WHAT'S NEW THIS THURSDAY: YELLOW FEVER OUTBREAK IN SUDAN

Wednesday, 27th of February 2013

• YELLOW FEVER OUTBREAK IN SUDAN

Lewis Markoff, M.D.

N Engl J Med 2013; 368:689-691February 21,  2013

Best viewed at http://www.nejm.org/doi/full/10.1056/NEJMp1300772?query=TOC&

On November 16, 2012, the Weekly Epidemiological Record of the World Health Organization (WHO) reported that an outbreak of yellow fever was under way in Sudan. By the end of November, the disease had been detected in 26 localities in Sudan's Darfur region, with 459 suspected cases and 116 related deaths.1 As of January 16, the Centers for Disease Control and Prevention (CDC) confirmed that 849 cases and 171 deaths had been reported.2

Since most suspected cases have occurred in Central, South, and West Darfur, Sudan's Federal Ministry of Health (supported by international partners) began a mass vaccination campaign in that region on November 20 in 12 highly affected localities with a total population of 2.2 million. The CDC is advising visitors to Sudan to receive the yellow fever vaccine in advance of travel to the area and to take precautions to avoid contact with mosquitoes while there.

Yellow fever virus is perhaps the most virulent and pantropic flavivirus, a genus that also includes dengue, West Nile, Japanese encephalitis, and tickborne encephalitis viruses, all of which are also arthropod-borne. In the first or acute phase of yellow fever disease, viremia is present. Symptoms include fever, severe muscle pain, headache, chills, anorexia, and nausea or vomiting. Physical examination reveals relative bradycardia, and laboratory findings include leukopenia, neutropenia, elevated liver-enzyme levels, and proteinuria.

Most patients recover after 3 to 6 days, but 15 to 25% enter a more toxic second phase within 24 hours after an initial remission. High fever returns. An acute fulminant hepatitis develops, with rapid deterioration of liver function heralded by jaundice. Severe abdominal pain may be accompanied by vomiting. Bleeding can occur anywhere in the gastrointestinal tract, resulting in hematemesis and hematochezia or melena. Petechiae and ecchymoses are seen secondary to a clotting disorder. Kidney function deteriorates, myocarditis occurs, and encephalopathy with stupor or coma may follow. Viremia is usually absent during this phase. Hypotension and shock with disseminated intravascular coagulation may be aggravated by cytokine dysregulation and bacterial sepsis. Half of patients who enter the toxic phase die within 10 to 14 days. The rest recover without clinically significant organ damage. Naturally acquired infection confers lifelong protection against disease.

Yellow fever is difficult to diagnose clinically. In Africa, the early phase is often confused with chikungunya or dengue fever. In the second stage, it can be confused with severe malaria, dengue hemorrhagic fever, leptospirosis, other types of acute fulminant viral hepatitis, and other viral hemorrhagic fevers. Neutralizing antibodies elicited by yellow fever infection may show cross-reactivity to other flaviviruses in diagnostic laboratory assays. Therefore, in regions where two or more flaviviruses circulate, diagnosis depends on the detection of IgM antibodies in serum or the detection of viremia, either by virus isolation or by reverse-transcriptase polymerase chain reaction. In 40 of the 732 suspected cases that had occurred by early December in the current outbreak, the presence of yellow fever infection was confirmed by one of these methods.3

Although an effective yellow fever vaccine has been available for more than 70 years, the disease remains endemic in tropical areas of South America and Africa. Failure to eradicate the disease in these regions can be attributed to several factors, including the sylvatic (forest) life cycle of the virus and intermittent or absent vaccination campaigns, especially in politically unstable and economically disadvantaged African countries. The WHO estimates that 200,000 cases of yellow fever and 30,000 related deaths occur annually worldwide. Ninety percent of these cases occur in sub-Saharan Africa (see map Yellow Fever Risk in Africa.).

Periodic outbreaks of disease are particularly common in East Africa. Substantial outbreaks of yellow fever occurred in this region almost every year between 1940 (when surveillance began) and 1956 (when there was an outbreak in Sudan). Since 1960, there have been well-documented major outbreaks in Ethiopia (1960–1962), Kenya (1992–1993), and Sudan (2003 and 2005).4 It is difficult to know the exact number of cases that occur in a country such as Sudan during the years between such outbreaks: the disease is not always recognized in its milder forms, and many suspected cases go unreported.

Three interrelated life cycles that depend on mosquitoes maintain the transmission of yellow fever virus in the areas where the disease is endemic: the sylvatic cycle, an intermediate cycle bridging the sylvatic and urban cycles, and an urban cycle. In the sylvatic cycle, the virus is transmitted from monkeys to mosquitoes that breed in tree holes in the forest canopy (haemagogus species in the Americas and aedes species in Africa). Humans living in savannas adjacent to the high-density forests where the sylvatic cycle occurs are exposed to tree-hole–breeding mosquitoes. Among other vectors that participate in the sylvatic cycle, Aedes africanus and Aedes bromeliae are also capable of transmitting the virus from monkeys to humans and from humans to humans. Thus, savannas are sometimes called the “zone of emergence.”

Some experts have theorized that epidemics recur in East Africa because its savanna is relatively dry, so the population density of tree-hole–breeding mosquitoes is lower than that in Central Africa's wetter savannas. Thus, the human population may be exposed to the virus less regularly than is the population of Central Africa,4 and large numbers of susceptible young persons, sufficient to seed an outbreak, may accumulate during the years between epidemics. Epidemiologic studies, in contrast, suggest that persistent “silent transmission” (without detectable disease outbreaks) may occur among inhabitants of the moister savannas of Central Africa, generating a type of herd immunity. Maintenance of yellow fever virus in the sylvatic and intermediate cycles is abetted by transovarial transmission from infected mosquitoes to their offspring and by the fact that monkeys remain mobile and active while viremic. An urban epidemic can be triggered when infected people travel from a savanna to a neighboring city. In the urban cycle, yellow fever is transmitted exclusively among infected humans by A. aegypti, a domestic aedes species that breeds in standing water. A. aegypti mosquitoes are also principal vectors for dengue and chikungunya.

Success of the large-scale vaccination program in Darfur will be defined by its capacity to prevent spread of disease to the major cities of Sudan and neighboring countries. Yellow fever 17D vaccines were derived more than 70 years ago from a Sudan isolate that was attenuated by serial passage in chick embryos. Two substrains, 17D-204 and 17DD, have been in continuous use worldwide ever since, and approximately 500 million doses have been dispensed. A single dose confers a protective antibody response within 10 days in 95% of vaccinees. Protection probably lasts for life, but the WHO requires a booster immunization every 10 years. Although 17D vaccines are historically regarded as very safe, rare serious adverse events temporally associated with vaccination have recently been documented. These have been classified as neurotropic or viscerotropic in nature. The cause is uncertain but appears to be host-dependent. In two instances, an aberrant innate immune response to the vaccine was implicated. An age of more than 60 years and a history of thymic dysfunction also confer an increased risk. In the United States, between 1990 and 2006, the yearly incidence of both syndromes was between 0.2 and 1.0 per 100,000 vaccinations in people younger than age 60 years, as compared with more than 3 per 100,000 in people older than 60 years.5 Because of this safety issue, the CDC recommends that yellow fever vaccine use be limited to persons traveling to known areas of risk for yellow fever.

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

This article was published on February 6, 2013, at NEJM.org.

Source Information

From the Laboratory of Vector-borne Virus Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD.

References

1 Yellow fever, Sudan -- update. Wkly Epidemiol Rec 2012;87:477-492

2 Centers for Disease Control and Prevention. Yellow fever in Sudan — travelers' health (http://wwwnc.cdc.gov/travel/notices/outbreak-notice/yellow-fever-sudan.htm).

3 World Health Organization. Yellow fever in Sudan — update (http://www.who.int/csr/don/2012_12_06/en/index.html).

4 Ellis BR, Barrett AD. The enigma of yellow fever in East Africa. Rev Med Virol 2008;18:331-346

5 Monath TP. Review of the risks and benefits of yellow fever vaccination including some new analyses. Expert Rev Vaccines 2012;11:427-448