Study Traces Global Spread Of Virulent Dengue Virus To U.S. Doorstep

The study, which appears online this week in the journal Emerging Infectious Diseases, a publication of the U.S. Centers for Disease Control and Prevention, used viral genetics to comprehensively demonstrate the global movement of a virus associated with severe disease.

The particular dengue virus subtype has been responsible for epidemics of dengue hemorrhagic fever in Sri Lanka, East Africa and Latin America.

The illness is characterized by internal hemorrhage that sometimes leads to shock – a drop in blood pressure and failure of blood cells to meet the metabolic demands of the body. It is a leading cause of death among children in Southeast Asia.

Dengue (pronounced den-GAY) includes four distinct viruses or serotypes, dengue 1 through 4. All are mainly transmitted via the bite of Aedes mosquitoes, two of which, Aedes albopictus and Aedes aegypti, are common in the southeastern United States. Mosquitoes become infected with dengue after taking a blood meal from a dengue-infected person.

People infected with dengue virus develop dengue fever or dengue hemorrhagic fever. Dengue fever is also known as "breakbone disease" because of severe headache and joint pain associated with it.

Dengue hemorrhagic fever is far more serious than the rarely fatal dengue fever.

After a short incubation period (one-to-two weeks), the mosquito can transmit the infection to a susceptible person. An infection with any of the four serotypes confers protective lifelong immunity only to that serotype. The risk of developing hemorrhagic dengue appears to be increased among people subsequently infected with a different serotype.

In recent years hemorrhagic dengue has become increasingly prevalent in tropical America.

"Historically, illness associated with the dengue serotypes native to the Americas has been very mild, and the virus that was responsible for hemorrhagic fever in this region was a dengue serotype 2 strain introduced from Southeast Asia," said Dr. Aravinda M. de Silva, assistant professor of microbiology and immunology at UNC School of Medicine and senior author of the study. "It was, therefore, surprising to learn that the spontaneous outbreaks of dengue hemorrhagic fever in Nicaragua and Panama in 1994 were caused by dengue serotype 3."

Although serotype 3 had been identified in the Americas more than 25 years ago, illness linked to it had been mild, de Silva said. "So those outbreaks associated with hemorrhagic fever meant one of two possibilities: Either the native virus had mutated to become more severe or dengue serotype 3 from another part of the world had been introduced into Latin America."

The answer – that the virus had moved across the globe to Latin America – was eventually revealed through research by Dr. Duane Gubler and CDC colleagues. The new UNC study describes the most likely route of spread and the relationship to virus strains established in Asia and Africa. The UNC study team worked in close collaboration with CDC researchers and the Medical Research Institute in Colombo, Sri Lanka.

"Our original intention had been to study how dengue hemorrhagic fever suddenly emerged in South Asia in the late 1980s," said Dr. William B. Messer, a doctoral graduate of the ecology curriculum at UNC, now a medical student at the university.

Hemorrhagic dengue fever has continued to be a large public health problem in Southeast Asian nations – Thailand, Indonesia and Malaysia – since the 1950s, Messer said. All four dengue serotypes have been documented there.

"It was puzzling that all four serotypes also circulated in South Asia, in Sri Lanka and parts of India, yet dengue hemorrhagic fever was extremely rare," Messer said.

Then, abruptly, beginning in 1989, dengue hemorrhagic illness became common in Sri Lanka.

"In the first studies in Sri Lanka, the first thing we did was to ask if the transmission had become more intense. Bill showed there were no changes in virus transmission rate," de Silva said.

The researchers then wanted to find out if the virus had changed. They isolated dengue virus from pediatric patients in Sri Lanka. In those with hemorrhagic disease, serotype 3 was prevalent. Patients with the milder disease, dengue fever, showed infection with the other serotypes.

"We then focused on serotype 3, collecting virus isolates from Sri Lanka and other parts of the world," de Silva said. "Bill found that serotype 3 from Sri Lanka formed two genetically distinct groups. In one group were viruses of serotype 3 that were related to dengue disease prior to 1989, while the second group contained only viruses related to disease after 1989."

These findings provided the clue that a genetic change in the dengue serotype 3 virus circulating in Sri Lanka was responsible for the unexpected emergence of severe disease, de Silva said.

The researchers then genetically sequenced dengue virus isolated from Latin America and compared them to isolates from South Asia.

"We found that the group of Latin American isolates linked to severe disease were more closely related to the same isolates associated with dengue hemorrhagic fever in Sri Lanka," Messer said. "And that virus has been isolated all through Latin America and associated with dengue hemorrhagic fever from Mexico down to Brazil."

Further investigation revealed an African connection. Dengue 3 virus isolates from hemorrhagic disease outbreaks in Mozambique in the mid-1980s were also closely related to the same hemorrhagic dengue virus isolates in Sri Lanka and Latin America.

Thus, the serotype 3 genetic subtype linked to severe dengue disease moved from a location where it had been circulating undetected – most likely somewhere in the Indian subcontinent – to East Africa and Sri Lanka in the 1980s and from East Africa into Latin America in the mid-1990s.

What does this mean for the United States? Given that the major mosquito vectors of dengue (Aedes aegypti and A. albopictus) are well established here, de Silva said, there is concern that dengue viruses could be introduced into the United States and transmitted to people. In fact, a handful of cases have been documented in south Texas, close to the Mexican border.

"I don’t think dengue would ever become a serious problem in the U.S. because humans are the main reservoir of this virus," de Silva said. Unlike the West Nile virus, "which is very difficult to control because birds are the main reservoir, human-mosquito exposure is a lot less here, as most people live in air-conditioned housing. I doubt you can have the frequent, year-round human-mosquito transmission required for establishment of the virus that occurs in poorer countries."

"We may worry about small epidemics of dengue fever, but not established disease."

This research was supported, in part, by a Junior Faculty Development Award from UNC.