunders; 2015.

2.    Centers for Disease Control and Prevention. Yellow fever. Available at: https://www.cdc.gov/yellowfever/index.html [accessed April 30, 2017].

3.     Deo M.G. Tropical Molecular Medicine. New Delhi: Oxford University Press; 1999.

4.    Ellis J.H. Yellow Fever and Public Health in the New South. Lexington, KY: University Press of Kentucky; 1992.

5.     Evans A.S., Kaslow R.A. Viral Infections of Humans: Epidemiology and Control. 4th ed. New York: Plenum Medical Book Company; 1997.

6.      Fauci A.S., Paules C.I. Yellow fever—Once again on the radar screen in the Americas. N Engl J Med. 2017;376:1397–1399.

7.    Kimberlin D.W., ed. Red Book: 2015 Report of the Committee on Infectious Diseases. 13th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015.

8.    Knipe D.M., Howley P. Fields Virology. 5th ed. Philadelphia: Lippincott Williams and Wilkins; 2007.

9.       Mahy B.W., ter Meulen V. Topley Wilson’s Microbiology and Microbial Infections. 10th ed. London: Hodder Arnold; 2005.

10.       Porter R.S. The Merck Manual of Diagnosis and Therapy. 19th ed. Whitehouse Station, NJ: Merck Sharp and Dohme; 2011.

11.    Wilks D., Farrington M., Rubenstein D. The Infectious Diseases Manual. 2nd ed. Oxford, UK: Blackwell Science; 2003.

12.       World Health Organization. Yellow fever factsheet. Available at: http://www.who.int/mediacentre/factsheets/fs100/en/ [accessed May 20, 2017].

1  Not FDA approved for this  indication.

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