What are the diagnostic criteria and management for dengue?

How to Diagnose Dengue

Dengue should be diagnosed using nucleic acid amplification testing (NAAT/PCR) on serum collected within the first 7 days of symptom onset, or NS1 antigen detection during the acute phase, followed by IgM antibody testing for specimens collected after 7 days or when NAAT is negative. 1

Clinical Criteria for Suspecting Dengue

Suspect dengue in any patient presenting with:

• Fever plus at least one of the following: nausea, vomiting, rash, headache, retro-orbital pain, myalgia, arthralgia, positive tourniquet test, leukopenia, or dengue warning signs 2
• Travel or residence history in dengue-endemic regions within the past 14 days, with most cases developing symptoms 4-8 days after infection 1
• Classic presentation: frontal headache, retro-orbital pain, muscle and joint pain ("breakbone fever"), and characteristic measles-like rash 1

Laboratory Diagnostic Algorithm

For Specimens Collected ≤7 Days After Symptom Onset:

First-line testing:

• NAAT (PCR) on serum is the preferred method during the first week of illness when patients are viremic 1
• NS1 antigen detection serves as an excellent alternative to NAAT, detectable from day 1 up to 10 days after symptom onset 1
• If NAAT is positive, this typically confirms acute infection and no antibody testing is needed 2
• If NAAT is negative, proceed to IgM antibody testing on the same specimen, as negative NAAT does not exclude dengue due to declining viremia or inaccurate symptom onset reporting 2

For Specimens Collected >7 Days After Symptom Onset:

Primary testing:

• IgM antibody capture ELISA (MAC-ELISA) becomes the primary diagnostic test 1
• IgM antibodies typically develop during the first week and remain detectable for 2-3 months 1
• A negative IgM result from 7 days to 12 weeks after symptom onset rules out recent dengue infection 2

Confirmatory Testing

When definitive diagnosis is needed (first local transmission, unusual clinical syndrome, or affects clinical management):

• Repeat NAAT on newly extracted RNA from the same specimen to rule out false-positive results 2
• Plaque reduction neutralization tests (PRNTs) should be performed when IgM is positive without positive NAAT or NS1 antigen, testing against dengue, Zika, and other endemic flaviviruses 2
• PRNT titer ≥10 against dengue virus with negative PRNTs (<10) against Zika and other flaviviruses confirms dengue 2

Case Classification

Confirmed case requires:

• Laboratory confirmation through isolation of dengue virus from serum/autopsy tissue, OR
• Fourfold or greater change in antibody titers in paired samples, OR
• Detection of dengue virus antigen or viral nucleic acid 1

Probable case requires:

• Clinically compatible illness with supportive serology (IgG titer ≥1280 or positive IgM on single specimen) 1

Critical Diagnostic Pitfalls

Cross-reactivity concerns:

• Serological tests can cross-react with other flaviviruses including Zika, West Nile, yellow fever, Japanese encephalitis, and tick-borne encephalitis 1
• Document vaccination history to interpret serological results accurately 1
• PRNTs provide improved specificity but are only available at select public health laboratories 1

Timing errors:

• A negative IgM test on specimens collected <7 days after onset may reflect collection before antibody development and does not rule out infection 2
• Some laboratories perform NAAT and IgM testing simultaneously rather than sequentially to avoid delays 2

FDA-Cleared Diagnostic Tests

Three FDA-cleared assays are available for dengue diagnosis:

• NAAT for use on serum and whole blood 2
• Enzyme immunoassay detecting dengue NS1 antigen in serum 2
• Enzyme immunoassay detecting dengue IgM antibodies in serum 2

Special Population Considerations

Pregnant women:

• Should receive comprehensive testing with both NAAT and serology regardless of outbreak patterns due to risk of maternal death, hemorrhage, preeclampsia, eclampsia, and vertical transmission 2, 1
• Test for both dengue and Zika virus given potential for adverse outcomes with either infection 2

Differential Diagnosis to Consider

Rule out other infectious etiologies including: chikungunya, malaria, rubella, measles, hepatitis A, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections 2