Dengue Diagnosis Protocol

1. Clinical Suspicion (WHO Case Definition)

Probable dengue = residence in/travel to an endemic area + fever + at least 2 of:

Nausea/vomiting
Rash
Headache, retro-orbital pain
Arthralgia/myalgia (severe "breakbone" pain), bone pain
Positive tourniquet test
Leukopenia
Any warning sign (see below)

Incubation period is 4-10 days after the mosquito bite. Fever typically lasts 2-7 days and can be biphasic, with headache, retro-orbital pain, severe myalgia/arthralgia, and maculopapular rash (Rosen's Emergency Medicine, p. 2630; Washington Manual of Medical Therapeutics, p. 570).

2. WHO Clinical Classification

Category	Features
Dengue without warning signs	Fever + 2 supporting criteria above, no warning signs
Dengue with warning signs	Abdominal pain/tenderness, persistent vomiting, clinical fluid accumulation (ascites, pleural effusion), mucosal bleeding, lethargy/restlessness, liver enlargement >2 cm, rising hematocrit with concurrent rapid platelet fall
Severe dengue	Severe plasma leakage -> shock (Dengue Shock Syndrome) or fluid accumulation with respiratory distress; severe bleeding; severe organ involvement (liver, CNS, heart)

The older classification (Dengue Fever / Dengue Hemorrhagic Fever / Dengue Shock Syndrome) is still used in many textbooks: DHF requires (1) increased vascular permeability, (2) thrombocytopenia, (3) fever 2-7 days, and (4) hemorrhagic tendency/spontaneous bleeding; DSS is DHF plus circulatory shock (Rosen's Emergency Medicine, p. 2630).

3. Laboratory Confirmation - Test Selection by Day of Illness

Diagnostic strategy depends on timing relative to fever onset, because viremia, NS1 antigenemia, and antibody responses occur in sequence:

Days since symptom onset	Preferred test(s)	Rationale
Day 0-5 (acute/febrile phase)	RT-PCR (viral RNA) and/or NS1 antigen ELISA	Virus and NS1 antigen are detectable during viremia; either alone confirms acute infection in a compatible clinical/travel context
Day 3-7	Add IgM ELISA alongside NS1/PCR	IgM becomes detectable around day 3-7; running both catches cases missed by either test alone
After day 7	IgM (and paired IgG) serology	Molecular and NS1 tests lose sensitivity after ~day 7; a single positive IgM suggests probable recent infection, while seroconversion (negative-to-positive IgM or IgG on paired samples) confirms current infection

Key caveats:

A single positive IgG is not diagnostic of acute infection because of long-lasting antibodies from past infection and cross-reactivity with other flaviviruses (Zika, West Nile, yellow fever) - paired (rising) IgG is needed.
IgM cross-reactivity with other flaviviruses is common; if travel history overlaps with other flavivirus-endemic areas, test for both dengue and the relevant alternative pathogens.
Only the NS1 ELISA is FDA-approved as an antigen test in the US; rapid NS1 immunochromatographic tests are largely research-use-only and have variable accuracy (per CDC and the 2024 meta-analysis below).

4. Supporting Labs (non-specific but useful)

Leukopenia and thrombocytopenia are characteristic.
Rising hematocrit with a concurrent rapid fall in platelet count is a specific warning sign for plasma leakage/progression to severe disease.
Elevated liver transaminases and, in severe cases, coagulopathy.
Positive tourniquet test supports probable dengue but is nonspecific.

5. Differential Diagnosis to Exclude

Zika, chikungunya, malaria, leptospirosis, rickettsial infections, measles (in travelers from co-endemic regions), and other viral hemorrhagic fevers (Ebola, Marburg, yellow fever, bunyaviruses) should be considered, especially given overlapping clinical pictures and serologic cross-reactivity (Rosen's Emergency Medicine, p. 2630).

6. Practical Workflow Summary

Assess exposure history (travel/residence in endemic area) + compatible symptoms.
Order NS1 antigen + RT-PCR if within first 5 days of fever; add IgM if day 3 or later.
If presenting after day 7, rely on IgM/IgG serology, ideally paired samples 2 weeks apart to confirm seroconversion.
Trend CBC (platelets, hematocrit) and liver enzymes daily during the febrile/critical phase to monitor for warning signs.
Classify severity per WHO criteria (with/without warning signs, or severe dengue) to guide admission and fluid management decisions.
Manage supportively: antipyretics (avoid NSAIDs/aspirin due to bleeding risk), careful IV fluid titration for plasma leakage, and blood products for significant hemorrhage. There is no specific antiviral treatment.

Recent Evidence Check

A 2025 systematic review/meta-analysis in The Lancet Microbe (PMID: 40209729) evaluated RT-PCR, NS1 ELISA, and IgM ELISA performance for acute dengue diagnosis - findings are broadly consistent with the testing windows above, reinforcing that no single test has adequate sensitivity across the full illness course, so combined/sequential testing is recommended. A 2024 meta-analysis (PMID: 38503028) similarly found variable accuracy for rapid immunochromatographic (point-of-care) tests, supporting caution about relying on rapid NS1/IgM cards alone, particularly for ruling out disease. These don't contradict the classic protocol but reinforce combining NS1/PCR with IgM rather than relying on any single rapid test.

Sources: Rosen's Emergency Medicine - Concepts and Clinical Practice, p. 2630; Washington Manual of Medical Therapeutics, p. 570; Harrison's Principles of Internal Medicine 22E; WHO dengue guidance; CDC Clinical Testing Guidance for Dengue.

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