Dengue Fever

CLP talks to Focus Diagnostics’ Jay M. Lieberman, MD, about what labs need to know.

For the first time in 2 decades, dengue fever has cropped up significantly in the continental United States. In the midst of a 20-year high for dengue infections across the Caribbean and Central America, more than 24 cases have been reported through the end of July among Florida residents alone.¹ Another 49 so-called “imported cases” involving individuals returning to the United States from areas under a dengue endemic, such as the Caribbean, have also been reported in the state. The growing number of infections has sparked fears that the disease could gain a more substantial foothold in the US.

According to the Centers for Disease Control and Prevention, patients with dengue fever typically experience fever, severe headache, pain behind the eyes, joint pain, muscle or bone pain, rash, mild bleeding, and a low white cell count. CLP recently spoke with Jay M. Lieberman, MD, medical director in charge of infectious diseases for Quest Diagnostics and the company’s Cypress, Calif-based Focus Diagnostics business, about dengue testing and how labs can assist clinicians in making an accurate diagnosis.

CLP: What is dengue fever? What characteristics make it particularly worrisome to health officials?

Lieberman: Dengue is the most common vector-borne viral disease in the world. By vector-borne we mean that it is transmitted by a mosquito, flea, tick, etc. Dengue causes an estimated 50 to 100 million infections around the world each year, and 25,000 deaths. Approximately 40% of the world’s population lives in areas where dengue fever occurs. Dengue is transmitted by specific mosquitoes, the most common of which is Aedes aegypti, often called the yellow fever mosquito. It can also be transmitted by Aedes albopictus, the Asian tiger mosquito. These mosquitoes are commonly found in tropical and subtropical parts of the world.

What has attracted interest and raised concern in the United States is that we have these mosquito vectors present, particularly in the southern and southeastern parts of the country. These mosquitoes can transmit dengue as well as other viruses of concern—for example, Chikungunya virus. What we have learned over the past 10 to 12 years is just how rapidly some of these mosquito-borne infections can emerge.

The best example, of course, is West Nile virus. Unheard of in the United States before 1999, it caused a localized outbreak in the New York City area that year. West Nile virus can be transmitted by a wide variety of mosquitoes, and over the next decade it rapidly spread. As the geographic range of infected mosquitoes spread, more and more birds got infected, and human cases increased dramatically. West Nile virus caused the largest outbreak of so called arboviral, meaning arthropod-borne, encephalitis ever in the United States.

Dengue is something that was not seen in the US for decades before 1980, when there were cases identified periodically along the Texas/Mexico border. Several years ago there was an outbreak on several Hawaiian Islands. That outbreak was interesting because the mosquito transmitting it was the Asian tiger mosquito, not the yellow fever mosquito. Then recently we heard about locally acquired dengue in Key West, Florida. The concern is that because we have the appropriate mosquito vectors, we are at risk of having outbreaks as the virus does get introduced periodically by people who may be traveling to the United States, and the potential for an extended outbreak is substantial.

As you are probably aware, the Caribbean has been hit hard by dengue. On July 23, the CDC reported on the dengue epidemic in Puerto Rico. Since the start of the year, they’ve had more than 6,300 suspected cases, with more than a third of these patients requiring hospitalization, and they’ve had five deaths.

When the virus is present in an area so close to the continental US, there is the potential for infected people to travel to the US while they are carrying the virus in their bloodstream. If they get bitten by a mosquito while they are viremic, the mosquito then becomes infected, and that mosquito then carries that virus for the rest of their lives and can infect every person they bite thereafter. That’s how you get local spread of a virus like dengue.

CLP: Do physicians often request a lab diagnosis for dengue?

Lieberman: It’s not common for most clinicians in the United States to even think of dengue. Many are not very familiar with the disease because it’s not very common here. Most dengue, and also Chikungunya virus infections, are travel-related. So an astute clinician has to recognize fever in a traveler returning from an international trip, suspect the diagnosis, and then do testing. For the locally acquired cases, it’s much less likely that clinicians will even think of the possibility because of the absence of a travel history.

The story in Key West is instructive because it took an astute clinician in New York—not surprisingly, an infectious disease specialist—to recognize the classic presentation in a woman who had no recent international travel history. She had been in south Florida and had reported mosquito bites, and the clinician recognized the possibility of dengue fever. He tested for it, found that she had antibodies, and the diagnosis was confirmed by the Florida health department. That spurred them to investigate, to alert clinicians that they might have dengue in the area, and to do more serologic testing to get an idea of how many people might be infected.

When they did that, they found a total of 28 infections, which is most likely an underestimate. The real point is had the clinician in New York not made that diagnosis, it’s possible that many, if not all, of the other cases would not have been recognized.

CLP: What are the testing options available to labs?

Lieberman: There are two primary ways to test. First, you can do serologic testing, which is looking for antibodies. The problem with antibody testing is that most patients do not develop antibodies until after the first 5 days of illness. So if you’re seeing the patient acutely, antibody tests—both IgM and IgG—may be negative even though they’re infected. In that stage, the way to make a diagnosis would be molecular, by PCR.

PCR testing can identify the virus in the blood, and a positive result indicates that the patient is viremic. The key thing there is when a patient is viremic, they are at risk of infecting mosquitoes that might bite them. If the initial serological test is negative, doing convalescent serologies 3 or 4 weeks later can confirm the diagnosis.

It is not a definitive diagnosis if all you have is a positive IgM. In that case, you would want to repeat testing to document that they seroconverted.

CLP: Are there POC tests available?

Lieberman: There are point-of-care rapid tests that are used in developing countries. I’m not aware of any such tests available in the United States.

CLP: How long does it typically take to receive results?

Lieberman: It depends on who is doing the testing. Much of the testing is done by health departments and the CDC. At Focus Diagnostics, we are the only commercial lab that does dengue PCR and we also do dengue serologies. Other labs do serologic testing as well. Because testing is being done by large reference labs, there can be some time delay before you get results depending on the logistics of getting the specimen to the right place.

CLP: A recent suspected case of dengue in Miami took officials 2 days to rule out. They performed two blood tests, a PCR test, and an antibody test. Is this a normal process or unusual?

Lieberman: They were obviously trying to get as much information as possible. The PCR is generally positive during the time when the patient has fever. When the fever resolves, the PCR is usually negative, but antibodies take some time to develop. So depending on where the patient was in the course of their illness, I certainly could understand them doing both to maximize their chances of making a definitive diagnosis. The reality is that laboratory diagnosis is not always necessary if you know you have the virus endemic in the area and the patient has classic symptoms.

CLP: So every patient does not need to be tested?

Lieberman: In the middle of an outbreak—in Puerto Rico for example—you are going to do a lot of testing to understand what’s happening, but that doesn’t mean that every patient has to be tested, because you know what a patient with classic symptoms has.

In the United States, the story is different. We don’t have a lot of the disease, so it’s important for clinicians to think of the diagnosis and attempt to confirm it because it gives you a window into what’s happening. Without making that initial diagnosis in the index patient, we might not have any idea that this is an issue at all.

In Key West they did the same thing that was done with West Nile. They looked at local mosquito populations and found mosquitoes infected with dengue there, which ties it all together. That allows you to focus your resources into trying to do what you need to do to stop or control the outbreak.

CLP: Do we expect to see more of this sudden emergence of infectious diseases?

Lieberman: I think that’s extremely likely; we live in a global society. In regards to Chikungunya, there was an outbreak in North Eastern Italy a few years back. It was sparked by one traveler returning from India, where Chikungunya was common, who was viremic when he arrived in North Eastern Italy. He arrived in an area that had the appropriate mosquito vector, and it led to a localized outbreak.

CLP: What would an appropriate—rather than a reactionary—response be to a sudden regional pandemic for labs?

Lieberman: Clinical laboratories need to be able to answer questions from clinicians, such as: “I have a patient with suspected or possible dengue fever or Chikungunya. How do I confirm it?” The labs will want to know what tests should be run and where to run those tests.

CLP: What have we learned from West Nile and other diseases that can be applied to how we handle dengue?

Lieberman: We learned how diseases previously unknown or not described in a certain area can emerge and spread rather quickly when they are transmitted by vectors such as mosquitoes. We also learned about the importance of collaboration between clinicians, laboratories, and public health. Clinicians need to recognize the symptoms and order the tests, laboratories need to be able to turn around the test in a timely manner to get answers, and public health has to use that information to understand what is going on in their communities.

The West Nile story in many ways has been a success on all of those fronts. It has led to much greater awareness of mosquito control measures, including things that individuals can do to protect themselves from mosquito bites and important functions of public health to control mosquito vectors in their communities.

West Nile emerged in the New York metropolitan area, and then, each year, the virus seemed to be migrating west and south and eventually across the United States. California was one of the last states significantly impacted. That gave the public health officials in California time to prepare. They actively looked for West Nile virus in dead birds and in mosquitoes. They had time to educate physicians about the symptoms, and to alert the general public about how to deal with mosquitoes and protect themselves from mosquito bites.

The impact of West Nile was significantly less than it might have been if, for example, California had been hit in the early years of the epidemic. It was a tremendous success story from a public health perspective. In the Florida Keys now, they are focused on monitoring mosquito populations and doing what they can to control the mosquito vector so this doesn’t take off and become a much larger problem.

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Stephen Noonoo is associate editor of CLP.

Reference

1. Florida Department of Health. Dengue Fever in Key West. www.doh.state.fl.us/environment/medicine/arboviral/Dengue_FloridaKeys.html. Accessed August 4, 2010.