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AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Hagop A Isnar, MD, FACEP, Associate Medical Director, Consulting Staff, Department of Emergency Medicine, Auburn Memorial Hospital
Hagop A Isnar is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine
Coauthor(s):
Deborah Sentochnik, MD, Consulting Staff, Department of Internal Medicine, Division of Infectious Disease, The Mary Imogene Bassett Hospital
Editors: Ashir Kumar, MBBS, MD, FAAP, Professor, Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University; Consulting Staff, Department of Pediatrics, EW Sparrow Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine; Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York-Upstate Medical University; Robert W Tolan Jr, MD, Chief, Division of Allergy, Immunology and Infectious Diseases, The Children's Hospital at Saint Peter's University Hospital; Clinical Associate Professor of Pediatrics, Drexel University College of Medicine; Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Author and Editor Disclosure
Synonyms and related keywords:
dengue, mosquito, Aden fever, bouquet fever, breakbone fever, dandy fever, date fever, dengue fever, DF, dengue hemorrhagic fever, DHF, dengue shock syndrome, DSS, dengue virus, exanthesis arthrosia, polka fever, scarlatina rheumatica, solar fever, DEN1, DEN2, DEN3, DEN4, yellow fever, thrombocytopenia, leukopenia, Aedes aegypti, hepatomegaly, peritoneal effusion, pleural effusion
Background
Dengue, a Spanish alteration of the Swahili word Ki-dinga, is the most common mosquito-borne viral illness in humans. The earliest known documentation of denguelike symptoms was recorded in the Chinese Encyclopedia of Symptoms during the Chin Dynasty (AD 265-420). The illness was called "the water poison" and was associated with flying insects near water. Today, dengue is known to be caused by a single-stranded RNA virus (approximately 11 kilobases long) with an icosahedral nucleocapsid and covered by a lipid envelope. The virus is in the family Flaviviridae (of the genus Flavivirus), and the type-specific virus is yellow fever. The dengue virus has 4 closely related but distinct serotypes, DEN1-DEN4.1 It maintains an infection cycle that uses mosquitoes, mostly the Aedes aegypti mosquito,2 as vectors to human hosts, who also serve as sources of viral amplification. A aegypti is a small, highly domesticated, black-and-white tropical insect that prefers to feed on humans (favoring ankles and the back of the neck). See Media files 1-2. The insect typically lays its eggs in artificial containers that contain water, and, as a consequence, dengue is frequently an urban-acquired disease. In 1779-1780, the first reported outbreak of dengue fever (DF) occurred almost simultaneously in Asia, North America, and Africa. This indicates that the virus and its vector have a worldwide distribution in the tropical regions of the world (see Media files 3-4). The clinical presentation of dengue infection involves a wide spectrum of findings, from asymptomatic or mild self-limiting infection of dengue fever to potentially fatal hemorrhage and shock (dengue hemorrhagic fever [DHF], dengue shock syndrome [DSS]).
Pathophysiology
The pathologic process of dengue infection starts with an intimate relationship between the host and the vector that carries the virus. Humans become infected with the virus after an infected mosquito feeds or probes on the susceptible human host (see Media file 7). Rare reports of human-to-human transmission via needlestick injuries have also been published.3 Infection with dengue virus manifests a wide spectrum of clinical presentations. In most cases, especially in children younger than 15 years, the patient is asymptomatic or has a mild undifferentiated febrile illness. Typical dengue fever is a self-limiting, acute, febrile illness, which occurs after an incubation period of 4-7 days. In younger children, it may be accompanied by a maculopapular rash. In older patients, the disease may also be mild or it may be more incapacitating, with rapid onset of high fever, headache, retroorbital pain, diffuse body pain (both muscle and bone), weakness, vomiting, sore throat, altered taste sensation, and a centrifugal maculopapular rash, among others. This painful "breakbone" and febrile phase lasts 2-7 days and, afterward, most patients slowly improve. Dengue virus disappears from the bloodstream at approximately the same time that the fever dissipates. Leukopenia and thrombocytopenia are common findings in dengue fever and are believed to be caused by direct destructive actions of the virus on bone marrow precursor cells. The resulting active viral replication and cellular destruction in the bone marrow are believed to cause the bone pain. Approximately one third of patients with dengue fever may have mild hemorrhagic symptoms, including petechiae, gingival bleeding, and a positive tourniquet test (>20 petechiae in an area of 2.5 cm X 2.5 cm). Dengue fever is rarely fatal. Dengue hemorrhagic fever occurs less frequently than dengue fever but has a more dramatic clinical presentation. In Asia, where it first was described, dengue hemorrhagic fever is primarily a disease of children. However, in the Americas, dengue hemorrhagic fever has an equal distribution in all ages. The critical feature of dengue hemorrhagic fever is plasma leakage. This results from endothelial gaps in the peripheral vascular bed without necrotic or inflammatory changes in the endothelium. Dengue hemorrhagic fever typically begins with the initial manifestations of dengue fever. The acute febrile illness (temperatures ≤40°C), like that of dengue fever, lasts approximately 2-7 days. However, in persons with dengue hemorrhagic fever, the fever reappears, giving a biphasic or "saddleback" fever curve that is not observed in individuals with dengue fever. Along with this biphasic fever, patients with dengue hemorrhagic fever have progressive thrombocytopenia, increasing hematocrit (20% absolute rise from baseline) that leads to hemoconcentration, more obvious hemorrhagic manifestations (>50% of patients have a positive tourniquet test), and progressive effusions (pleural or peritoneal). Accompanying the hemorrhagic phenomena, patients with dengue hemorrhagic fever may have circulatory failure and hepatomegaly. The major pathologic difference between dengue fever and dengue hemorrhagic fever is that the marked vascular leakage, with resultant hemoconcentration and serous effusions, can lead to circulatory collapse (ie, dengue shock syndrome). The progression of dengue hemorrhagic fever to dengue shock syndrome can be prevented by close observation of clinical changes and the use of isotonic intravenous fluids. As the term implies, dengue shock syndrome is essentially dengue hemorrhagic fever with progression into circulatory failure, with ensuing hypotension, narrow pulse pressure (<20 mm Hg), and, ultimately, shock and death if untreated. Death may occur 8-24 hours after onset of signs of circulatory failure. The most common clinical findings in impending shock include hypothermia, abdominal pain, vomiting, and restlessness. The mechanism of progression from dengue fever to dengue hemorrhagic fever is not clearly understood. However, immune enhancement is the most commonly accepted current explanation. This hypothesis states that individuals who have had a prior infection (ie, primary infection) with 1 of the 4 dengue virus serotypes have circulating nonneutralizing antiviral antibodies. When an individual is infected with another serotype (ie, secondary infection), these nonneutralizing antibodies recognize the dengue virus but do not neutralize or inhibit virus replication. Instead, the virus and antibody form an antigen-antibody complex. This complex is recognized by receptors on macrophages, which then internalize the immune complex and allow the virus to replicate unchecked (ie, immune enhancement). The affected macrophages release vasoactive mediators that increase vascular permeability, leading to vascular leakage, hypovolemia, and shock. Recent research demonstrated that this mechanism, along with individual host and viral genome variations, plays an active role in pathogenesis.
Frequency
United States
The US Centers for Disease Control and Prevention (CDC) fact sheet on dengue and DHF reports approximately 100-200 suspected cases of dengue infection per year.4 Most patients are travelers to endemic regions of the American and Asian tropics (see Media file 4). During 1977-1995, a total of 2706 suspected cases were reported; 22% were confirmed by laboratory findings.
International
Each year, an estimated 50-100 million cases of dengue fever and several hundred thousand cases of dengue hemorrhagic fever occur. In 1995, 250,000 cases of dengue fever and 7,000 cases of dengue hemorrhagic fever occurred in the Americas alone. As many as 3 billion people live in areas where dengue is endemic (see Media files 3-4 and Media file 6).
Mortality/Morbidity
- Dengue fever is typically a self-limiting disease with a mortality rate of less then 1%.
- When treated, dengue hemorrhagic fever has a mortality rate of 5%. Untreated, dengue hemorrhagic fever has a mortality rate as high as 50%.
Race
The disease is distributed worldwide in tropical areas.
Sex
Incidence is equal in males and females.
Age
Persons of all ages can be infected and develop dengue fever. However, children younger than 15 years typically present with only a nonspecific, self-limited, febrile illness. In Southeast Asia, dengue hemorrhagic fever is primarily an illness of children and is the leading cause of death and hospitalization in that population. Elsewhere, the disease affects all ages.
History
Infection with the dengue virus produces a wide spectrum of disease manifestations, from asymptomatic or mild febrile illness to fatal hemorrhagic shock.
- Classic dengue fever (DF)
- Children younger than 15 years usually have a nonspecific febrile syndrome, which may be accompanied by a maculopapular rash.
- Patients present with fever and any combination of the following symptoms:
- Headache
- Retroorbital pain
- General body pain (arthralgias, myalgias)
- Vomiting
- Centrifugal maculopapular rash
- Weakness
- Altered taste sensation
- Anorexia
- Sore throat
- Mild hemorrhagic manifestations (eg, petechiae, bleeding gums, epistaxis, menorrhagia, hematuria)
- Lymphadenopathy
- The febrile and painful breakbone phase lasts approximately 2-7 days and is followed by a period of slow but complete recovery. The convalescent phase may last for 2 weeks.
- Dengue hemorrhagic fever (DHF)
- Initial phase is similar to that of dengue fever and other febrile viral illnesses.
- When the fever breaks, after 2-7 days, signs of plasma leakage appear, suggesting the diagnosis of dengue hemorrhagic fever (usually within 24 h before or after fever resolution).
- The World Health Organization (WHO) has 4 minimal criteria to make the diagnosis of dengue hemorrhagic fever:5
- Fever
- Hemorrhagic manifestations (eg, hemoconcentration, thrombocytopenia, positive tourniquet test)
- Circulatory failure, such as signs of vascular permeability (eg, hypoproteinemia, effusions)
- Hepatomegaly
- Dengue shock syndrome (DSS)
- Untreated, dengue hemorrhagic fever mostly likely progresses to dengue shock syndrome.
- Common symptoms in impending shock include abdominal pain, vomiting, and restlessness. Patients also may have symptoms related to circulatory failure.
Physical
Common clinical findings include the following: - Dengue fever
- Fever
- Injected conjunctivae
- Inflamed pharynx
- Lymphadenopathy
- Maculopapular rash
- Hemorrhagic findings (petechiae, purpura, bleeding gums, epistaxis, menorrhagia, positive tourniquet test, hematuria)
- Dengue hemorrhagic fever: Findings for dengue hemorrhagic fever are similar to dengue fever and also include the following:
- Biphasic fever curve
- Hemorrhagic findings more pronounced than in dengue fever
- Signs of peritoneal effusion, pleural effusion, or both
- Dengue shock syndrome
- Hypotension
- Bradycardia (paradoxical) or tachycardia associated with hypovolemic shock
- Hepatomegaly
- Hypothermia
- Narrow pulse pressure (<20 mm Hg)
- Signs of decreased peripheral perfusion
Causes
- Living in endemic areas of the tropics (or warm moist climates such as the southern United States) where the vector mosquito thrives is an important risk factor for infection.1, 6, 7, 8, 9
- Poorly planned urbanization combined with explosive global population growth brings the mosquito and the human host into close proximity.
- Increased air travel easily transports infectious diseases between populations.
- The most widely used mosquito-control technique, spraying cities to kill adult mosquitoes, is not effective. Efforts should target the larval phase with larvicides and cleaning up larvae habitats (eg, garbage, areas that accumulate stagnant water).
- Poor sanitation and poor refuse control provide excellent conditions for mosquito larvae to grow.
- Lack of immunity to the virus serotypes contributes to infection rates in a population.
- Hurricanes and other natural disasters increase the habitat for mosquito growth in urban areas by increasing rubble and garbage, which act as water reservoirs.
Bacteremia
Influenza
Leptospirosis
Malaria
Measles
Meningitis, Bacterial
Rickettsial Infection
Rocky Mountain Spotted Fever
Sepsis
Yellow Fever
Other Problems to be Considered
Typhoid fever
River Virus
Chikungunya
West Nile encephalitis
Roseola infantum
Scarlet fever
Idiopathic thrombocytopenic purpura
Other causes of viral hemorrhagic fever
Lab Studies
- Hematologic and chemistry studies may reveal hemorrhagic or organ dysfunction.
- CBC count to evaluate for leukopenia, thrombocytopenia (<100 X 109/L), and increasing hematocrit levels (increase of 20% indicates hemoconcentration; serial hematocrit levels needed every 4 h)
- Chemistry panel to evaluate for imbalances
- Serum protein and albumin levels
- Liver function tests to evaluate for elevated transaminases
- Disseminated intravascular coagulation (DIC) panel
- Urinalysis identifies hematuria.
- Type and crossmatch may be needed if significant hemorrhage ensues.
- Dengue can be identified by using virus isolation (ie, growing sample in a cell line) or serologic identification, using enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin (Ig) G or IgM. Request that a sample be sent to CDC for further testing.
- A reverse-transcriptase polymerase chain reaction (PCR) test demonstrates more promise, yielding a serotype-specific diagnosis very rapidly; however, this test is currently available only in research laboratories.
Imaging Studies
- Perform chest radiography to look for pleural effusions.
Procedures
- Patient may need a central line for volume replacement and an arterial line for accurate blood pressure (BP) monitoring and frequent blood tests.
- Exercise caution when placing intravascular catheters because of the increased bleeding complications of dengue hemorrhagic fever (DHF).
Medical Care
Supportive care is the only known therapy effective in dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). - Prehospital
- Start an intravenous access line and initiate intravenous fluid supplementation with normal saline (NS) solution.
- Administer fluid boluses as needed to maintain adequate blood pressure (BP).
- Administer oxygen.
- Hospital
- Continue supportive care by administering isotonic NS solution intravenously to maintain adequate BP and adequate urine output.
- Bolus of 10-20 mL/kg every 30 minutes may be required to maintain BP.
- Foley catheter is helpful in monitoring urine output.
- The plasma leakage period is short (24-48 h), and intravenous fluids may be reduced if the patient maintains adequate oral hydration.
- When the plasma leakage phase starts to resolve, the hematocrit level begins to fall, making identification of significant occult hemorrhage difficult.
- Administer blood transfusion if significant hemorrhage ensues. (GI bleeding may be profound.)
- Administer fresh frozen plasma or platelets if disseminated intravascular coagulation (DIC) is extensive.
- Administer acetaminophen for fever control (not salicylates or ibuprofen, which can further hinder platelet function and increase bleeding complications).
- Glucocorticoids are not indicated.
Consultations
Obtain consultation with an infectious disease specialist and phone consultation with the CDC. Intensive care is mandatory for all patients in hemorrhagic shock.
With the exception of volume replacement (with isotonic fluids) and acetaminophen, no specific medications are available for the treatment of dengue infection.
Early research by Novartis Institute for Tropical Diseases (NITD) in Singapore is carrying out research to find inhibitors of dengue viral targets proteins to reduce the viral load during active infection.10
Drug Category: Antipyretic agents
These agents are used to reduce fever. They inhibit central synthesis and the release of prostaglandins that mediate the effect of endogenous pyrogens in the hypothalamus and, thus, promote the return of the set-point temperature to normal.
| Drug Name | Acetaminophen (Tylenol, Feverall, Tempra, Aspirin Free Anacin) |
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| Description | Has both analgesic and antipyretic properties similar to aspirin and other NSAIDs. Has no peripheral anti-inflammatory activity or effects on platelet function. |
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| Adult Dose | 325-650 mg/dose PO/PR q4-6h prn; not to exceed 4 g/d |
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| Pediatric Dose | <12 years: 10-15 mg/kg/dose PO/PR q4-6h prn; not to exceed 5 doses/d and 2.6 g/d
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Rifampin can reduce analgesic effects; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity |
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| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
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| Precautions | Hepatotoxicity possible in persons with chronic alcoholism following various dose levels; severe or recurrent pain or high or continued fever may indicate serious illness; contained in many OTC products, and combined use with these products may result in cumulative doses exceeding recommended maximum dose |
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Drug Category: Fluid therapy
Isotonic 0.9% sodium chloride solution is intravenously administered to maintain adequate BP and adequate urine output.
| Drug Name | Sodium chloride 0.9% (Normal saline) |
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| Description | To increase intravascular volume and maintain adequate BP and urine output. Restores sodium ion in patients with restricted oral intake, especially hyponatremia states or low-salt syndrome. |
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| Adult Dose | 24-h maintenance plus 5% body-weight deficit
10-20 mL/kg IV bolus q30min prn to maintain BP and urine output; discontinue 48 h after resolution of shock |
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| Pediatric Dose | 24-h maintenance plus 5% body-weight deficit
10-20 mL/kg IV q30min prn to maintain BP and urine output; discontinue 48 h after resolution of shock |
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| Contraindications | Fluid overload |
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| Interactions | None reported |
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| Pregnancy | A - Fetal risk not revealed in controlled studies in humans
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| Precautions | Avoid fluid overload, which may produce massive effusion, congestive heart failure, and eventual respiratory failure; close monitoring of BP (q30-60min), urine output (qh), and serial hematocrits |
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Further Inpatient Care
- Patients with dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS) require admission into the ICU.
- Patients with dengue fever (DF) require transfer into the ICU if their illness progresses to dengue hemorrhagic fever or dengue shock syndrome.
Further Outpatient Care
- Patients may be discharged when they meet the following criteria:
- Afebrile for 24 hours
- Appetite returned
- Clinical picture improved
- Respiratory distress (ie, from pleural effusions) absent
- Hematocrit stable
- Platelet count greater than 50 X 109/L
- Hospital monitoring for at least 3 days after the resolution of shock
- Obtain a second (ie, convalescent) blood sample for serologic testing 4-6 weeks after the illness.
Transfer
- Transfer patients with dengue hemorrhagic fever or dengue shock syndrome if unable to observe in an ICU.
Deterrence/Prevention
- Avoid risk factors listed in Causes.
- Use insect repellents and protective clothing to prevent bites by disease-carrying mosquitoes.
- Apply insecticides in living and sleeping areas.
- Control larvae by reducing larval habitat (eg, garbage) and using larvicides.
- A tetravalent (containing all 4 serotypes) vaccine was tested in volunteers in Thailand and was found safe and immunogenic.
- Given the proposed pathogenic mechanism of progression from dengue fever to dengue hemorrhagic fever and/or dengue shock syndrome (ie, immune enhancement), any effective vaccine clearly must be immunoprotective for all 4 serotypes. Inadequate vaccines may prove more harmful than good.
- No approved vaccine is available. The estimates of the time needed for further testing range from 5-10 years. In 2007, Sanofi Pasteur announced good results in its study of a tetravalent vaccine, with further testing to follow.11 Registration is anticipated in 2012.
Complications
- Complications and sequelae of dengue virus infections are rare but may include the following:
- Cardiomyopathy
- Encephalopathy and viral encephalitis
- Hepatic injury
- Although rare, numerous incidents of vertical transmission of the dengue virus from an infected mother to her newborn, leading to dengue fever and dengue hemorrhagic fever and/or dengue shock syndrome, have been reported.
Prognosis
- If adequate supportive measures are given, prognosis is excellent; no sequelae are reported in most individuals with the virus.
Patient Education
Medical/Legal Pitfalls
- Failure to admit patient for supportive care and other causes of fever
- Failure to investigate other symptoms
| Media file 1:
Drawing of Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 2:
Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 3:
Worldwide distribution of dengue in 2000. Picture from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 4:
Worldwide distribution of dengue in 2003. Picture from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 5:
Worldwide distribution of dengue in 2005. Picture from the Centers for Disease Control and Prevention (CDC) Web site |
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| Media file 6:
Increasing rates of dengue infection by regions of the world. Graphs from the World Health Organization (WHO) Web site. |
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| Media file 7:
Dengue transmission cycle. Illustration from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 8:
Distribution of Aedes aegypti mosquito vector in 1997. Picture from the Centers for Disease Control and Prevention (CDC) Web site. |
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| Media file 9:
Reinfestation by Aedes aegypti in the Americas after the 1970 (left) mosquito eradication program and most recent distribution as of 2002 (right). Picture from the Centers for Disease Control and Prevention (CDC) Web site |
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Dengue excerpt Article Last Updated: Oct 7, 2008
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