AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Dengue, a Spanish alteration of a 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, with the type-specific virus being yellow fever.

The dengue virus has 4 closely related but distinct serotypes, DEN1-DEN4. It maintains an infection cycle that uses mosquitoes, mostly the Aedes aegypti mosquito, 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 Images 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 Images 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 Image 7). Rare reports of human-to-human transmission of the virus via needlestick injuries have also been published.

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 a 2.5 X 2.5-cm area). Dengue fever is rarely fatal.

DHF occurs less frequently than DF but has a more dramatic clinical presentation. In Asia, where it first was described, DHF is primarily a disease of children. However, in the Americas, DHF has an equal distribution in all ages.

The critical feature of DHF is plasma leakage. This results from endothelial gaps in the peripheral vascular bed without necrotic or inflammatory changes in the endothelium. DHF typically begins with the initial manifestations of DF. The acute febrile illness (temperatures as high as 40°C), like that of DF, lasts approximately 2-7 days. However, in persons with DHF, the fever reappears, giving a biphasic or "saddleback" fever curve that is not observed in individuals with DF. Along with this biphasic fever, patients with DHF 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 DHF may have circulatory failure and hepatomegaly. The major pathologic difference between DF and DHF is that the marked vascular leakage, with resultant hemoconcentration and serous effusions, can lead to circulatory collapse (ie, DSS).

The progression of DHF to DSS can be prevented by close observation of clinical changes and the use of isotonic intravenous fluids. As the term implies, DSS is essentially DHF 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 DF to DHF 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. Most patients are travelers to endemic regions of the American and Asian tropics (see Image 4). During 1977-1995, a total of 2706 suspected cases were reported, of which, 22% were confirmed by laboratory findings.

International

Each year, an estimated 50-100 million cases of DF and several hundred thousand cases of DHF occur. In 1995, 250,000 cases of DF and 7,000 cases of DHF occurred in the Americas alone. As many as 3 billion people live in areas where dengue is endemic (see Images 3-4 and Image 6).

Mortality/Morbidity

• DF is typically a self-limiting disease with a mortality rate of less then 1%.
• When treated, DHF has a mortality rate of 5%.
• Untreated, DHF 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 DF. However, children younger than 15 years typically present with only a nonspecific, self-limited, febrile illness.
• In Southeast Asia, DHF is primarily an illness of children and is the leading cause of death and hospitalization in that population. Elsewhere, the disease affects all ages.

CLINICAL

Section 3 of 11  

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• Follow-up
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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 DF and other febrile viral illnesses.
  • When the fever breaks, after 2-7 days, signs of plasma leakage appear, suggesting the diagnosis of DHF (usually within 24 h before or after fever resolution).
  • The World Health Organization (WHO) has 4 minimal criteria to make the diagnosis of DHF:
    • 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, DHF mostly likely progresses to DSS.
  • 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:

• DF
• • Fever
  • Injected conjunctivae
  • Inflamed pharynx
  • Lymphadenopathy
  • Maculopapular rash
  • Hemorrhagic findings (petechiae, purpura, bleeding gums, epistaxis, menorrhagia, positive tourniquet test, hematuria)
• DHF: Findings for DHF are similar to DF and also include the following:
• • Biphasic fever curve
  • Hemorrhagic findings more pronounced than in dengue fever
  • Signs of peritoneal and/or pleural effusion
• DSS
• • 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.
• 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.

DIFFERENTIALS

Section 4 of 11  

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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

WORKUP

Section 5 of 11  

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• Clinical
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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

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.
• Recently developed, 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 DHF.

TREATMENT

Section 6 of 11  

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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 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 DIC is extensive.
  • Administer acetaminophen for fever control (not salicylates or ibuprofen, which further can 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.

MEDICATION

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With the exception of volume replacement (with isotonic fluids) and acetaminophen, no specific medications are available for the treatment of dengue infection.

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 Category: Fluid therapy

Isotonic 0.9% sodium chloride solution is administered intravenously to maintain adequate BP and adequate urine output.

FOLLOW-UP

Section 8 of 11  

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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 DHF or DSS.

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
• Take a second (ie, convalescent) blood sample for serologic testing 4-6 weeks after the illness.

Transfer

• Transfer patients with DHF or DSS 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 DF to DHF and/or DSS (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 exists. The estimates of the time needed for further testing range from 5-10 years.

Complications

• Complications and sequelae of dengue virus infections are rare but may include the following:
• • Cardiomyopathy
  • Encephalopathy and viral encephalitis
  • Hepatic injury
• Although rare, a number of incidents of vertical transmission of the dengue virus from an infected mother to her newborn, leading to DF and DHF and/or DSS, 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

• Please see Deterrence/Prevention section.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to admit patient for supportive care and other causes of fever
• Failure to investigate other symptoms

MULTIMEDIA

Section 10 of 11  

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• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

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 theWorld 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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REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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• Follow-up
• Miscellaneous
• Multimedia
• References

• Bhamarapravati N, Sutee Y. Live attenuated tetravalent dengue vaccine. Vaccine. May 26 2000;18 Suppl 2:44-7. [Medline].
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• Bruce MG, Sanders EJ, Leake JA, et al. Leptospirosis among patients presenting with dengue-like illness in Puerto Rico. Acta Trop. Oct 2005;96(1):36-46. [Medline].
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• Isturiz RE, Gubler DJ, Brea del Castillo J. Dengue and dengue hemorrhagic fever in Latin America and the Caribbean. Infect Dis Clin North Am. Mar 2000;14(1):121-40, ix. [Medline].
• Mota J, Acosta M, Argotte R, et al. Induction of protective antibodies against dengue virus by tetravalent DNA immunization of mice with domain III of the envelope protein. Vaccine. May 16 2005;23(26):3469-76. [Medline].
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• Thammapalo S, Chongsuwiwatwong V, Geater A, et al. Socio-demographic and environmental factors associated with Aedes breeding places in Phuket, Thailand. Southeast Asian J Trop Med Public Health. Mar 2005;36(2):426-33. [Medline].
• Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis. Jan 2000;181(1):2-9. [Medline].
• WHO. Dengue haemorrhagic fever: diagnosis, treatment, prevention and control. 2nd ed. Geneva: World Health Organization;1997. [Full Text].
• Wagner D, de With K, Huzly D, et al. Nosocomial acquisition of dengue. Emerg Infect Dis. Oct 2004;10(10):1872-3. [Medline].
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Article Last Updated: Nov 9, 2006