Key points
- Clinicians should consider dengue in patients with fever, who live in or recently traveled to areas with risk of dengue. In addition to fever, common dengue symptoms include severe headache, retro-orbital pain, myalgia and arthralgia, macular or maculopapular rash.
- For acute dengue diagnosis, clinicians should order NAAT and IgM tests or NS1 ELISA and IgM tests.
- If dengue is suspected, clinicians should provide appropriate management without waiting for diagnostic test results.
Overview
To determine if recent illness is due to infection with dengue virus, healthcare providers should review:
- patient’s medical history,
- patient's place of residence and recent travel history,
- CDC travel notices regarding disease outbreaks,
- and vaccination records (especially for dengue, yellow fever, and Japanese encephalitis).
Acute phase: initial 0-7 days after symptom onset
- During this period, laboratory diagnosis should be made on serum samples using either one of these test combinations:
- A nucleic acid amplification test (NAAT) (e.g., RT-PCR) and an IgM antibody test OR
- A NS1 ELISA test and an IgM antibody test
- A serum sample is preferred for dengue testing.
- Dengue virus RNA can be detected with NAAT in blood, serum, and plasma. Most of these tests identify the infecting dengue virus serotype. A positive NAAT test does not require further confirmatory testing.
- The presence of the dengue virus non-structural protein 1 (NS1) in serum during the first 7 days of illness is indicative of a current or recent dengue virus infection. Indications for use of commercial NS1 ELISA tests, and interpretation of positive NS1 ELISA test results may vary.
- A negative result from a NAAT or NS1 ELISA test does not rule out infection.
- A positive result by NAAT or NS1 ELISA meets the confirmatory laboratory criteria for diagnosis in the National Notifiable Diseases Surveillance System (NNDSS) dengue case definition.
Convalescent Phase: >7 days post symptom onset
- When the acute (0-7 days) sample is negative in the recommended test combinations or is not available, a convalescent serum sample can be collected and tested.
- IgM ELISA antibody test is recommended as the primary test after day 7 of symptom onset.
- Some patients may be positive on NAAT or NS1 ELISA tests after day 7 of illness.
- IgM antibodies can be reliably detected by an IgM antibody test for 3 months or longer after infection.
Interpreting test results
- Patients with a positive NAAT (E.g., RT-PCR) or NS1 ELISA test have a confirmed acute dengue virus infection.
- Patients who have IgM antibodies against dengue virus in a single sample are classified as having a presumptive, recent dengue virus infection.
- Patients with a change from negative to positive IgM results in paired samples (first sample collected during the first 7 days of illness, and second sample collected after symptoms subside) are classified as recent dengue infections.
IgG testing
- Serologic testing by IgG in a single specimen is not recommended for diagnosis of acute dengue in patients, as these tests may detect antibodies from dengue infections or other flavivirus infections that occurred in the past
- Patients with a change from negative to positive IgG results in paired samples (first sample collected during the first 7 days of illness, and second sample collected after symptoms subside) are classified as recent dengue infections.
Recommended tests
For symptomatic persons with dengue virus infection, dengue virus RNA can usually be detected by molecular tests for the first 0-7 days in the course of illness. After day 7, molecular tests may not be optimal.
NS1 is detectable during the acute phase of dengue virus infections. NS1 ELISA tests can be as sensitive as molecular tests during the first 0-7 days of symptoms. After day 7, NS1 tests may not be optimal.
IgM antibody testing can identify most recent dengue infections after day 3 of illness. These tests should be run on samples with negative NS1 ELISA and PCR results, particularly after day 3 of illness. Interpreting positive IgM results is complicated because of cross-reactivity with other flaviviruses, like Zika.
Plaque Reduction Neutralization Tests (PRNT) can resolve false-positive IgM antibody results caused by non-specific reactivity, and, in some cases, can help identify the infecting virus. However, in areas with high prevalence of dengue and Zika virus neutralizing antibodies, PRNT may not confirm a significant proportion of IgM positive results.
Diagnosis
- All patients with clinically suspected dengue should receive appropriate management without waiting for diagnostic test results. Clinicians should monitor for shock and reduce the risk of complications resulting from increased vascular permeability, plasma leakage, and organ damage.
- Clinical samples can be referred to most state health departments or to commercial laboratories that offer dengue diagnostic testing.
Diagnosis in special circumstances
Cross reactivity is a limitation of dengue serological tests and is seen when antibodies against other flaviviruses react on the dengue IgM ELISA test. For people living in or traveling to an area with concurrently circulating flaviviruses, clinicians will need to order plaque reduction neutralization test (PRNT) to rule out dengue on IgM-positive specimens. Physicians may consult with state or local public health laboratories or CDC for guidance. Zika, Japanese encephalitis, St. Louis encephalitis, West Nile, and yellow fever viruses are examples of other flaviviruses to be considered when ruling out dengue by PRNT. PRNT does not always a give conclusive diagnostic result, particularly in patients that have previously been exposed to more than one flavivirus. Current dengue molecular tests (E.g., RT-PCR) and NS1 ELISA tests do not have cross-reactivity with other flaviviruses of concern.
If the patient is pregnant and symptomatic and lives in or has traveled to an area with risk of exposure to Zika virus, test for Zika using molecular tests in addition to dengue.
Reporting cases
In the United States, all suspected cases should be reported to the local health department, because dengue is a nationally notifiable disease.
- Suspected dengue cases should be notified to public health authorities in the respective states and jurisdictions.
- CDC can provide confirmatory dengue testing on samples submitted by state labs.
- CDC will report results to the submitting state or jurisdictional lab.
Resources
- Hunsperger EA, Munoz-Jordan J, Beltran M, Colon C, Carrion J, Vazquez J, Acosta LN, Medina-Izquierdo JF, Horiuchi K, Biggerstaff BJ, Margolis HS. Performance of dengue diagnostic tests in a single-specimen diagnostic algorithm. J Infect Dis. 2017 Sept 15;214(7):837-44.
- Santiago GA, Verge E, Quiles Y, Cosme J, Vazquez J, Medina JF, Medina F, Colon C, Margolis H, Munoz-Jordan. Analytical and clinical performance of the CDC real time RT-PCR assay for detection and typing of dengue virus. PLoS Negl Trop Dis. 2013 July;7(7):e2311.
- Santiago GA, Vazquez J, Courtney S, Matias KY, Andersen LE, Butler AE, Roulo R, Bowzard J, Villanueva JM, Munoz-Jordan JL. Performance of the Trioplex real-time RT-PCR assay for detection of Zika, dengue, and chikungunya viruses. Nat Commun. April 2018;11;9(1):1391-1401.
- Sharp TM, Fischer M, Muñoz-Jordán JL, Paz-Bailey G, Staples JE, Gregory CJ, Waterman SH. Dengue and Zika virus diagnostic testing for patients with a clinically compatible illness and risk for infection with both viruses. MMWR. 2019 June 14;68(1):1-10.
- Waterman SH, Margolis HS, Sejvar JJ. Surveillance for dengue and dengue-associated neurologic syndromes in the United States. Am J Trop Med Hyg. 2015 May 7;92(5):997-98.