Dengue seen as potential threat to US public health

A disease most Americans have never heard of could soon become more prevalent if dengue, a flu-like illness that can turn deadly, continues to expand into temperate climates and increase in severity, according to a new commentary by Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and David M. Morens, M.D., Fauci's senior scientific advisor.

Their commentary appears in the January 9 and 16 double issue of the Journal of the American Medical Association.

Previously confined to tropical and subtropical climates, the mosquito-borne illness is becoming a much more serious problem along the U.S.-Mexico border and in the commonwealth of Puerto Rico. Dengue occurs sporadically and has had a relatively small impact on the United States thus far, so the amount of dengue-related illness in this country is presently minimal. However, the disease tends to occur in explosive epidemics. Moreover, the NIAID scientists note, efforts to control the populations of mosquitoes that transmit dengue have fallen short of their goal.

These trends stimulated Drs. Fauci and Morens to call for more research to understand and combat dengue. “Widespread appearance of dengue in the continental United States is a real possibility,” the NIAID scientists write in their commentary. “Worldwide, dengue is among the most important reemerging infectious diseases with an estimated 50 to 100 million annual cases…[and] 22,000 deaths.” Public health officials need to take the threat seriously, the scientists assert, because no specific treatments or vaccines for dengue are available. To fight the disease, they state, “The formidable challenges of understanding dengue pathogenesis and of developing effective therapies and vaccines must be met.”

Dengue (pronounced “DENG-ee”) is caused by any of four related viruses transmitted to humans by the mosquitoes Aedes albopictus (nicknamed “Asian tiger mosquito”) and Aedes aegypti. First seen in the United States in 1985, Ae. albopictus has been found in 36 states, while Ae. aegypti has been found in several southern states. Experience elsewhere in the world shows that where these mosquitoes go, the disease usually follows.

In their commentary, Drs. Fauci and Morens provide a historical and clinical overview of dengue; discuss the controversy about the origins and development of the most severe forms of the disease; describe the implications of dengue pathogenesis for safe vaccination strategies; and note the challenges to dengue treatment, control and prevention. The scientists highlight the hypothesis that naturally and maternally acquired dengue antibody may precipitate severe disease on subsequent infection. This hypothesis has implications for dengue vaccine development, the authors write, because a vaccine could potentially stimulate the immune system to cause more severe disease on subsequent natural infection.

Most people infected with a dengue virus have no symptoms or a mild fever. Those who do get sick sometimes experience minor bleeding, such as from the nose or gums, and frequently develop a high fever, severe headache, pain behind the eyes and in joints and muscles, and a rash. Sometimes the disease leads to leakage of blood plasma out of the circulatory system and into tissues, causing blood pressure to drop. This condition often can be reversed by giving patients fluids and electrolytes. With proper treatment, case fatality rates for severe dengue can be less than 1 percent. If left untreated, however, the person may become unresponsive, slip into a coma and possibly die. Early diagnosis and treatment of dengue are critical to preventing shock and death. The severe forms of dengue disease have been defined by the World Health Organization as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).

Recognizing the threat to public health posed by dengue, NIAID allocated $33.2 million in fiscal year 2007 for nearly 60 dengue research projects, including basic research on dengue, DHF and DSS; projects to develop vaccines, diagnostics and therapeutics for the disease; and clinical trials of vaccines.

The priorities of NIAID's dengue research program include the following:

• Develop animal models to study the basic mechanisms of infection and perform preliminary tests of vaccines and therapeutics
• Design and evaluate vaccines and therapeutics
• Understand how dengue viruses can elicit antibodies—normally a form of protection against disease—that may help the viruses infect host cells and exacerbate the disease
• Learn what causes capillaries to leak plasma in DHF and DSS
• Understand the genetic factors in both people and dengue viruses that influence the severity of the disease
• Identify biological markers that might predict whether an individual is protected from dengue viruses and whether a person with dengue fever will likely develop DHF or DSS

By vigorously pursuing these research priorities, NIAID hopes to advance the development of medical tools to fight this important reemerging infectious disease.