Dengue fever classification

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alonso Alvarado, M.D. [2]

Overview

Current WHO guideline classifies dengue into non-severe and severe disease depending on whether there is severe plasma leakage, severe bleeding, or severe organ impairment. For practical purposes, non-severe cases can be further divided into two subgroups: those with warning signs and those without them. Patients with suspected dengue should be triaged and managed accordingly.

Classification

1997 WHO Classification

Historically, symptomatic dengue virus infections were classified as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. The case definitions were found too difficult to apply in resource-limited settings and too specific, as it failed to identify a substantial proportion of severe dengue cases, including cases of hepatic failure and encephalitis.

The tables below describe the 1997 WHO dengue case classification:

Dengue Fever Probable Dengue Fever ❑ An acute febrile illness PLUS ❑ Two or more of the following manifestations:    ❑ Headache    ❑ Retro-orbital pain    ❑ Myalgia    ❑ Arthralgia    ❑ Rash    ❑ Hemorrhagic manifestations    ❑ Leukopenia PLUS ❑ Supportive serology    ❑ A reciprocal hemagglutination-inhibition antibody titre ≥1280    ❑ A comparable IgG enzyme-linked immunosorbent assay (ELISA) titer    ❑ A positive IgM test on a late acute or convalescent-phase serum specimen Confirmed Dengue Fever ❑ A case confirmed by laboratory criteria    ❑ Isolation of the dengue virus from serum or autopsy samples    ❑ Demonstration of a fourfold or greater change in reciprocal IgG or IgM antibody titers to one or more dengue virus antigens in paired serum samples    ❑ Demonstration of dengue virus antigen in autopsy tissue, serum or cerebrospinal fluid (CSF) samples by immunohistochemistry, immunofluorescence or ELISA    ❑ Detection of dengue virus genomic sequences in autopsy tissue serum or CSF samples by polymerase chain reaction (PCR) Reportable Dengue Fever ❑ Any probable or confirmed case should be reported

Dengue Hemorrhagic Fever & Dengue Shock Syndrome Dengue Hemorrhagic Fever (DHF) ❑ Fever, or history of acute fever, lasting 2–7 days, occasionally biphasic PLUS ❑ Hemorrhagic tendencies, evidenced by at least one of the following:    ❑ A positive tourniquet test†    ❑ Petechiae, ecchymoses, or purpura    ❑ Bleeding from the mucosa, gastrointestinal tract, injection sites or other locations    ❑ Hematemesis or melena PLUS ❑ Thrombocytopenia (100,000 cells per mm3 or less) PLUS ❑ Evidence of plasma leakage due to increased vascular permeability, manifested by at least one of the following:    ❑ A rise in the hematocrit equal to or greater than 20% above average for age, sex and population    ❑ A drop in the hematocrit following volume-replacement treatment equal to or greater than 20% of baseline    ❑ Signs of plasma leakage such as pleural effusion, ascites and hypoproteinemia Dengue Shock Syndrome (DSS) ❑ All of the above four criteria for DHF must be present PLUS ❑ Evidence of circulatory failure manifested by:    ❑ Rapid and weak pulse AND narrow pulse pressure ❑ OR manifested by:    ❑ Hypotension for age AND cold, clammy skin and restlessness

   ^† The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressures for 5 minutes. A test is considered positive when 20 or more petechiae per 2.5 cm (1 inch) square are observed. The test may be negative or mildly positive during the phase of profound shock. It usually becomes positive, sometimes strongly positive, if the test is conducted after recovery from shock.

2009 WHO Classification

A newer classification published by WHO in 2009 categorizes the disease into probable dengue or laboratory-confirmed dengue (with or without warning signs) and severe dengue (encompassing severe plasma leakage, severe bleeding, and severe organ involvement). However, it has been criticized as overly inclusive for several reasons:

• It allows several different ways to qualify for severe dengue.
• Nonspecific warning signs are used as diagnostic criteria.
• Severity determination is dependent on individual judgment due to the lack of explicit clinical criteria for establishing severe dengue.

The tables below describe the 2009 WHO dengue case classification:

Dengue ± Warning Signs Probable Dengue (live in or travel to dengue endemic area) ❑ Fever PLUS ❑ Two of the following criteria:    ❑ Nausea or vomiting    ❑ Rash    ❑ Aches and pains    ❑ Tourniquet test positive†    ❑ Leukopenia    ❑ Any warning sign Warning Signs ❑ Warning signs requiring strict observation and medical intervention:    ❑ Abdominal pain or tenderness    ❑ Persistent vomiting    ❑ Clinical fluid accumulation    ❑ Mucosal bleed    ❑ Lethargy, restlessness    ❑ Liver enlargment >2 cm    ❑ Increase in hematocrit with rapid decrease in platelet count

Severe Dengue Severe Plasma Leakage ❑ Severe plasma leakage leading to:    ❑ Shock (dengue shock syndrome)    ❑ Fluid accumulation with respiratory disrtess Severe Bleeding ❑ Severe bleeding as evaluated by clinician:    ❑ Persistent and/or severe overt bleeding in the presence of unstable hemodynamic status, regardless of the hematocrit level    ❑ A decrease in hematocrit after fluid resuscitation together with unstable hemodynamic status    ❑ Refractory shock unresposive to fluid resuscitation of 40–60 ml/kg    ❑ Hypotensive shock with low/normal hematocrit before fluid resuscitation    ❑ Persistent or worsening metabolic acidosis ± a well-maintained systolic blood pressure, especially in those with severe abdominal tenderness and distension Severe Organ Involvement ❑ Severe organ involvement indicated by:    ❑ Liver: AST or ALT ≥1000 IU/L    ❑ CNS: impaired consciousness    ❑ Heart or other organs

   ^† The tourniquet test is performed by inflating a blood pressure cuff on the upper arm to a point midway between the systolic and diastolic pressures for 5 minutes. A test is considered positive when 20 or more petechiae per 2.5 cm (1 inch) square are observed. The test may be negative or mildly positive during the phase of profound shock. It usually becomes positive, sometimes strongly positive, if the test is conducted after recovery from shock.

Laboratory Tests for Confirmed and Probable Dengue Infection

• A diagnosis of confirmed dengue infection is established by isolation of the virus, detection of viral genome or NS1 antigen, or seroconversion of IgM or IgG (from negative to positive IgM/IgG or fourfold increase in the specific antibody titer) in paired sera.

• A positive IgM serology or a hemagglutination inhibition assay (HIA) antibody titer of 1280 or higher (or comparable figures by ELISA in a single specimen), are diagnostic of a probable dengue infection. Both probable and confirmed dengue cases should be notified to health authorities.

Definition	Method†	Interpretation†	Sample Characteristics
Confirmed Dengue Infection	Viral isolation	Virus isolated	Serum (collected at 1–5 days of fever) or necropsy tissues
	Genome detection	Positive RT-PCR or positive real-time RT-PCR
	Antigen detection	Positive NS1 Ag
		Positive immunohistochemical	Necropsy tissues
	IgM seroconversion	From negative IgM to positive IgM in paired sera	Acute serum (days 1–5) and convalescent serum (15–21 days after first serum)
	IgG seroconversion	From negative IgG to positive IgG in paired sera or 4-fold increase IgG levels among paired sera
Probable Dengue Infection	Positive IgM	Positive IgM	Single serum collected after day 5
	High IgG levels	High IgG levels by ELISA or hemagglutination inhibition assay (≥1280)

   ^† ELISA = enzyme-linked immunosorbent assay; IgG = immunoglobulin G; IgM = immunoglobulin M; NS1 Ag = non-structural protein 1 antigen; RT-PCR = reverse transcriptase polymerase chain reaction