Diagnosis of dengue: an update

Figures & data

Figure 1. Approximate window of detection for dengue diagnostics.

NS1: Non-structural protein 1.

Data taken from [1].

Figure 2. Positive- and negative- predictive values of the various diagnostic approaches for dengue at different rates of prevalence.

Results were generated from median values of sensitivity and specificity presented in Table 2 for PCR (conventional and real time), IgM (ELISA), IgM (Rapid) and NS1 detection, respectively. Aspecificity of 96% was assumed for conventional PCR and real-time PCR as most studies have limited population sizes. Diagnosis using the WHO 2009 classification was used to represent clinical diagnosis. Data for WHO criteria were obtained from Low etal. [12] and separated into two age groups (<56 and ≥56 years). NPV: Negative-predictive value; NS1: Non-structural protein 1; PPV: Positive-predictive value.

Table 1. Symptoms differentiating dengue infection from other febrile illnesses.

Symptoms	Den|OFIs	p-value	Children (<15 years)|adults (>15 years)	p-value	Ref.
Nausea	50.0|28.9% 68.0|49.0%^† 51.3|30.5%	<0.00001 <0.05 <0.001	50.2|76.4%	<0.001	[12,103,145,146]
Vomitting	16.4|8.4% 16.2|8.5% 57.0–64.0|31.0–46.0%^† 70.0|52.0%^†	<0.00001 0.03 <0.01 <0.05	50.2|76.4%	<0.001	[12,103,145–148]
Retro-orbital pain	26.0|15.9% 26.6|13.5% 10.01^§	<0.00001 0.003 0.001	8.7|29.1%	<0.001	[12,103,146,148]
Aches/pains	1.4^§	<0.0001	20.3|36.4%	0.012	[12,146]
Rash	11.2–41.2|3.0–6.4%	<0.003/0.007	NA	NA	[12,103,134,149]
Tourniquet test positive	34.0|19.0% 42.0|5.0%^† 43.0–65.0|21.0–39.0% 1.86^§	0.02 <0.01 <0.1 <0.001	NA	NA	[12,103,134,149]
Leukopenia	3.8 × 10^3|7.3 × 10^3/µl 4.5 × 10^3|8.1 × 10^3/μl <4.5 × 10^3/μl: 72.1|11.5%	<0.0001 <0.1 <0.001	NA	NA	[12,37,103,145]
Thrombocytopenia (platelet/mm^3)	16|4% (≤100,000)^† 16|82%^‡ (≤100,000) 66|95%^‡ (≤100,000) 14.9|1.5% (≤100,000) 32,000|96,500 163,500|239,000 70,000|104,000^¶	NA NA <0.01 <0.001 <0.001 <0.0001 NA	NA	NA	[12,103,145,147,150]

^†Studies perfomed in children younger than 15 years.

^‡Dengue and severe dengue comparison, performed in children younger than 15 years.

^§Risk ratio.

^¶Average.

Den: Confirmed dengue cases; NA: Not applicable; OFI: Other febrile illness.

Table 2. Laboratory diagnostics for dengue: sensitivity and specificity.

Category	Technique	Parameters			Ref.
		Sensitivity (%)	Specificity (%)	Detection limit
Viral detection	Virus isolation (mosquitoes)	71.5–84.2	100	NA	[6,40–42,44]
	Virus isolation (mouse intrecerebral inoculation)	NA	NA	NA	[46,47]
	Virus isolation (cell culture)	40.5	100	≥1 viable virus	[54]
	Viral RNA RT-PCR (conventional)	48.4–100	100	1–50 PFUs	[54–57]
	Viral RNA RT-PCR (real-time detection)	58.9–100	100	0.1–3.0 PFUs	[54,57,63–67,79]
	Viral RNA RT-PCR (NASBA)	98.5	100	<25 PFUs/ml	[81]
	Viral antigen detection (NS1 detection)	54.2–93.4	92.5–100	0.2 ng/ml^†	[79,91–103,110]
Antibody detection	IgM detection	61.5–100	52.0–100	NA	[54,102,115,116]
	IgG detection	46.3–99.0	80.0–100	NA
	Rapid IgM detection (strips)	20.5–97.7	76.6–90.6	NA	[115]
Antigen/antibody combined detection	NS1 and IgM	89.9–92.9	75.0–100	NA	[91,100–102]
	NS1 and IgM/IgG	93.0	100	NA	[101,151]

NA: Not applicable; NASBA: Nucleic acid sequence-based amplification; PFU: Plaque forming unit; RT-PCR: Reverse transcriptase PCR.

^†Data taken from [110].

Table 3. Warning signs and symptoms leading to potential severe dengue (dengue hemorrhagic fever/dengue shock syndrome).

Warning signs for severe disease progression
Signs	Den|OFIs	p-value	Ref.
Abdominal pain & tenderness	63.3|22.6% 78.0|22.0%^†	<0.05 0.03	[150,152]
Persistent vomiting	NA	NA	[153]
Clinical fluid accumulation	46.4|7.1%	0.002	[154]
Mucosal bleed/ spontaneous bleeding	84.1|65.9% 26.6|10.4%	0.008 0.05	[150,153]
Lethargy, restlessness	12.7|2.2% 54.0|20.0%^†	0.05 0.002	[150,152]
Liver enlargement >2 cm	91.6|72.4%^‡	0.01	[146]
Severe dengue (DHF/DSS)
Symptoms	Mild|severe	p-value	Ref.
Severe plasma leakage leading to shock and fluid accumulation with respiratory distress	92.9–100% in severe den	NA	[154]
Severe bleeding (evaluated by clinician)	10.0–35.7% in severe den Gums: 5.7–6.0|65.0–67.8% Nose: 0.9|12.0–16.9%	<0.01	[139,154]
Severe organ involvement  Liver: increased AST/ALT  CNS: impaired consciousness  Heart and other organs	AST: 1293|196 IU/l ALT: 309|132 IU/l AST: 76|12 U/l ALT: 30|20 U/l	0.015 0.075 <0.01 <0.01	[37,145,153,155]
Thrombocytopenia ≤100,000/mm^3	16|82%	NA	[145]

^†Dengue and severe dengue comparison, performed in children younger than 15 years of age.

^‡Children (younger than 15 years of age) versus adults (older than 15 years of age).

ALT: Alanine aminotransferase;

AST: Aspartate aminotransferase; Den: Confirmed dengue cases; DHF: Dengue hemorrhagic fever; DSS: Dengue shock syndrome; IU/l: International units per liter; NA: Not applicable; OFI: Other febrile illness.

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