How to manage a patient with suspected false positive dengue (Dengue Virus) serology, particularly those from non-endemic areas with non-specific symptoms?

Management of False Positive Dengue Serology

For patients from non-endemic areas with non-specific symptoms and positive dengue serology, perform confirmatory plaque reduction neutralization testing (PRNT) to distinguish true dengue infection from cross-reactivity with other pathogens, particularly other flaviviruses and EBV. 1

Understanding the Problem

False positive dengue IgM results are common and occur through two mechanisms 1:

• Nonspecific reactivity in patients without any flavivirus exposure
• Cross-reactivity with other pathogens, particularly other flaviviruses (West Nile, yellow fever, Japanese encephalitis, Zika) and even EBV 1

The problem is magnified in non-endemic areas where the positive predictive value drops significantly due to low disease prevalence, meaning a higher proportion of positive tests represent false positives rather than true infections 1, 2

Diagnostic Algorithm for Suspected False Positives

Step 1: Assess Clinical Context and Timing

• Travel history: Did the patient travel to a dengue-endemic area within the past 2 weeks? 2
• Symptom timing: When did symptoms start relative to testing? IgM appears 3-5 days after symptom onset, so very early testing may miss true infections 2
• Vaccination history: Prior dengue vaccination causes persistent IgM/IgG that cannot be distinguished from natural infection using standard assays 3
• Other exposures: Consider other flavivirus exposures (West Nile, Zika, yellow fever vaccine) or recent EBV infection 1

Step 2: Determine Optimal Confirmatory Testing Based on Presentation Timeline

If patient presents ≤7 days after symptom onset 2:

• Order nucleic acid amplification test (NAAT/PCR) as the gold standard—this is not affected by cross-reactivity or vaccination 1, 3
• Order NS1 antigen testing (sensitivity 75-90% during days 1-5, remains useful up to day 10) 2
• These tests confirm active viral replication and are unaffected by antibody cross-reactivity 3

If patient presents >7 days after symptom onset or only has antibody results 2:

• Order PRNT testing against dengue and other endemic flaviviruses to definitively distinguish dengue from cross-reactive antibodies 1, 2
• PRNT titer ≥10 for dengue and <10 for other flaviviruses confirms recent dengue infection 2
• This is the reference standard for specificity when antibody results are ambiguous 2

Step 3: Interpret Specific Serological Patterns

IgM positive alone (IgG negative) 1:

• Most likely represents either very early primary dengue infection OR false positive from cross-reactivity
• Action: Perform NAAT/NS1 if within 7 days of symptom onset, or PRNT for definitive diagnosis 1, 2

Both IgM and IgG positive 2:

• Indicates either secondary dengue infection, late primary infection, or past infection with persistent IgM
• Cannot determine timing from serology alone—IgM can persist for months after initial infection 2
• Action: Requires PRNT for confirmation, especially in non-endemic areas 2

NS1 positive with negative IgM/IgG 2:

• Confirms acute primary dengue in very early phase (days 1-5)
• No further confirmatory testing needed—NS1 positivity already confirms acute infection 2

Critical Pitfalls to Avoid

• Never rely on a single serological test for definitive diagnosis in non-endemic populations 1
• Do not assume acute infection based on positive IgM alone, as IgM persists for months and timing cannot be determined from serology 2
• Beware of the 2-month post-vaccination window where false positive IgM/IgG is particularly common due to vaccine-induced antibodies (specificity drops to 85.1%) 3, 4
• Do not rule out dengue with negative IgM in the first 3-5 days of illness, as antibodies may not have developed yet 2
• Consider EBV testing (VCA IgM, VCA IgG, EBNA antibodies) when dengue serology is positive but clinical context doesn't fit, as EBV can cause cross-reactive dengue IgM 1

When PRNT is Not Available

If PRNT testing is unavailable and both IgM and IgG are positive for dengue, report as "presumptive recent dengue virus infection" but acknowledge that timing and definitive diagnosis cannot be determined 2. In non-endemic areas with low clinical suspicion, this should prompt consideration of alternative diagnoses and repeat testing if clinically indicated.

Cross-Reactivity with SARS-CoV-2

Recent evidence shows minimal cross-reactivity between dengue and SARS-CoV-2 (98% specificity), so COVID-19 is unlikely to cause false positive dengue serology with standard assays 5. However, some studies have reported potential cross-reactivity, so consider COVID-19 testing if respiratory symptoms are prominent 6.