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Dengue

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With more than one-third of the world's population living in areas at risk for infection, dengue virus is a leading cause of illness and death in the tropics and subtropics. As many as 400 million people are infected yearly. Dengue is caused by any one of four related viruses transmitted by mosquitoes. There are not yet any vaccines to prevent infection with dengue virus and the most effective protective measures are those that avoid mosquito bites. When infected, early recognition and prompt supportive treatment can substantially lower the risk of medical complications and death.

Dengue has emerged as a worldwide problem only since the 1950s. Although dengue rarely occurs in the continental United States, it is endemic in Puerto Rico and in many popular tourist destinations in Latin America, Southeast Asia and the Pacific islands.

What is dengue?

Dengue (pronounced den' gee) is a disease caused by any one of four closely related dengue viruses (DENV 1, DENV 2, DENV 3, or DENV 4). The viruses are transmitted to humans by the bite of an infected mosquito. In the Western Hemisphere, the Aedes aegypti mosquito is the most important transmitter or vector of dengue viruses. It is estimated that there are over 100 million cases of dengue worldwide each year.

What is dengue hemorrhagic fever (DHF)?

DHF is a more severe form of dengue infection. It can be fatal if unrecognized and not properly treated in a timely manner. DHF is caused by infection with the same viruses that cause dengue fever. With good medical management, mortality due to DHF can be less than 1%.

How are dengue and dengue hemorrhagic fever (DHF) spread?

Dengue is transmitted to people by the bite of an Aedes mosquito that is infected with a dengue virus. The mosquito becomes infected with dengue virus when it bites a person who has dengue virus in their blood. The person can either have symptoms of dengue fever or DHF, or they may have no symptoms. After about one week, the mosquito can then transmit the virus while biting a healthy person. Dengue cannot be spread directly from person to person.

What are the symptoms of the disease?

The principal symptoms of dengue fever are high fever, severe headache, severe pain behind the eyes, joint pain, muscle and bone pain, rash, and mild bleeding (e.g., nose or gums bleed, easy bruising). Generally, younger children and those with their first dengue infection have a milder illness than older children and adults.

Dengue hemorrhagic fever is characterized by a fever that lasts from 2 to 7 days, with general signs and symptoms consistent with dengue fever. When the fever declines, symptoms including persistent vomiting, severe abdominal pain, and difficulty breathing, may develop. This marks the beginning of a 24- to 48-hour period when the smallest blood vessels (capillaries) become excessively permeable ("leaky"), allowing the fluid component to escape from the blood vessels into the peritoneum (causing ascites) and pleural cavity (leading to pleural effusions). This may lead to failure of the circulatory system and shock, followed by death, if circulatory failure is not corrected. In addition, the patient with DHF has a low platelet count and hemorrhagic manifestations, tendency to bruise easily or other types of skin hemorrhages, bleeding nose or gums, and possibly internal bleeding.

What is the treatment for dengue?

There is no specific medication for treatment of a dengue infection. Persons who think they have dengue should use analgesics (pain relievers) with acetaminophen and avoid those containing aspirin. They should also rest, drink plenty of fluids, and consult a physician. If they feel worse (e.g., develop vomiting and severe abdominal pain) in the first 24 hours after the fever declines, they should go immediately to the hospital for evaluation.

Is there an effective treatment for dengue hemorrhagic fever (DHF)?

As with dengue fever, there is no specific medication for DHF. It can however be effectively treated by fluid replacement therapy if an early clinical diagnosis is made. DHF management frequently requires hospitalization.

Where can outbreaks of dengue occur?

Outbreaks of dengue occur primarily in areas where Ae. aegypti (sometimes also Ae. albopictus) mosquitoes live. This includes most tropical urban areas of the world.

What can be done to reduce the risk of acquiring dengue?

There is no vaccine for preventing dengue. The best preventive measure for residents living in areas infested with Ae. aegypti is to eliminate the places where the mosquito lays her eggs, primarily artificial containers that hold water.

Items that collect rainwater or to store water (for example, plastic containers, 55-gallon drums, buckets, or used automobile tires) should be covered or properly discarded. Pet and animal watering containers and vases with fresh flowers should be emptied and cleaned (to remove eggs) at least once a week. This will eliminate the mosquito eggs and larvae and reduce the number of mosquitoes present in these areas.

Using air conditioning or window and door screens reduces the risk of mosquitoes coming indoors. Proper application of mosquito repellents containing 20% to 30% DEET as the active ingredient on exposed skin and clothing decreases the risk of being bitten by mosquitoes. The risk of dengue infection for international travelers appears to be small. There is increased risk if an epidemic is in progress or visitors are in housing without air conditioning or screened windows and doors.

How can we prevent epidemics of dengue hemorrhagic fever (DHF)?

The emphasis for dengue prevention is on sustainable, community-based, integrated mosquito control, with limited reliance on insecticides (chemical larvicides, and adulticides). Preventing epidemic disease requires a coordinated community effort to increase awareness about dengue fever/DHF, how to recognize it, and how to control the mosquito that transmits it. Residents are responsible for keeping their yards and patios free of standing water where mosquitoes can be produced.

Travel & Dengue Outbreaks

How to reduce your risk while visiting areas with dengue

International travelers' risk of dengue infection can vary dependant on transmission in the area as well as exposure to mosquitoes. You are at greater risk when an outbreak or epidemic is occurring. If your hotel or resort does not have air conditioning or windows and doors with secure, intact screens you may be at higher risk. You should take precautions like using repellent and killing any visible mosquitoes. CDC recommends repellents containing DEET, picaridin, oil of lemon eucalyptus or IR3535 as the active ingredient. Repellent can be applied to exposed skin and/or clothing. Clothing impregnated with permethrin is another option (pre-treated or you can treat yourself). Some spatial repellent/insecticide products (mosquito coils, plug-in or butane powered devices), may assist in reducing the risk of mosquito around you.

Prevention

How to reduce your risk of dengue infection:

There is no vaccine available against dengue, and there are no specific medications to treat a dengue infection. This makes prevention the most important step, and prevention means avoiding mosquito bites if you live in or travel to an endemic area.

The best way to reduce mosquitoes is to eliminate the places where the mosquito lays her eggs, like artificial containers that hold water in and around the home. Outdoors, clean water containers like pet and animal watering containers, flower planter dishes or cover water storage barrels. Look for standing water indoors such as in vases with fresh flowers and clean at least once a week.

The adult mosquitoes like to bite inside as well as around homes, during the day and at night when the lights are on. To protect yourself, use repellent on your skin while indoors or out. When possible, wear long sleeves and pants for additional protection. Also, make sure window and door screens are secure and without holes. If available, use air-conditioning.

If someone in your house is ill with dengue, take extra precautions to prevent mosquitoes from biting the patient and going on to bite others in the household. Sleep under a mosquito bed net, eliminate mosquitoes you find indoors and wear repellent!

Symptoms and What To Do If You Think You Have Dengue

The principal symptoms of dengue are:

  • High fever and at least two of the following:
    • Severe headache
    • Severe eye pain (behind eyes)
    • Joint pain
    • Muscle and/or bone pain
    • Rash
    • Mild bleeding manifestation (e.g., nose or gum bleed, petechiae, or easy bruising)
    • Low white cell count

Generally, younger children and those with their first dengue infection have a milder illness than older children and adults.

Watch for warning signs as temperature declines 3 to 7 days after symptoms began.
Go IMMEDIATELY to an emergency room or the closest health care provider if any of the following warning signs appear:

  • Severe abdominal pain or persistent vomiting
  • Red spots or patches on the skin
  • Bleeding from nose or gums
  • Vomiting blood
  • Black, tarry stools (feces, excrement)
  • Drowsiness or irritability
  • Pale, cold, or clammy skin
  • Difficulty breathing

Dengue hemorrhagic fever (DHF) is characterized by a fever that lasts from 2 to 7 days, with general signs and symptoms consistent with dengue fever. When the fever declines, warning signs may develop. This marks the beginning of a 24 to 48 hour period when the smallest blood vessels (capillaries) become excessively permeable ("leaky"), allowing the fluid component to escape from the blood vessels into the peritoneum (causing ascites) and pleural cavity (leading to pleural effusions). This may lead to failure of the circulatory system and shock, and possibly death without prompt, appropriate treatment. In addition, the patient with DHF has a low platelet count and hemorrhagic manifestations, tendency to bruise easily or have other types of skin hemorrhages, bleeding nose or gums, and possibly internal bleeding.

Treatment

There is no specific medication for treatment of a dengue infection. Persons who think they have dengue should use analgesics (pain relievers) with acetaminophen and avoid those containing ibuprofen, Naproxen, aspirin or aspirin containing drugs. They should also rest, drink plenty of fluids to prevent dehydration, avoid mosquito bites while febrile and consult a physician.

As with dengue, there is no specific medication for DHF. If a clinical diagnosis is made early, a health care provider can effectively treat DHF using fluid replacement therapy. Adequate management of DHF generally requires hospitalization.

Epidemiology

Dengue fever (DF) is caused by any of four closely related viruses, or serotypes: dengue 1-4. Infection with one serotype does not protect against the others, and sequential infections put people at greater risk for dengue hemorraghic fever (DHF) and dengue shock syndrome (DSS).

Transmission of the Dengue Virus

Dengue is transmitted between people by the mosquitoes Aedes aegypti and Aedes albopictus, which are found throughout the world. Insects that transmit disease are vectors. Symptoms of infection usually begin 4 – 7 days after the mosquito bite and typically last 3 – 10 days. In order for transmission to occur the mosquito must feed on a person during a 5- day period when large amounts of virus are in the blood; this period usually begins a little before the person become symptomatic. Some people never have significant symptoms but can still infect mosquitoes. After entering the mosquito in the blood meal, the virus will require an additional 8-12 days incubation before it can then be transmitted to another human. The mosquito remains infected for the remainder of its life, which might be days or a few weeks.

In rare cases dengue can be transmitted in organ transplants or blood transfusions from infected donors, and there is evidence of transmission from an infected pregnant mother to her fetus. But in the vast majority of infections, a mosquito bite is responsible.

Global Dengue

Today about 2.5 billion people, or 40% of the world’s population, live in areas where there is a risk of dengue transmission. The World Health Organization (WHO) estimates that 50 to 100 million infections occur yearly, including 500,000 DHF cases and 22,000 deaths, mostly among children.

Entomology & Ecology

Aedes aegypti, the principal mosquito vector of dengue viruses is an insect closely associated with humans and their dwellings. People not only provide the mosquitoes with blood meals but also water-holding containers in and around the home needed to complete their development. The mosquito lays her eggs on the sides of containers with water and eggs hatch into larvae after a rain or flooding. A larva changes into a pupa in about a week and into a mosquito in two days. See Aedes main aquatic habitats; from tree cavities to toilets and learn about the mosquitoes life cycle. People also furnish shelter as Ae. aegypti preferentially rests in darker cool areas, such as closets leading to their ability to bite indoors.

It is very difficult to control or eliminate Ae. aegypti mosquitoes because they have adaptations to the environment that make them highly resilient, or with the ability to rapidly bounce back to initial numbers after disturbances resulting from natural phenomena (e.g., droughts) or human interventions (e.g., control measures). One such adaptation is the ability of the eggs to withstand desiccation (drying) and to survive without water for several months on the inner walls of containers. For example, if we were to eliminate all larvae, pupae, and adult Ae. aegypti at once from a site, its population could recover two weeks later as a result of egg hatching following rainfall or the addition of water to containers harboring eggs.

It is likely that Ae.aegypti is continually responding or adapting to environmental change. For example, it was recently found that Ae. aegypti is able to undergo immature development in broken or open septic tanks in Puerto Rico, resulting in the production of hundreds or thousands of Ae.aegypti adults per day. In general, it is expected that control interventions will change the spatial and temporal dispersal of Ae. aegypti and perhaps the pattern of habitat utilization. For these reasons, entomological studies should be included to give support before and throughout vector control operations.

Mosquito Life-Cycle

Aedes aegypti and other mosquitoes have a complex life-cycle with dramatic changes in shape, function, and habitat. Female mosquitoes lay their eggs on the inner, wet walls of containers with water. Larvae hatch (picture 1, inset) when water inundates the eggs as a result of rains or the addition of water by people. In the following days, the larvae (picture 2) will feed on microorganisms and particulate organic matter, shedding their skins three times to be able to grow from first to fourth instars. When the larva has acquired enough energy and size and is in the fourth instar, metamorphosis is triggered, changing the larva into a pupa (picture 3). Pupae do not feed; they just change in form until the body of the adult, flying mosquito is formed. Then, the newly formed adult emerges from the water after breaking the pupal skin (picture 4, inset). The entire life cycle lasts 8-10 days at room temperature, depending on the level of feeding. Thus, there is an aquatic phase (larvae, pupae) and a terrestrial phase (eggs, adults) in the Ae. aegypti life-cycle.

It is this life-cycle complexity that makes it rather difficult to understand where the mosquitoes come from. Similar complex life-cycles with aquatic and terrestrial forms are observed in amphibians. For educational and training purposes, it is rather useful to make life-cycle kits, so people have an opportunity to watch how the aquatic stages turn into terrestrial ones.

There is a very important adaptation of dengue vectors that makes controlling their populations a difficult task. Their eggs can withstand desiccation for several months, which means that even if all larvae, pupae, and adults were eliminated at some point in time, repopulation will occur as soon as the eggs in the containers are flooded with water. Unfortunately, there is no effective way to control the eggs in containers.

Mosquitoes' Main Aquatic Habitats

Aquatic habitats are containers in which eggs develop into adult mosquitoes. Mosquitoes that transmit dengue lay eggs on the walls of water-filled containers in the house and patio. The eggs hatch when submerged in water and can survive for months. Mosquitoes can lay dozens of eggs up to 5 times during their lifetime.

There is a great variety of man-made containers on backyards or patios that collect rain water or that are filled with water by people where dengue vectors thrive. Disposing of unused containers, placing useful containers under a roof or protected with tight covers, and frequently changing the water of animal drinking pans and flower pots will greatly reduce the risk of dengue infections. Water storage containers should be kept clean and sealed so mosquitoes cannot use them as aquatic habitats.

Dengue and Climate

Dengue viruses are transmitted by Aedes mosquitoes, which are highly sensitive to environmental conditions. Temperature, precipitation, and humidity are critical to mosquito survival, reproduction, and development and can influence mosquito presence and abundance. Additionally, higher temperatures reduce the time required for the virus to replicate and disseminate in the mosquito. This process, referred to as the "extrinsic incubation period", must occur before the virus can reach the mosquitoes salivary glands and be transmitted to humans. If the mosquito becomes infectious faster because temperatures are warmer, it has a greater chance of infecting a human before it dies.

Although environmental factors are important they are not the only factors critical to dengue transmission. Virus must be present, there must be sufficient numbers of humans still susceptible, or non-immune, to the virus, and there must be contact between those susceptible humans and the mosquito vectors

In countries where transmission does routinely occur, short-term changes in weather, particularly temperature, precipitation, and humidity, are often correlated with dengue incidence. These associations, however, do not describe the occurrence every few years of major epidemics in these areas, suggesting that long-term climate variability does not regulate long-term patterns in transmission. A more important regulator of epidemics might be the interplay of the four different dengue serotypes. The level of prior exposure of a human population to each of the dengue serotypes may be a more critical determinant of whether a large epidemic occurs than climatic cycles.

Globally, the reported incidence of dengue has been increasing. Although climate may play a role in changing dengue incidence and distribution, it is one of many factors; given its poor correlation with historical changes in incidence, its role may be minor. Other important factors potentially contributing to global changes in dengue incidence and distribution include population growth, urbanization, lack of sanitation, increased long-distance travel, ineffective mosquito control, and increased reporting capacity.

Clinical Guidance

Dengue Virus

Dengue infection is caused by any one of four distinct but closely related dengue virus (DENV) serotypes (called DENV-1, -2, -3, and -4). These dengue viruses are single-stranded RNA viruses that belong to the family Flaviviridae and the genus Flavivirus—a family which includes other medically important vector-borne viruses (e.g., West Nile virus, Yellow Fever virus, Japanese Encephalitis virus, St. Louis Encephalitis virus, etc.). Dengue viruses are arboviruses (arthropod-borne virus) that are transmitted primarily to humans through the bite of an infected Aedes species mosquito. Transmission may also occur through transfusion of infected blood or transplantation of infected organs or tissues. Human transmission of dengue is also known to occur after occupational exposure in healthcare settings (e.g., needle stick injuries) and cases of vertical transmission have been described in the literature (i.e., transmission from a dengue infected pregnant mother to her fetus in utero or to her infant during labor and delivery).

Clinical Dengue

Infection with any of the four dengue serotypes can produce the full spectrum of illness and severity. The spectrum of illness can range from a mild, non-specific febrile syndrome to classic dengue fever (DF), to the severe forms of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Severe forms typically manifest after a two to seven day febrile phase and are often heralded by clinical and laboratory warning signs. Early clinical recognition of dengue infection and anticipatory treatment for those who develop DHF or DSS can save lives. While no therapeutic agents exist for dengue infections, the key to the successful management is timely and judicious use of supportive care, including administration of isotonic intravenous fluids or colloids, and close monitoring of vital signs and hemodynamic status, fluid balance, and hematologic parameters. (Recommended therapies and treatment courses for DF, DHF and DSS can be found at the links provided below.)

As the early presentations of DF and DHF/DSS are similar and the course of infection is short, timely identification of persons that will develop severe manifestations can be challenging. There is a long-standing debate as to whether DHF/DSS represents a separate pathophysiological process or is merely the opposite end of a continuum of the same illness. DF follows an uncomfortable but relatively benign self-limited course. DHF may appear as a relatively benign infection at first but can quickly develop into life-threatening illness as fever abates. DHF can usually be distinguished from DF as it progresses through its three predictable pathophysiological phases:

  • Febrile phase: Viremia-driven high fevers
  • Critical/plasma leak phase: Sudden onset of varying degrees of plasma leak into the pleural and abdominal cavities
  • Convalescence or reabsorption phase: Sudden arrest of plasma leak with concomitant reabsorption of extravasated plasma and fluids

For optimal management of the patient with dengue infection, it is important to understand these phases and to be able to distinguish DHF from DF. Early recognition of a patient's clinical phase is important in order to tailor clinical management, monitor effectiveness of the treatment, and to anticipate when changes in their management are needed.

Dengue infected patients are either asymptomatic or they have one of three clinical presentations:

Asymptomatic Infection: As many as one half of all dengue infected individuals are asymptomatic, that is, they have no clinical signs or symptoms of disease._

Undifferentiated Fever: The first clinical course is a relatively benign scenario where the patient experiences fever with mild non-specific symptoms that can mimic any number of other acute febrile illnesses. They do not meet case definition criteria for DF. The non-specific presentation of symptoms make positive diagnosis difficult based on physical exam and routine tests alone. For the majority of these patients, unless dengue diagnostic serological or molecular testing is performed, the diagnosis will remain unknown. These patients are typically young children or those experiencing their first infection, and they recover fully without need for hospital care.

Dengue Fever with or without hemorrhage: The second clinical presentation occurs when a patient develops DF with or without hemorrhage. These patients are typically older children or adults and they present with two to seven days of high fever (occasionally biphasic) and two or more of the following symptoms: severe headache, retro-orbital eye pain, myalgias, arthralgias, a diffuse erythematous maculo-papular rash, and mild hemorrhagic manifestation. Subtle, minor epithelial hemorrhage, in the form of petechiae, are often found on the lower extremities (but may occur on buccal mucosa, hard and soft palates and or subconjunctivae as well), easy bruising on the skin, or the patient may have a positive tourniquet test. Other forms of hemorrhage such as epistaxis, gingival bleeding, gastrointestinal bleeding, or urogenital bleeding can also occur, but are rare. Leukopenia is frequently found and may be accompanied by varying degrees of thrombocytopenia. Children may also present with nausea and vomiting. Patients with DF do not develop substantial plasma leak (hallmark of DHF and DSS, see below) or extensive clinical hemorrhage. Serological testing for anti-dengue IgM antibodies or molecular testing for dengue viral RNA or viral isolation can confirm the diagnosis, but these tests often provide only retrospective confirmation, as results are typically not available until well after the patient has recovered.

Clinical presentation of DF and the early phase of DHF are similar, and therefore it can be difficult to differentiate between the two forms early in the course of illness. With close monitoring of key indicators, the development of DHF can be detected at the time of defervescence so that early and appropriate therapy can be initiated. The key to successfully managing patients with dengue infection and lowering the probability of medical complications or death due to DHF or DSS is early recognition and anticipatory treatment.

Dengue Hemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS): The third clinical presentation results in the development of DHF, which in some patients progresses to DSS. Vigilant is critical for identifying warning signs of progressing illness and early symptoms of DHF which are very similar to those of DF.

There are three phases of DHF: the Febrile Phase ; the Critical (Plasma Leak) Phase; and the Convalescent (Reabsorption) Phase.

The Febrile Phase: Early in the course of illness, patients with DHF can present much like DF, but they may also have hepatomegaly without jaundice. The hemorrhagic manifestations that occur in the early course of DHF most frequently consist of mild hemorrhagic manifestations as in DF. Less commonly, epistaxis, bleeding of the gums, or frank gastrointestinal bleeding occur while the patient is still febrile (gastrointestinal bleeding may commence at this point, but commonly does not become apparent until a melenic stool is passed much later in the course). Dengue viremia is typically highest in the first three to four days after onset of fever but then falls quickly to undetectable levels over the next few days. The level of viremia and fever usually follow each other closely, and anti-dengue IgM anti-bodies increase as fever abates.

The Critical (Plasma Leak) Phase: About the time when the fever abates, the patient enters a period of highest risk for developing the severe manifestations of plasma leak and hemorrhage. At this time, it is vital to watch for evidence of hemorrhage and plasma leak into the pleural and abdominal cavities and to implement appropriate therapies replacing intravascular losses and stabilizing effective volume. If left untreated, this can lead to intravascular volume depletion and cardiovascular compromise. Evidence of plasma leak includes sudden increase in hematocrit (≥20% increase from baseline), presence of ascites, a new pleural effusion on lateral decubitus chest x-ray, or low serum albumin or protein for age and sex. Patients with plasma leak should be monitored for early changes in hemodynamic parameters consistent with compensated shock such as increased heart rate (tachycardia) for age especially in the absence of fever, weak and thready pulse, cool extremities, narrowing pulse pressure (systolic blood pressure minus diastolic blood pressure <20 mmHg), delayed capillary refill (>2 seconds), and decrease in urination (i.e., oliguria). Patients exhibiting signs of increasing intravascular depletion, impending or frank shock, or severe hemorrhage should be admitted to an appropriate level intensive care unit for monitoring and intravascular volume replacement. Once a patient experiences frank shock he or she will be categorized as having DSS. Prolonged shock is the main factor associated with complications that can lead to death including massive gastrointestinal hemorrhage. Interestingly, many patients with DHF/DSS remain alert and lucid throughout the course of the illness, even at the tipping point of profound shock.

Anticipatory management and monitoring indicators are essential in effectively administering therapies as the patient enters the Critical Phase. New-onset leucopenia (WBC <5,000 cells/mm3) with a lymphocytosis and an increase in atypical lymphocytes indicate that the fever will likely dissipate within the next 24 hours and that the patient is entering into the Critical Phase. Indicators that suggest the patient has already entered the Critical Phase include sudden change from high (>38.0°C) to normal or subnormal temperatures, thrombocytopenia (≤100,000 cells/mm3) with a rising or elevated hematocrit (≥20% increase from baseline), new hypoalbuminemia or hypocholesterolemia, new pleural effusion or ascites, and signs and symptoms of impending or frank shock.

Again, the key to successfully managing patients with DHF and lowering the probability of complications or death is early recognition and anticipatory treatment. Supportive care and timely but measured intravascular volume replacement during the Critical Period are the mainstays of treatment for DHF and DSS. Fortunately, the Critical Period lasts no more than 24 to 48 hours. Most of the complications that arise during this period—such as hemorrhage and metabolic abnormalities (e.g., hypocalcemia, hypoglycemia, hyperglycemia, lactic acidosis, and hyponatremia) are frequently related to prolonged shock. Hence, the principal objective during this period is to prevent prolonged shock and support vital systems until plasma leak subsides. Careful attention must be paid to the type of intravenous fluid (or blood product if transfusion is needed) administered, the rate, and the volume received over time. Frequent monitoring of intravascular volume, vital organ function, and the patient's response are essential for successful management during the Critical Phase. Monitoring for overt and occult hemorrhage (which may be another source of intravascular depletion) is also important. Transfusion of volume-replacing blood products should be considered if substantial hemorrhage is suspected during this phase.

The Convalescent (Reabsorption) Phase: The third phase begins when the Critical Phase ends and is characterized when plasma leak stops and reabsorption begins. During this phase, fluids that leaked from the intravascular space (i.e., plasma and administered intravenous fluids) during the Critical Phase are reabsorbed. Indicators suggesting that the patient is entering the Convalescent Phase include sense of improved well being reported by the patient, return of appetite, stabilizing vital signs (widen pulse pressure, strong palpable pulse), bradycardia, hematocrit levels returning to normal, increased urine output, and appearance of the characteristic Convalescence Rash of Dengue (i.e., a confluent sometimes pruritic, petechial rash with multiple small round islands of unaffected skin). At this point, care must be taken to recognize signs indicating that the intravascular volume has stabilized (i.e., that plasma leak has halted) and that reabsorption has begun. Modifying the rate and volume of intravenous fluids (and often times discontinuing intravenous fluids altogether) to avoid fluid overload as the extravasated fluids return to the intravascular compartment is important. Complications that arise during Convalescent (Reabsorption) Phase are frequently related to the intravenous fluid management. Fluid overload may result from use of hypotonic intravenous fluids or over use or continued use of isotonic intravenous fluids during the Convalescence Phase.

Although an infected patient will likely have been very uncomfortable (from eye, joint, bone, muscle, or head pain) during the illness, barring complications such as fluid overload or mechanical ventilation nearly all patients with DHF recover rapidly with timely initiation of judicious fluid management and careful monitoring. This is due to the fact that the period of increased vascular permeability is time-limited (lasting 24 to 48 hours) and the functional change in the vascular endothelium appears to be entirely reversible with no known permanent structural defect. Even those with complications, if managed successfully, often recover fully without sequelae.

CDC DENV-1-4 Real-Time RT-PCR Assay

The CDC Real Time RT-PCR Assay for Dengue Diagnosis

Dengue is one of the most common causes of fever. Dengue virus (DENV) infection can be divided into two phases: acute and convalescent. The acute phase begins with the onset of symptoms and lasts approximately 5 days. The convalescent phase begins once the fever subsides and lasts 4 to 7 days.

Patients with dengue usually have symptoms when DENV is present in the blood. Virus levels in the blood are usually higher during the first 5 days of the illness. The CDC Real Time RT-PCR assay detects DENV in a significantly high proportion of cases during this time, very early after the onset of symptoms of dengue. This is important because an early laboratory confirmation of a dengue diagnosis helps physicians managing the case.

The CDC developed this assay using the Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument, used for influenza testing. CDC adapted their dengue RT-PCR test to take advantage of this widely used testing platform in order to facilitate the use of molecular testing for dengue diagnosis.

Characteristics of the CDC Real Time RT-PCR Assay

This assay detects DENV serotypes 1, 2, 3 or 4 from human serum or plasma collected from human patients with signs and symptoms consistent with dengue infection. The assay is intended to be used as a diagnostic test in patients and is not approved for blood bank screening.

The CDC DENV-1-4 Real-Time RT-PCR Assay includes:

  • Oligonucleotide primers and dual-labeled hydrolysis (Taqman®) probes for in vitro qualitative detection of dengue virus serotypes 1, 2, 3 or 4 from serum or plasma collected from human patients with signs and symptoms consistent with dengue (mild or severe).
  • Positive control virus mix, which consists of heat-inactivated DENV-1 Haw, DENV-2 NGC, DENV-3 H87, and DENV-4 H241.
  • Human Specimen Control (HSC) is a noninfectious cultured human cell material that provides a positive signal in the assay and demonstrates successful recovery of RNA as well as the integrity of the RNA extraction reagent.

The human RNase P RNA (RP) is present in cultured cell material and in most clinical samples and detectable by RT-PCR using the primers and probes provided. The device does not include ancillary reagents.

The CDC DENV-1-4 Real-Time RT-PCR Assay can be run in singleplex (each DENV serotype detected in a separate reaction) or in multiplex (the four DENV serotypes are run in the same reaction). These two formats provide equal sensitivity.

Intended Use of the CDC DENV-1-4 Real Time RT-PCR Assay

The CDC DENV-1-4 Real-Time RT-PCR Assay is intended for use on an Applied Biosystems (ABI) 7500 Fast Dx Real-Time PCR Instrument:

  • For the diagnosis of dengue in serum or plasma collected from patients with signs and symptoms consistent with dengue (mild or severe);
  • For the identification of dengue virus serotypes 1, 2, 3 or 4 from viral RNA in serum or plasma (sodium citrate) collected from human patients with dengue;
  • To provide epidemiologic information for surveillance of circulating dengue viruses.
  • Testing of clinical blood specimens (serum or plasma) with the CDC DENV-1-4 Real-Time RT-PCR Assay should not be performed unless the patient meets clinical and/or epidemiologic criteria for testing suspect dengue cases.

The CDC DENV-1-4 Real-Time RT-PCR Assay is not approved for the screening of blood or plasma donors.

Positive results on the CDC DENV-1-4 Real Time RT-PCR Assay indicate current dengue infection. Blood samples from patients suspected of having dengue taken 1-5 days after fever onset should be tested with this device. Negative results obtained with this test do not preclude the diagnosis of dengue and should not be used as the sole basis for treatment or other patient management decisions. If RT-PCR results are negative, anti-DENV IgM testing should be considered (E.g. Inbios DENV Detect IgM Capture ELISA). If the blood sample is taken from a patient 5 or more days after the onset of symptoms, laboratory diagnosis is best made using a test for IgM antibody to DENV.

Assay Distribution

The CDC DENV-1-4 Real Time RT-PCR Assay will be distributed to laboratories with personnel who have training and experience in standardized molecular diagnostic testing procedures and viral diagnosis, and appropriate biosafety equipment and containment.

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