Anna Manzanarez seemed the picture of health, except for the bad case of “flu” that she was fighting. Then, the 28-year-old waitress from the coastal community of Seaside, Calif., collapsed while getting out of the shower one morning. Her family rushed her to the hospital, where she died the next day. While the young woman's sudden death understandably shocked family and friends, the discovery of what killed her was even more shocking to public health officials. The Centers for Disease Control and Prevention confirmed that Manzanarez died of dengue hemorrhagic fever, an illness almost unheard of in this country, which she had apparently contracted during a trip to Mexico.¹

In January, Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, warned that “widespread appearance of dengue in the continental United States is a real possibility. Worldwide, dengue is among the most important reemerging infectious diseases. Public health officials need to take the threat seriously.”² Yet most healthcare providers in the United States are not familiar with dengue.

West Nile virus was unknown in this country until 1999. Passed by the bite of infected mosquitoes, West Nile has now reached nearly every state, killed over 1,000 Americans, and sickened 27,000 more.³ SARS was a disease never before seen in humans until it crossed the species barrier and swept around the world in 2003. West Nile and SARS were unpleasant surprises. However, dengue fever does not have to surprise us. We as nurses have a chance to prepare for its possible arrival by arming ourselves with knowledge of the disease’s cause, its symptoms, diagnosis, and treatment.

Dengue fever is among the four dozen emerging or re-emerging infectious diseases tracked by the CDC. Dengue is considered a re-emerging disease because it’s returning to locations once free of it. Dengue is also increasing in virulence. Fauci calls it “one of the world’s most aggressive re-emerging infections.”⁴ The World Health Organization estimates there are 50 million to 100 million cases of dengue annually, with half a million hospitalizations and at least 22,000 deaths.⁴ In 2007, the Pan American Health Organization reported nearly 1 million cases of dengue fever in the Americas.⁴ Fatality rates can exceed 40%, but average 2.5%; with rapid recognition and proper treatment, the fatality rate can be reduced to 1% or less.⁵

More than 2 billion of the world’s 6.5 billion inhabitants are at risk of acquiring dengue, making it the world's most important mosquitoborne viral disease.⁵ Dengue is endemic — constantly present — in over 100 countries in Southeast Asia, Africa, the Western Pacific, the Americas, and the Caribbean.⁵ Dengue fever is no stranger to the United States: Outbreaks occurred in Hawaii during 2001-2002 and in Texas in 2005.

The primary mosquito vector for dengue fever is Aedes aegypti, which is believed to have been dispersed to tropical and subtropical settings from its original African home by shipping and trade over 400 years ago.⁵ Aedes albopictus, also known as the Asian tiger mosquito, is becoming an increasingly important alternate vector and was identified as the vector in the Hawaiian outbreak. Both species are present in the continental United States. Ae. aegypti is prevalent in over a dozen southern states while Ae. albopictus has spread to 36 states since its introduction in 1985.⁴

All about Aedes

Aedes is an urban, day-biting mosquito that prefers to live in heavily populated areas where adequate food (human beings) and habitat (small amounts of standing water in empty food and drink containers, discarded tires, etc.) abound. Aedes is not seasonal, but bites year-round in areas warm enough to sustain its life cycle. Ae. aegypti is an especially efficient vector because its bite is nearly painless. These mosquitoes typically feed from several people before obtaining enough blood to promote egg maturation, thus increasing the likelihood of spreading the virus between people. By comparison, the Anopheles mosquito that carries the malaria parasite typically obtains its full blood meal with one feeding. Aedes mosquitoes are also capable of transovarial transmission, the passage of virus from infected female to egg, meaning that a new generation of offspring may be capable of passing the virus without having bitten infected people.

Dengue fever is caused by a flavivirus, the family of viruses that includes yellow fever and West Nile virus, as well as Japanese and St. Louis encephalitis. It's a single-stranded RNA virus with four serotypes — closely related groups of viruses differentiated by characteristic antigens — known as DEN-1, DEN-2, DEN-3, and DEN-4. Infection with one serotype confers lifelong immunity to future infection by the same serotype and transient protection against the other serotypes. That protection lasts only a few months. Humans are the principal reservoir for the dengue virus although Asian and African primates also may be infected.

Dengue viruses have an unusual quirk. Infection by a second serotype after the transient protection wears off may lead to immune enhancement, a condition that sets the stage for the far more serious illnesses known as dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which will be discussed later. One study found that a second infection by a different serotype increases the risk for these dangerous complications by 15 to 80 times.⁶ Thus, the danger of having more than one serotype circulating in a region lies not with the first illness, but with subsequent infections caused by different serotypes.

The original epidemics

The first reported epidemics of dengue fever occurred in 1779 and 1780 in Asia, Africa, and North America.⁷ The nearly simultaneous occurrence of outbreaks on three continents suggests that the virus has had a worldwide distribution for at least 225 years.⁷ Widespread mosquito-control projects during the 20th century helped to curb dengue’s spread in some countries. However, with a 30-fold increase in incidence over the past 50 years, dengue has expanded to almost all tropical and subtropical countries, many of which are popular tourist destinations.⁸ Dengue now appears to be moving into temperate climes.⁸ Since the 1980s, dengue has dramatically expanded throughout its range, with regions changing from hypoendemic (areas of infection with one serotype) to hyperendemic (areas of infection with two or more serotypes).⁹

Human factors — such as uncontrolled urbanization and population growth, the deterioration of public health infrastructure, the large increase in the number of air travelers, and the lack of effective mosquito-control programs — have all contributed to the spread of dengue fever, especially over the past two decades.⁸

Dengue viruses collect within the salivary glands of infected Aedes mosquitoes. Each time a mosquito feeds, she injects saliva into the bloodstream. (Only female mosquitoes take blood meals.) Most cases of dengue are transmitted by the bite of infected mosquitoes; however, placental transmission is not uncommon. After an infected mosquito bites a person, the dengue virus replicates in regional lymph nodes and is disseminated through the lymphatic and blood systems to other tissues.⁹ The virus circulates for seven to 10 days, allowing ample time for mosquitoes to bite the viremic person and carry the virus to uninfected people.⁵

The incubation period for dengue — the time before symptoms appear — varies from three to 14 days, with four to seven days being the norm.⁹ Dengue presents with a continuum of disease that includes asymptomatic infection, mild febrile illness, dengue fever, DHF, and DSS. The majority of people who become infected with dengue for the first time are asymptomatic or experience fever and symptoms similar to that found with a mild case of flu.⁹ Yet the presence of dengue antibodies sets the stage for more serious disease should a subsequent infection with another serotype occur.

A classic case of dengue fever may include sudden onset of some or all of the following:^8-10

• Fever up to 105 F (can last five to seven days)

• Frontal headache, often severe
• Retro-orbital pain, often severe
• Bone, joint, and muscle pain, often severe. Dengue fever was once called “break-bone fever” because of the severity of the pain.
• Maculopapular rash (a flat red rash with small raised bumps) with island sparing (areas within the rash in which skin appears normal); rash begins as fever wanes and lasts two to four days.
• Lymphadenopathy
• GI symptoms (nausea/vomiting/diarrhea)
• Upper respiratory infection symptoms (sore throat/nasal congestion/cough/reddened conjunctiva)
• Depression following recovery

As previously mentioned, infection with a second dengue serotype may cause DHF or DSS. The mechanisms for this are not fully understood. But scientists believe that crossreactive antidengue antibodies from the previous infection bind to the new infecting serotype, enhancing viral uptake of monocytes and macrophages.⁹ This results in an amplified cascade of cytokines and complement activation, causing endothelial dysfunction, platelet destruction, and consumption of coagulation factors.⁹ This in turn leads to plasma leakage and hemorrhagic manifestations.9 The severity of symptoms depends on the strain and serotype of the infecting virus, the patient’s age and genetic background, and the viral load.⁹

A patient with dengue hemorrhagic fever may manifest some or all of the above symptoms and the following, as well: petechiae and ecchymosis, heavy menses, bleeding from the nose or gums, melena, hematuria, and hematemesis.^8,10 Plasma leakage develops four to seven days after the onset of the disease and may be heralded by abdominal pain and vomiting, restlessness, a change in the level of consciousness, a sudden change from a febrile to a hypothermic stage, and a marked decrease in platelet count.⁹

Worst-case scenario

According to the WHO classification of dengue hemorrhagic fever (see sidebar by clicking on Sidebars in the Course Tools), DSS is a subset of DHF, a worst-case scenario, with bleeding and substantial plasma leakage leading to hypovolemic shock and cardiovascular collapse. DSS is characterized by a rapid, weak pulse with a narrowing pulse pressure or profound hypotension.⁹ The duration of shock is short, with patients either recovering rapidly or dying within 12 to 24 hours.9 The mortality for DSS is as high as 40%.⁹ Shock is more common in children while hemorrhage is more common in adults.¹¹

Some health authorities are calling for revision of the WHO classification, saying that often symptoms don't fit into the categories. For example, some DHF signs, such as thrombocytopenia, epistaxis, and petechiae, are present in 10% of uncomplicated dengue cases and are not necessarily predictive of disease severity or progression to shock.^4,12 On the other hand, several studies showed that 18% to 69% of infants and children with shock and laboratory-confirmed dengue did not meet all four WHO criteria for DHF.¹²

The WHO classification doesn't even mention some symptoms. For example, a study in Singapore found relative bradycardia among dengue patients.¹³ Normally febrile patients experience tachycardia — heart rates above 100 beats per minute. In the study, patients with dengue fever averaged 87.6 bpm, or nearly 20 bpm less than patients with other infections and similar temperatures.¹³ This led researchers to believe that dengue fever may directly affect cardiac function, a symptom not included in the WHO system.¹³ Researchers recommended that large studies be undertaken to obtain the evidence needed to formulate a more robust dengue classification scheme that clinicians and epidemiologists can use regardless of their location.¹²

Making the diagnosis 

Similar to West Nile virus infections, most infections with dengue virus result in a subclinical and virtually asymptomatic illness.⁶ Clinical disease usually causes an acute febrile illness, or dengue fever. Patients typically recover completely within two weeks although they may be left with fatigue or depression lasting several weeks or months.⁶ An estimated quarter-million cases of DHF occur annually.⁹ About 95% of the people who develop DHF and DSS are children under age 15, usually after having been previously infected by a different serotype.⁶

Some researchers feel undue emphasis is placed on hemorrhage, pointing out that DSS derives not from hemorrhage, but from capillary leakage of intravascular fluids, electrolytes, and small proteins into perivascular tissues.^4,12 This may lead to pleural and pericardial effusions, decreasing blood pressure, low tissue perfusion, and oliguria.⁴ Shock can be predicted by a gradually increasing hematocrit over several hours despite normal hydration.⁴ Rarely, hepatic damage, cardiomyopathy, and encephalopathy may occur, with high mortality.¹²

As with many other viral diseases, making a definitive diagnosis of dengue fever can be a challenge that requires sophisticated laboratory capabilities. None of the available tests can easily aid the clinician in making an immediate positive diagnosis. This is in contrast to malaria, which usually can be quickly diagnosed by visualizing  the parasite in blood. Tests for dengue virus include:^8,9,14,15

• Isolating dengue virus from serum, tissue, or cerebrospinal fluid. This test has a sensitivity of less than 50% and is not commonly available. While dengue virus may be present in blood early in the disease process, it can take days or weeks to isolate the virus and obtain results.

• Detecting dengue antigens in blood. Dengue antigens can be identified in serum and in peripheral blood mononuclear cells (PBMCs, or white blood cells with round nuclei, such as lymphocytes and monocytes) using the ELISA test (enzyme-linked immunosorbent assay). The antigens can be found most easily on Day 4 of illness in the PBMC and on Day 5 in the serum.
• Identifying viral RNA. The genomic sequence of dengue's RNA can be found by polymerase chain reaction (PCR) testing. The test has a sensitivity of 90% in the first few days of illness, but quickly declines to less than 10% a week after the onset of symptoms.
• Detecting dengue antibodies. Rapid diagnostic tests to detect antibodies to dengue virus have high sensitivity (71% to 100%) and high specificity (86% to 100%). However, it takes the body several days to produce antibodies to dengue infection, so these tests are most accurate four to five days after the onset of symptoms.

DHF may be suspected when laboratory findings of thrombocytopenia and hemoconcentration are present plus pleural effusion and spontaneous bleeding, most often from the nose or gums.⁸ The tourniquet test is a crude measure of hemorrhagic tendencies, performed by inflating a blood pressure cuff to a point halfway between the patient's systolic and diastolic blood pressure for five minutes.⁹ The test is positive if there are 20 or more petechiae per square inch on the forearm; in one study, 44% of patients were positive.^8,9 When positive, the test is suggestive of DHF, but a negative test does not exclude it.⁸

No cure

No cure or specific treatment exists for dengue infection. General supportive care includes treating pain and fever with acetaminophen rather than aspirin or other NSAIDs, which may aggravate the bleeding tendency associated with the disease.^4,9 The patient should receive adequate fluids to prevent volume depletion, with electrolytes added as needed. Large amounts of fluids may be needed to treat capillary leakage associated with DHF and DSS.^4,9 One study among Vietnamese children with DSS showed that Ringer’s lactate produced better outcomes than other tested fluids although it’s uncertain if these findings can be extrapolated to other populations.¹⁶ Blood and blood products may be administered if hemorrhage warrants their use.^4,9

While many nurses will never encounter patients with dengue fever, certainly some will, for example, military nurses and nurses working in developing nations. Also, nurses working in EDs in the United States may encounter patients presenting with fevers of unknown origin. Such patients should be questioned about their recent travel. With 14 million Americans annually traveling to areas of endemic dengue fever, such as Asia, the Caribbean, Mexico, Central and South America, and the Pacific (Tahiti, the Philippines, Fiji), dengue patients will probably turn up in the nation’s EDs.⁶ Most dengue infections occur among people who have traveled to Asia and the Americas.⁹ Some studies have shown that dengue infection is second only to malaria as the most frequent cause of hospitalization among travelers returning from areas of endemic dengue.⁹ Nurses can advise patients, family members, friends, and the community about the danger of traveling to tropical and subtropical regions where dengue fever is endemic.

Unlike with malaria, no medications are available to prevent dengue infection. However, nurses can ensure that people know how to protect themselves from mosquito bites. This includes using mosquito repellents that contain DEET on bare skin. These products come in various formulations, such as sprays and lotions, and some are safe to use on infants as young as 2 months. Wearing long-sleeved shirts and pants or clothing made of newer fabrics treated with mosquito repellent also offers protection. Travelers should stay in rooms with window and door screens, and should use insecticide-treated bed nets while camping or sleeping in rural areas without screens.

Risks in health care

While dengue is largely transmitted by mosquitoes, health workers should know that dengue has been transmitted by mucocutaneous exposure to infected blood, by accidental needlestick, by bone marrow transplantation, and by blood transfusion.^12,17 The American Public Health Association recommends blood precautions with patients with suspected or confirmed dengue fever.¹⁸ A study of blood donors in Puerto Rico during a 2005 dengue epidemic found that one in every 1,300 donors tested positive for the virus, leading the American Red Cross and public health officials to institute a research project to screen donated blood for dengue virus in Puerto Rico.¹⁹ At present, screening for dengue virus is not part of blood bank protocol in the United States.

No vaccine is yet available to prevent dengue infection although several are in Phase II clinical trials. A successful vaccine must protect against all four serotypes because immunity to one serotype — whether acquired naturally or by vaccination — could lead to DHF or DSS if subsequent infection by another serotype occurs.

Investigational vaccines include those made with inactivated and live attenuated viruses or viral RNA and genetically modified or chimeric formulations.^4,6 One example of a chimera vaccine uses the yellow fever vaccine as its genetic backbone, replacing protein genes from the yellow fever virus's envelope with those from dengue viruses.⁶ The Walter Reed Army Institute of Research has produced a vaccine made of attenuated dengue viruses that has achieved an 80% to 90% seroconversion rate (development of antibodies in response to antigens) among a few human volunteers.⁶ A major concern of all dengue vaccine candidates is this: Will antibodies decline over time to the point that they no longer protect from infection, but in fact enhance it?⁴

One day, a vaccine will be available to prevent dengue infection plus perhaps antiviral medications to cure it. In the meantime, nurses should keep themselves and their patients informed about the potential for this dangerous and widespread disease.