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Dengue Workup

  • Author: Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Oct 05, 2015
 

Approach Considerations

Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory confirmation of dengue infection is important. Laboratory criteria for diagnosis include one or more of the following:

  • Isolation of the dengue virus from serum, plasma, leukocytes, or autopsy samples
  • Demonstration of a fourfold or greater change in reciprocal immunoglobulin G (IgG) or immunoglobulin M (IgM) antibody titers to one or more dengue virus antigens in paired serum samples
  • Demonstration of dengue virus antigen in autopsy tissue via immunohistochemistry or immunofluorescence or in serum samples via enzyme immunoassay (EIA)
  • Detection of viral genomic sequences in autopsy tissue, serum, or cerebral spinal fluid (CSF) samples via polymerase chain reaction (PCR)

A reverse-transcriptase PCR test has demonstrated promise, yielding a serotype-specific diagnosis very rapidly.[51, 52] However, this test is currently available only in research laboratories.

The following laboratory tests should also be performed:

  • Complete blood count (CBC)
  • Metabolic panel
  • Serum protein and albumin levels
  • Liver panel
  • Disseminated intravascular coagulation (DIC) panel

Characteristic findings in dengue fever are thrombocytopenia (platelet count < 100 x 109/L), leukopenia, and mild-to-moderate elevation of aspartate aminotransferase and alanine aminotransferase values. Jaundice and acute liver failure are uncommon. Peak liver enzyme levels occur later than other complications in adults studied prospectively in Vietnam. Enzyme levels begin to rise during the early stage and peak during the second week. Clinically severe involvement was found to be idiosyncratic and infrequent but did contribute to severe bleeding.[53]

A hematocrit level increase greater than 20% is a sign of hemoconcentration and precedes shock. The hematocrit level should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in severe cases of dengue hemorrhagic fever or dengue shock syndrome.

In patients with dengue hemorrhagic fever, the following may be present:

  • Increased hematocrit level secondary to plasma extravasation and/or third-space fluid loss
  • Hypoproteinemia
  • Prolonged prothrombin time
  • Prolonged activated partial thromboplastin time
  • Decreased fibrinogen
  • Increased amount of fibrin split products

Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult blood in the stool. Guaiac testing should be performed on all patients in whom dengue virus infection is suspected.

Typing and crossmatching of blood should be performed in cases of severe dengue hemorrhagic fever or dengue shock syndrome because blood products may be required.

Urinalysis identifies hematuria. Cultures of blood, urine, CSF, and other body fluids should be performed as necessary to exclude or confirm other potential causes of the patient's condition.

Arterial blood gas should be assessed in patients with severe cases to assess pH, oxygenation, and ventilation.

Electrocardiography may demonstrate nonspecific changes as a result of fever, electrolyte disturbances, tachycardia, or medications. The usefulness of these changes as a marker of cardiac involvement is unclear.

Biopsy of the skin lesions in patients with nonfatal, uncomplicated dengue fever reveals an abnormality of the small blood vessels. Endothelial swelling, perivascular edema, and mononuclear cell infiltration are the primary histologic findings.

Perform chest radiography to look for pleural effusions and bronchopneumonia. Right-sided pleural effusion is typical. Bilateral pleural effusions are common in patients with dengue shock syndrome. Head computed tomography without contrast may be indicated in patients with altered level of consciousness, to detect intracranial bleeding or cerebral edema from dengue hemorrhagic fever.

Since January 2010, dengue has been a reportable illness in the United States. Report known or suspected cases of dengue fever, dengue hemorrhagic fever, or dengue shock syndrome to public health authorities. Such reports should include the following:

  • Patient demographics and recent travel history
  • Case classification
  • Date of onset of illness
  • Whether hospitalization was necessary
  • Outcome

When multiple patients are involved, reports should include the number of cases of dengue fever and dengue hemorrhagic fever/dengue shock syndrome stratified by age, number of confirmed cases and serotypes, and number of hospitalizations and deaths.

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Complete Blood Cell Count

Leukopenia, often with lymphopenia, is observed near the end of the febrile phase of illness. Lymphocytosis, with atypical lymphocytes, commonly develops before defervescence or shock. A systematic review found that patients with dengue had significantly lower total WBC, neutrophil, and platelet counts than patients with other febrile illnesses in dengue-endemic populations.[54]

A hematocrit level increase greater than 20% is a sign of hemoconcentration and precedes shock. The hematocrit level should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever and every 3-4 hours in severe cases of dengue hemorrhagic fever or dengue shock syndrome.

Thrombocytopenia has been demonstrated in up to 50% of dengue fever cases. Platelet counts less than 100,000 cells/μL are seen in dengue hemorrhagic fever or dengue shock syndrome and occur before defervescence and the onset of shock. The platelet count should be monitored at least every 24 hours to facilitate early recognition of dengue hemorrhagic fever.

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Metabolic Panel and Liver Enzymes

Hyponatremia is the most common electrolyte abnormality in patients with dengue hemorrhagic fever or dengue shock syndrome. Metabolic acidosis is observed in those with shock and must be corrected rapidly. Elevated blood urea nitrogen (BUN) levels are observed in those with shock. Acute kidney injury is uncommon.[55, 56]

Transaminase levels may be mildly elevated into the several thousands in patients with dengue hemorrhagic fever who have acute hepatitis. Low albumin levels are a sign of hemoconcentration.

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Coagulation Studies

Coagulation studies may help to guide therapy in patients with severe hemorrhagic manifestations. Findings are as follows:

  • Prothrombin time is prolonged
  • Activated partial thromboplastin time is prolonged
  • Low fibrinogen and elevated fibrin degradation product levels are signs of disseminated intravascular coagulation
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Serum Studies

Serum specimens should be sent to the laboratory for serodiagnosis, PCR, and viral isolation. Because the signs and symptoms of dengue fever are nonspecific, attempting laboratory confirmation of dengue infection is important. Serodiagnosis is made based on a rise in antibody titer in paired specimens obtained during the acute stage and during convalescence. Results vary depending on whether the infection is primary or secondary.

The IgM capture enzyme-linked immunosorbent assay (MAC-ELISA) has become the most widely used serologic assay for dengue. Other tests are also used, however, including the following:

  • Complement fixation (CF)
  • Neutralization test (NT)
  • Hemagglutination inhibition (HI)
  • IgG ELISA
  • NS1 strip test [57]

Draw serum specimens for diagnosis as soon as possible after the onset of illness or hospitalization and at the time of death or discharge from the hospital. Immediately place specimens on wet ice and send to the laboratory. Obtain a second (ie, convalescent) blood sample for convalescent-phase serologic testing 7-21 days after the acute-phase serum specimen was drawn. Ideally, draw the convalescent-phase serum specimen 10 days after the acute-phase specimen.

A European study found that if only a single serum sample is available, a single positive result on enzyme-linked ELISA (PanBio IgM or IgG) has a high rate of false positivity and should be confirmed using a second, more specific diagnostic technique. In the absence of further testing, platelet and white blood cell counts can be diagnostically helpful, because the combination of thrombocytopenia and leukopenia is present in 40.4% of confirmed cases but in only 6.1% of false-positive cases.[58, 59]

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Ultrasonography

Ultrasonography is a potentially timely, cost-effective, and easily used modality in the evaluation of potential dengue hemorrhagic fever. Positive and reliable ultrasonographic findings include fluid in the chest and abdominal cavities, pericardial effusion, and a thickened gallbladder wall. Thickening of the gallbladder wall may presage clinically significant vascular permeability.[4, 60]

The utility of previous studies was limited because patients underwent only a single scan. However, in a study by Srikiatkhachorn et al, daily serial ultrasonographic examinations of the thorax and abdomen proved useful in the evaluation of patients with suspected dengue hemorrhagic fever.[60]

Plasma leakage was detected in some patients within 3 days of fever onset. Pleural effusion was the most common sign. Based on ultrasonographic findings, dengue hemorrhagic fever was predicted in 12 patients before hemoconcentration criteria had been met.

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Case Definitions

Cases are classified as suspected dengue if they are compatible with the clinical description. They are classified as probable dengue if they are compatible with the clinical definition and satisfy one or more of the following criteria:

  • Supportive serology (reciprocal hemagglutination-inhibition antibody titer greater than 1280, comparable IgG EIA titers, or positive IgM antibody test in late acute or convalescent-phase serum specimen)
  • Occurrence at the same location and time as other confirmed cases of dengue fever

A confirmed case of dengue is one that is compatible with the clinical definition and is confirmed by the laboratory.

Criteria for the diagnosis of dengue hemorrhagic fever include a probable or confirmed case of dengue infection and hemorrhagic tendencies as evidenced by one or more of the following:

  • A positive result from the tourniquet test
  • Petechiae, ecchymoses, or purpura
  • Bleeding from the mucosa, gastrointestinal tract, injection sites, or other sites
  • Hematemesis or melena and thrombocytopenia (< 100,000 cells/μL)
  • Evidence of plasma leakage due to increased vascular permeability

Plasma leakage may manifest as one or more of the following:

  • Greater than 20% rise in average hematocrit level for age and sex
  • Greater than 20% drop in hematocrit level following volume replacement compared with baseline
  • Signs of plasma leakage (eg, pleural effusion, ascites, hypoproteinemia)

Dengue shock syndrome is diagnosed in cases meeting all of the above criteria plus evidence of circulatory failure, such as the following:

  • Rapid, weak pulse
  • Narrow pulse pressure (< 20 mm Hg), with increased peripheral vascular resistance (PVR) and elevated diastolic pressure
  • Hypotension
  • Cool, clammy skin
  • Altered mental status, although the patient may initially remain alert

The onset of shock may be subtle, indicated by raised diastolic pressure and increased PVR in an alert patient.

WHO classification

The accuracy of the World Health Organization (WHO) classification system for dengue has been called into question.[61] A study in Indonesian children found that the WHO classification system was in only modest agreement with the intuitive classification by treating physicians, whereas several modified classification systems were in good agreement.[62]

The WHO classification system was found to have a sensitivity of 86% for the detection of dengue shock syndrome.[18] Modified systems that added the above early predictors of compensated shock and considered models using varying combinations of evidence of hemorrhagic tendencies, thrombocytopenia, and hemoconcentration were found to yield higher sensitivities (88-99%).

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Contributor Information and Disclosures
Author

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM Professor of Emergency Medicine, Education Officer, Department of Emergency Medicine, Hospital of the University of Pennsylvania; Director of Education and Research, PENN Travel Medicine; Medical Director, Fast Track, Department of Emergency Medicine

Suzanne Moore Shepherd, MD, MS, DTM&H, FACEP, FAAEM is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, Wilderness Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Patrick B Hinfey, MD Emergency Medicine Residency Director, Department of Emergency Medicine, Newark Beth Israel Medical Center; Clinical Assistant Professor of Emergency Medicine, New York College of Osteopathic Medicine

Patrick B Hinfey, MD is a member of the following medical societies: American Academy of Emergency Medicine, Wilderness Medical Society, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

William H Shoff, MD, DTM&H Director, PENN Travel Medicine; Associate Professor, Department of Emergency Medicine, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine

William H Shoff, MD, DTM&H is a member of the following medical societies: American College of Physicians, American Society of Tropical Medicine and Hygiene, International Society of Travel Medicine, Society for Academic Emergency Medicine, Wilderness Medical Society

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Hagop A Isnar, MD, FACEP Department of Emergency Medicine, Crouse Hospital

Hagop A Isnar, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Thomas M Kerkering, MD Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia

Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society

Disclosure: Nothing to disclose.

Deborah Sentochnik, MD Consulting Staff, Department of Internal Medicine, Division of Infectious Disease, The Mary Imogene Bassett Hospital

Deborah Sentochnik, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America, and Medical Society of the State of New York

Disclosure: Nothing to disclose.

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

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Drawing of Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
Aedes aegypti mosquito. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
Aedes albopictus. From CDC Public Domain.
Worldwide distribution of dengue in 2000. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
Worldwide distribution of dengue in 2003. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
Worldwide distribution of dengue in 2005. Picture from the Centers for Disease Control and Prevention (CDC) Web site.
Increasing rates of dengue infection by regions of the world. Graphs from the World Health Organization (WHO) Web site.
Dengue transmission cycle. Illustration from the Centers for Disease Control and Prevention (CDC) Web site.
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.
A child with dengue hemorrhagic fever or dengue shock syndrome may present severely hypotensive with disseminated intravascular coagulation (DIC), as this severely ill pediatric ICU patient did. Crystalloid fluid resuscitation and standard DIC treatment are critical to the child's survival.
Delayed capillary refill may be the first sign of intravascular volume depletion. Hypotension usually is a late sign in children. This child's capillary refill at 6 seconds was delayed well beyond a normal duration of 2 seconds.
Signs of early coagulopathy may be as subtle as a guaiac test that is positive for occult blood in the stool. This test should be performed on all patients in whom dengue virus infection is suspected.
 
 
 
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