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Mayo Clinic Laboratories

Test Code DENVP Dengue Virus Antibody/Antigen Panel, Serum

Useful For

Aiding in the diagnosis of dengue virus infection by detection of IgM and IgG antibodies and the nonstructural protein 1 (NS1)

Profile Information

Test ID	Reporting Name	Available Separately	Always Performed
DENG	Dengue Virus Ab, IgG, S	No	Yes
DENM	Dengue Virus Ab, IgM, S	No	Yes
DENS1	Dengue NS1 Ag, S	Yes, (DNSAG)	Yes
INT69	Dengue Interpretation	No	Yes

Reporting Name

Dengue Virus Ab/Ag Panel, S

Specimen Type

Serum

Specimen Required

Collection Container/Tube:

Preferred: Serum gel

Acceptable: Red top

Submission Container/Tube: Plastic vial

Specimen Volume: 1 mL

Collection Instructions: Centrifuge and aliquot serum into plastic vial.

Specimen Minimum Volume

0.8 mL

Specimen Stability Information

Specimen Type	Temperature	Time	Special Container
Serum	Refrigerated (preferred)	14 days
	Frozen	14 days

Reject Due To

Gross hemolysis	Reject
Gross lipemia	Reject
Gross icterus	Reject
Heat-inactivated specimen	Reject

Clinical Information

Dengue virus (DV) is a globally distributed flavivirus with 4 distinct serotypes (DV-1, -2, -3, -4). It is primarily transmitted by the Aedes aegypti mosquito, which is found throughout the tropical and subtropical regions of over 100 countries. DV poses a significant worldwide public health threat with approximately 2.5 to 3 billion people residing in DV endemic areas, among whom 100 to 200 million individuals will be infected, and approximately 30,000 patients will succumb to the disease, annually.

Following dengue infection, the incubation period varies from 3 to 7 days, and while some infections remain asymptomatic, the majority of individuals will develop classic dengue fever. Symptomatic patients become acutely febrile and present with severe musculoskeletal pain, headache, retro-orbital pain, and a transient macular rash, most often observed in children. Fever defervescence signals disease resolution in most individuals. However, children and young adults remain at increased risk for progression to dengue hemorrhagic fever and dengue shock syndrome, particularly during repeat infection with a new DV serotype.

Detection of dengue-specific IgM and IgG-class antibodies remains the most commonly utilized diagnostic method. Seroconversion occurs approximately 3 to 7 days following exposure, and therefore, testing of acute and convalescent sera may be necessary to make the diagnosis. Detection of the DV nonstructural protein 1 (NS1) has emerged as an alternative biomarker to both serologic- and molecular-based techniques for diagnosis of acute DV infection. NS1 antigenemia is detectable within 24 hours and up to 9 days following symptoms onset. This overlaps with the DV viremic phase, and NS1 is often detectable prior to IgM seroconversion. Concurrent evaluation (as performed in this profile) for the NS1 antigen alongside testing for IgM- and IgG-class antibodies to DV provides optimal diagnostic potential for both early and late dengue disease.

Reference Values

IgG: Negative

IgM: Negative

NS1: Negative

Reference values apply to all ages.

Interpretation

The presence of IgG-class antibodies to dengue virus (DV) is consistent with exposure to this virus sometime in the past. By 3 weeks following exposure, nearly all immunocompetent individuals should have developed IgG antibodies to DV.

The presence of IgM-class antibodies to DV is consistent with acute-phase infection.

IgM antibodies become detectable 3 to 7 days following infection and may remain detectable for up to 6 months or longer following disease resolution.

The absence of IgM-class antibodies to DV is consistent with lack of infection. However, specimens collected too soon following exposure may be negative for IgM antibodies to DV. If DV remains suspected, a second specimen, collected approximately 10 to 12 days following exposure should be tested.

The presence of dengue nonstructural protein 1 (NS1) antigen is consistent with acute-phase infection with dengue virus.

The NS1 antigen is typically detectable within 1 to 2 days following infection and up to 9 days following symptom onset.

NS1 antigen may also be detectable during secondary dengue virus infection, but for a shorter duration of time (1-4 days following symptom onset).

The absence of dengue NS1 antigen is consistent with the lack of acute-phase infection.

The NS1 antigen may be negative is samples collected immediately following dengue virus infection (<24-48 hours) and is rarely detectable following 9 to 10 days of symptoms.

Cautions

Test results should be used in conjunction with clinical evaluation, including exposure history and clinical presentation.

False-positive results, particularly with the dengue virus (DV) IgG enzyme-linked immunosorbent assay, may occur in persons infected with other flaviviruses, including Zika virus, West Nile virus, and St. Louis encephalitis virus. Obtaining a detailed exposure history and additional laboratory testing may be necessary to determine the infecting virus.

Positive test results may not be valid in persons who have received blood transfusions or other blood products within the last several months.

The significance of a negative result in an immunosuppressed patient is unclear.

Results should be used in conjunction with clinical presentation and exposure history.

Though uncommon, false-positive nonstructural protein 1 (NS1) results may occur in individuals with active infection due to other flaviviruses, including West Nile virus and yellow fever virus.

Negative NS1 antigen results may occur if the specimen was collected more than 7 days following symptom onset. Serologic testing for the presence of IgM and IgG antibodies to DV is recommended in such cases.

Supportive Data

A total of 200 prospective serum samples submitted for dengue virus (DV) IgM and IgG testing by the Focus Diagnostics DV IgM and IgG enzyme immunoassays (EIA) were also tested by the InBios IgM and IgG DV assays. The results were compared and the data summarized in Tables 1 and 2.

Table 1. Comparison of the InBios and Focus (Quest) Diagnostics DV IgM EIA

InBios DV IgM EIA	Focus (Quest) Diagnostics DV IgM EIA
	Positive	Negative
Positive	14	0
Negative	1	184
Equivocal	1	0

Sensitivity: 87.5% (14/16); 95% CI 62.7%-97.7%

Specificity: 100% (184/184); 95% CI 97.5%-100%

Agreement: 99% (198/200); 95% CI 96.1%-99.9%

Table 2. Comparison of the InBios and Focus (Quest) Diagnostics DV IgG EIA

InBios DV IgG EIA	Focus (Quest) Diagnostics DV IgG EIA
	Positive	Negative
Positive	34	0
Negative	0	164
Equivocal	2	0

Sensitivity: 94.4% (34/36); 95% CI 80.9%-99.4%

Specificity: 100% (164/164); 95% CI 97.2%-100%

Agreement: 99% (198/200); 95% CI 96.1%-99.9%

An additional 42 serum samples positive for IgG-class antibodies to West Nile virus (n=24), St. Louis encephalitis virus (n=9) and California (LaCrosse) virus (n=9) were also tested by the InBios DV IgG EIA and the data are summarized below in Table 3.

Table 3. Cross-reactivity of the InBios DV IgG EIA with antibodies to West Nile virus, St. Louis encephalitis virus, and California (LaCrosse) virus

InBios DV IgG EIA	West Nile virus IgG positive	St. Louis encephalitis virus positive	California (LaCrosse) virus positive
Positive	18	7	1
Negative	2	0	8
Equivocal	4	2	0

Note that the InBios DV IgG EIA shows significant cross-reactivity with antibodies to West Nile virus and St. Louis encephalitis virus.

The presence of nonstructural protein 1 (NS1) antigen overlaps with the DV viremic phase for the first 4 to 5 days following infection and therefore, the performance characteristics of the InBios DV NS1 EIA were compared to the Focus Diagnostics DV real-time PCR (RT-PCR), which detects RNA from all 4 DV serotypes. Seventy-seven serum samples previously evaluated by the Focus Diagnostics RT-PCR assay were also tested by the InBios DV NS1 EIA and the results are compared in Table 4 below. Discordant samples were also tested by the Platelia NS1 Ag EIA (BioRad Laboratories, Marnes-la-Coquette, France).

Table 4. Comparison of the InBios NS1 EIA to RT-PCR for DV detection

InBios DV NS1 EIA	Focus Diagnostics DV RT-PCR
	Positive	Negative
Positive	24	7(b)
Negative	1(a)	43
Equivocal	0	2(c)

a. This sample was negative by the Platelia NS1 EIA

b. Five samples were also positive by the Platelia NS1 EIA

c. One sample was negative and 1 sample was indeterminate by the Platelia NS1 EIA

Sensitivity: 96% (24/25); 95% CI: 79.1%-100%

Specificity: 82.7% (43/52); 95% CI: 70.1%-90.9%

Overall Agreement: 87.1% (67/77); 95% CI: 77.6%-93%

Clinical Reference

1. Bhatt S, Gething PW, Brady OJ, et al: The global distribution and burden of dengue. Nature. 2013 Apr 25;496:504-507. doi: 10.1038/nature12060

2. Dengue--an infectious disease of staggering proportions. Lancet. 2013 Jun 22;381(9884):2136. doi: 10.1016/S0140-6736(13)61423-3

3. Rigau-Perez JG, Clark GG, Gubler DJ, Reiter P, Sanders EJ, Vorndam AV: Dengue and dengue haemorrhagic fever. Lancet. 1998 Sep 19;352(9132):971-977

4. Tang KF, Ooi EE: Diagnosis of dengue: an update. Expert Rev Anti Infect Ther. 2012 Aug;10(8):895-907. doi: 10.1586/eri.12.76

5. Guzman MG, Kouri G: Dengue diagnosis, advances and challenges. Int J Infect Dis. 2004 Mar;8(2):69-80

Method Description

Dengue virus IgM:

In this enzyme-linked immunosorbent assay (ELISA), samples and controls are diluted in sample dilution buffer and incubated in microtiter wells coated with antihuman IgM antibodies. This incubation is followed by incubation with dengue-derived recombinant antigens (DENRA) and normal cell antigen (NCA) separately. After incubation and washing, the wells are treated with a DEN-specific monoclonal antibody labeled with horseradish peroxidase (HRP). After a second incubation and washing step, the wells are incubated with tetramethylbenzidine (TMB) substrate. Acid stop is added and absorbance at 450 nm is read. The ratio of absorbencies of the DENRA and the control antigen wells determine whether the result is positive or negative.(Package insert: InBiOS DENV Detect IgM CAPTURE ELISA. InBios International, Inc; Revision 10/01/2019)

Dengue virus IgG:

In this ELISA assay, controls and diluted samples are incubated in microtiter wells coated with monoclonal antibody bound to DENRA. After incubation and washing, wells are treated with IgG antibody labeled with HRP. After a second incubation and washing, wells are incubated with TMB substrate. Acid stop is added and absorbance at 450 nm is measured. The ratio of the absorbencies of the DENRA and the control wells determines whether a result is positive or negative.(Unpublished Mayo method)

Nonstructural protein 1:

The InBios nonstructural protein 1 (NS1) ELISA is a 2-step sandwich-format colorimetric immunoassay for qualitative detection of NS1 antigen in serum. Diluted patient samples and controls are incubated in wells coated with purified capture antibody, specific for the dengue NS1 antigen. Following incubation, wells are washed, incubated with HRP-conjugated polyclonal antibody specific to NS1 antigen and reincubated. Wells are subsequently washed and TMB substrate is added and incubated at room temperature in the dark. Stop solution is added next and the optical density (OD) of the reaction is measured at 450/620 nm. The immune status ratio for each sample is calculated from the ratio of the OD obtained with the test sample divided by the OD from the calculated cutoff value (determined by the cutoff control sample).(Package insert: InBios DENV Detect NS1 ELISA.InBios International, Inc; Revision 01/18/2019)

Day(s) Performed

Tuesday

Report Available

Same day/1 to 7 days

Performing Laboratory

Mayo Clinic Laboratories in Rochester

CPT Code Information

86790 x 3

LOINC Code Information

Test ID	Test Order Name	Order LOINC Value
DENVP	Dengue Virus Ab/Ag Panel, S	104595-4

Result ID	Test Result Name	Result LOINC Value
INT69	Dengue Interpretation	69048-7
DENG	Dengue Virus Ab, IgG, S	29661-6
DENM	Dengue Virus Ab, IgM, S	29663-2
DENS1	Dengue NS1 Ag, S	75377-2

Highlights

Detection of the dengue virus nonstructural protein 1 (NS1) antigen and/or antidengue virus IgM is suggestive of recent exposure and/or acute infection with dengue virus.

This test should be used for diagnostic purposes only.

Dengue NS1 antigenemia overlaps with dengue virus viremia and can be used as an acute phase marker for infection.

Infection with other flaviviruses, including West Nile virus, can lead to false-positive antibody results.

Method Name

Enzyme-Linked Immunosorbent Assay (ELISA)

Secondary ID

62869

Specimen Retention Time

14 days

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. It has not been cleared or approved by the US Food and Drug Administration.

Forms

If not ordering electronically, complete, print, and send Infectious Disease Serology Test Request (T916) with the specimen.

Testing Algorithm

See Mosquito-borne Disease Laboratory Testing.

Special Instructions

Mosquito-borne Disease Laboratory Testing

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