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Predicting Who Will Get Sickest From Dengue Virus

Boy with dengue
Doctor in Thailand examines boy with dengue.
Credit: WHO/TDR/Crump
U.S. and Thai researchers are finding ways to quickly identify children most likely to develop severe cases of dengue fever. By taking frequent blood samples beginning shortly after children become infected with the mosquito-borne dengue virus, NIAID grantee Alan Rothman, M.D., of University of Massachusetts Medical School, Worcester, and his colleagues are creating a kind of time-lapse movie of viral and human immune response interactions as the disease progresses. If the team can determine which early immune responses signal a poor prognosis, doctors could use the information to focus fast on those youngsters in danger of taking a turn for the worse—and perhaps avert catastrophe.


Dengue Fever: Often Miserable, Sometimes Fatal

Most people infected with any of the four forms of dengue virus will not develop any symptoms or at most will have a mild fever. However, 50 to 100 million people a year do suffer the fever, headache, and severe joint pain that give the disease its nickname of break-bone fever. Sadly, some 20,000 people—mostly children and young adults experiencing their second episode of infection—die of dengue annually. The severest forms of dengue occur when blood plasma leaks out of blood vessels and into the surrounding tissues, which can lead to a drop in blood pressure, shock, and, if left untreated, death.

“As clinicians,” notes Dr. Rothman, “we often cannot see the impending shock syndrome until it is too late.” And yet, he adds, “we know that there are physiological differences between those who go on to develop dengue shock syndrome and those who do not.”

Thai-U.S. Collaboration Yields a Wealth of Data

Since 1994, the University of Massachusetts researchers have collaborated with U.S. scientists at the Armed Forces Research Institute of Medical Sciences in Bangkok and with Thai co-investigators on a series of studies aimed at better diagnosing, treating, and preventing dengue. One project, conducted at Queen Sirikit National Institute of Child Health in Bangkok, comprised three clinical studies each lasting several years. Children with fevers of unknown cause were enrolled only if the fever had begun less than 72 hours earlier. This meant that the information gathered through frequent blood sampling (as well as through serial ultrasound imaging) could be used to build a picture of the evolving illness from its early stage until resolution. To date, the investigators have followed 1,104 children. Of those, 437 were diagnosed with dengue virus infection and 273 developed dengue fever, while 163 children eventually developed dengue hemorrhagic fever, a serious form of disease that can include shock syndrome.

Already, the team’s observations are helping care givers better manage children with suspected dengue infection. For example, the group showed that simple lab tests measuring white blood cell count and other parameters allow clinicians to rapidly distinguish dengue from other fever-causing infections. Currently, says Dr. Rothman, biostatisticians are searching through the reams of data for factors—either in the immunological response or in the virus itself—that accurately predict when an infection will develop into severe disease. For example, if elevated levels of a specific immune molecule early in illness can be correlated with a poor outcome, then doctors could look for that blood-borne signal by performing the appropriate lab tests and would get early warning that a given patient is at heightened risk for dengue hemorrhagic fever or dengue shock syndrome.

Next Steps, New Techniques

Next steps for Dr. Rothman and his colleagues include expanding the clinical studies to include more seriously ill children. In Thailand, the investigators are developing novel, minimally invasive ways to measure immunological responses in infected children without taking blood samples. These minimally invasive techniques could be used more or less continuously to give clinicians a full picture of the developing illness without subjecting children to frequent blood-draws.

Another project is based in Massachusetts and involves collaboration with a local biotech firm, says Dr. Rothman. The goal of the project is to develop an inexpensive, fully-automated, and simple-to-use device that can rapidly diagnose dengue infection. Diagnosing dengue (and other hemorrhagic fevers) is currently difficult and requires specialized labs and technically trained experts. In resource-poor countries, such facilities and expertise are not readily available. With the so-called lab-in-a-tube technology now under development, a healthcare worker would simply insert a blood sample into the tube and seal it. The sample would then move automatically through series of compartments and chemical processes that would reveal the presence of dengue virus genetic material in the blood. When perfected, the device should be able to detect the presence of dengue virus in a plasma sample in under an hour.

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Last Updated November 10, 2009