Table 1. Characteristics of included studies.
| Method | Age* | Time† | Markers | Severe | Non-severe‡ | Outcomes | Comments on findings | Risk of bias | |
|---|---|---|---|---|---|---|---|---|---|
| Aguilar et al., 2014, Mexico [45] | Prospective | 25 ± 15 yrs | Day 2–3 after fever onset (or day -2, -1 before fever subsided) | Viral load | NR | NR | 2009 WHO classification | Although viremia’s kinetic changes showed significant differences between SD and NSD during the entire course of illness, there was no association between viremia and illness severity in the early stage | High |
| Avirutnan et al., 2006, Thailand [46] | Prospective | 9.6 ± 3.0 yrs | Day -3, -2 before fever subsided | Viral load, NS1, SC5b-9 | NR | NR | 1997 WHO classification | The alterations of viral load and NS1 levels were undifferentiated between shock and non-shock cases. On the contrary, SC5b-9 levels were specific to the illness severity, significantly higher in those with shock | Low |
| Biswas et al., 2015, Nicaragua [47] | Prospective | 64% of children aged from 5–12 yrs | Day 2–3 after fever onset | Total serum cholesterol, LDL, HDL | 38–77 | 34–137 | 1997 and 2009 WHO classification | On day 2 after fever onset, LDL-C level in SD was significantly lower than in NSD | Low |
| Butthep et al., 2006, Thailand§ [48] | Retrospective | 10.6 ± 3.7 yrs | Day -3, -2 before fever subsided | WBC, platelet counts, sTM, sVCAM-1, sICAM, sE-selectin, CECs, AAL, ANC, ALC | 1–3 | 7–21 | 1997 WHO classification | sTM was significantly higher in DSS patients than in DF and DHF patients during 3 days before fever subsided | High |
| Butthep et al., 2012, Thailand [49] | Retrospective | NR | Day -2 before fever subsided | IL-4, IL-6, IL-8, IL-10, IFN-γ, TNF-α, MCP-1, IL-1β, IL-2, VEGF, EGF, platelet counts | NR | NR | 1997 WHO classification | The alteration of most markers was not specific to DSS on this day. Notably, IL-6 level differentially increased in DSS as compared to non-DSS cases | Unclear |
| Chaiyaratana et al., 2008, Thailand [50] | Prospective | 11.0 (9.0–13.0) yrs | Day 3 after fever onset | Serum ferritin levels | 1 | 5 | 1997 WHO classification | Ferritin levels increased proportionally to dengue severity. At the cutoff ≥ 1200 ng/mL, ferritin was likely to be a predictor of DHF | High |
| Chandrashekhar et al., 2019, India [51] | Prospective | 37.7% of the children < 5 yrs | Day 2–3 after fever onset | Serum neopterin level | 19 | 58 | 2009 WHO classification | Neopterin level in SD was significantly higher than in NSD | Low |
| Chen et al., 2015, Taiwan§ [15] | Retrospective | 52.6 ± 16.0 yrs | Day 1–3 of after fever onset | CRP | 4–10 | 87–93 | 1997 and 2009 WHO classification | Regardless of the classifications, CRP levels successfully predicted the development of severe outcomes. For shock, at the cutoff of 30.1 mg/L, CRP yielded the sensitivity and specificity of 100% and 76.3%, respectively. For severe dengue, at the cutoff of 24.2 mg/L, the sensitivity and specificity was 70% and 71.3%, respectively | High |
| Chunhakan et al., 2015, Thailand§ [52] | Retrospective | 4–17 yrs | Day -2 before fever subsided | Platelet counts, IL-10, TNF-α, IL-1β | 2 | 16 | 1997 WHO classification | No association found | Unclear |
| Fernando et al., 2016, Sri Lanka§ [53] | Prospective | 32.3 ± 13.6 yrs | Day 3 after fever onset | AST, ALT, GGT, ALP, total bilirubin, albumin, IL-10, IL-17, viral load | 2 | 4 | 2009 WHO classification | ALP levels were slightly higher in SD than in NSD, which promptly returned to the normal range from day 4. IL-10 and IL-17 levels were likely to be associated with SD; however, the number of cases was inappropriate to see the effects | High |
| Hapugaswatta et al., 2020, Sri Lanka [54] | Retrospective | 28.5 in mean | Within the first 3 days of illness | The expression of the following microRNAs and putative target genes: let-7e, miR-30b, miR-30e, miR-33a, miR-150, EXH2, DNMT3A, RIP140, ABCA1 | 15 | 8 | 2009 WHO classification | miR-150 was highly abundant in SD as compared to that in NSD. At the cutoff of 7.54 ΔCq, miR-150 showed the good discriminative ability with a sensitivity of 80% and specificity of 88% | High |
| Hoang et al., 2010, Vietnam§ [55] | Prospective | 2–30 yrs | Less than 3 days after fever onset | Viral load, NS1 level, ANC, whole-blood transcriptional signature | 24 | 56 | Severe plasma leak according to the 2009 WHO classification | Neutrophil-associated CAMP and MPO plus the decoy receptor IL1R2 were differentially expressed between DSS and non-DSS patients. The findings suggested the association between neutrophil activation and the risk of shock in dengue. Plasma NS1 concentrations significantly increased in DSS | High |
| Hober et al., 1993, French Polynesia§ [56] | Retrospective | 3 mths–15 yrs | Day 1–3 after fever onset | Serum TNF-α, IL-6, IL-1β | 5–6 | 7–9 | 1975 WHO classification | TNF-α levels were indistinguishable amongst the severities; the highest value was observed in children with shock on day 3 of illness. IL-6 did not invariably increase; the highest values were seen in DHF1 on day 1, which sharply decreased on days 2 and 3, and were subsequently supplanted by DSS | High |
| Hober et al., 1996, French Polynesia [57] | Retrospective | 3 mths–15 yrs | Day 1–3 after fever onset | Serum sTNFR p75, TNF-α | 4 | 9 | 1980 WHO classification | sTNFR p75 increased in all the severity groups without marked differences. In addition, there was no relationship between sTNFR p75 and TNF-α levels | High |
| Koraka et al., 2004, Indonesia [58] | Retrospective | 7 mths–14 yrs | Day 2–3 after fever onset | sVCAM-1 | 10 | 22 | 1997 WHO classification | sVCAM-1 levels increased proportionally to the degrees of severity | Unclear |
| Kurane et al., 1991, Thailand§ [59] | Prospective | 4–14 yrs | Day -1 before fever subsided | sIL-2R, sCD4, sCD8, IL-2, IFN-γ | 3–5 | 4–10 | 1980 WHO classification | There were no striking differences in the proposed markers amongst dengue grades. By observation, DSS had lower IL-2 and IFN-γ levels than that in non-DSS dengue | High |
| Kurane et al., 1993, Thailand [60] | Retrospective | 5–14 yrs | Day -1 before fever subsided | IFN-α | 4 | 9 | 1986 WHO classification | No association found | High |
| Lam et al., 2017, Vietnam§ [61] | Prospective | 12 (10–13) yrs | Day 1–3 after fever onset | Vomiting, mucosal bleeding, abdominal pain, hepatomegaly, platelet counts | 80–81 | 1156–1186 | 1997 WHO classification | Patients who developed shock were likely to have lower platelet counts than those without shock, particularly one day before shock. Platelet counts during this timeframe had poorly predictive value with an AUC of 0.68 | Low |
| Lee et al., 2012, Singapore [62] | Retrospective | 35 (27–43) yrs | Day 1–3 after fever onset | AST, ALT | NR | NR | 1997 and 2009 WHO classification | According to the 2009 WHO dengue case classification, AST and ALT were specific to SD, whereas this trend was no longer held when categorized by the 1997 WHO classification. Overall, AST and ALT yielded the low discriminative ability of the complications in dengue | High |
| Liao et al., 2015, China [63] | Retrospective | 39.2 ± 15.4 yrs | Day 1–3 after fever onset | Viremia titer, sVCAM-1, IL-6, TNF-α, IL-10, IFN-γ, IL-17A, sTNFR1 | NR | NR | 2009 WHO classification | sVCAM-1, IL-6, and TNF-α levels in SD were significantly higher than in NSD | High |
| Lin et al., 2019, Taiwan§ [64] | Prospective | 22–90 yrs | Day 1–3 after fever onset | Hyaluronan, WBC, platelet counts, albumin, AST, ALT | 15 | 93 | 2009 WHO classification | At the cutoff ≥ 70 ng/mL, hyaluronan level successfully differentiated DWS+ and SD from DWS-; however, the discriminative ability was limited with sensitivity and specificity corresponding to 76% and 55% | Low |
| Low et al., 2018, Malaysia [65] | Prospective | 31.7 ± 14.4 yrs | Day 1–3 after fever onset | PTX-3, VEGF | 2–10 | 2–51 | 2009 WHO classification | At the cutoff ranging from 19.03 to 50.53 pg/mL, VEGF levels on days 2 and 3 after fever onset successfully predicted the progression of SD with the sensitivity and specificity of at least 70% and 76.47%, respectively | Low |
| Mekmullica et al., 2005, Thailand [66] | Retrospective | 8.8 ± 3.5 yrs | Day 1–3 after fever onset | Serum and urine sodium | 6 | 43 | 1997 WHO classification | Sodium was significantly higher in shock patients than in those without shock | Unclear |
| Nguyen et al., 2016, Vietnam§ [67] | Prospective | 1–15 yrs | Less than 3 days after fever onset | Vomiting, abdominal pain, mucosal bleeding, WBC, platelet counts, albumin, AST, viremia titer | 117 | 1943 | 2009 WHO classification | Vomiting, platelets, and AST were significantly different between SD and NSD, which yielded a good discriminative ability with an AUC of 0.95 when combined with positive NS1 rapid test | Low |
| Pandey et al., 2015, India§ [68] | Retrospective | 70% of the participants ≤ 35 yrs | Day -3, -2 before fever subsided | Serum level and mRNA expression of the following cytokines: IL-8, IFN-γ, IL-10, TGF-β | 21–40 | 30–31 | 2009 WHO classification | IL-8 level in SD was higher than in NSD; however, there were no differences in the transcriptional expression of IL-8 between the two groups. Inversely, IFN-γ mRNA was highest in SD these days, yet serum IFN-γ was indistinguishable between the groups. IL-10 shared the similar pattern | High |
| Park et al., 2018, Thailand§ [69] | Retrospective | 9.0 ± 3.0 yrs | Day -3 before fever subsided | AST, ALT, WBC, RLC, albumin, platelet counts | 9 | 147 | 1997 WHO classification | No association found | High |
| Patil et al., 2018, India [70] | Prospective | 24 ± 5.8 yrs | Day 1–3 after fever onset | AnnexinV, platelet counts, RBC, platelet MPs, RBC MPs, activated endothelial cell-derived MPs | 1 | 59 | 2009 WHO classification | No association found | High |
| Phuong et al., 2019, Vietnam§ [71] | Prospective | 6–44 yrs, 65.6% of the participants ≤15 yrs | Day 1–3 after fever onset | Abdominal pain, vomiting, mucosal bleeding, hepatomegaly, cfDNA level | 8 | 53 | 2009 WHO classification | Plasma cfDNA in SD was significantly higher than in NSD. At the cutoff ≥ 36.85 ng/mL, cfDNA showed fair discriminative ability with sensitivity and specificity corresponding to 87.5% and 54.7%, respectively | High |
| Prasad et al., 2020, India [72] | Prospective | 72 (48–96) mths | Day 3 after fever onset | AST, ALT, ALP, GGT, albumin, total proteins | NR | NR | 2009 WHO classification | Amongst the markers, liver transaminases increased early in the first 3 days of the illness course, which were higher in SD than in NSD | Unclear |
| Sehrawat et al., 2018, India [73] | Prospective | NR | Day 2–3 after fever onset | INF-γ, IL-6, TNF-α | NR | NR | 2009 WHO classification | TNF-α level was significantly higher in SD than in NSD. For INF-γ, the difference between the severities was observed only on day 2 of the illness course | High |
| Sigera et al., 2019, Sri Lanka§ [74] | Prospective | 27.5 (20–40) yrs | Day 1–3 after fever onset | Hgb, WBC, platelet counts, ANC, ALC, AST, ALT, sodium, potassium, creatinine, CRP, total bilirubin | 10 | 76 | 2011 WHO classification | No associations found | Low |
| Soundravally et al., 2008, India [75] | Retrospective | 26–53 yrs | Day 3 after fever onset | MDA, TAS, PCOs, platelet counts | NR | NR | 1997 WHO classification | PCOs levels were successfully discriminated DSS from DF and DHF. Platelet counts and MDA levels in DSS were significantly higher than in DF but not DHF | High |
| Srichaikul et al., 1989, Thailand§ [76] | Retrospective | 5–14 yrs | Day -2 before fever subsided | Platelet counts, PTT, PT, TT, fibrinogen, FDP, ECL, FM, BTG, PF4 | 0–3 | 0–4 | 1986 WHO classification | No association found | High |
| Suwarto et al., 2017, Indonesia§ [77] | Prospective | 22 (18–30) yrs | Day 3 after fever onset | Syndecan-1, heparan sulfate, chondroitin sulfate, hyaluronan, Claudin-5, VE-cadherin | 23 | 80 | 2011 WHO classification | High levels of Syndecan-1 and Claudin-5 were strongly associated with the subsequent development of severe plasma leakage | Low |
| Trung et al., 2010, Vietnam§ [78] | Prospective | 22 (15–35) yrs | Day 1–3 after fever onset | AST, ALT | 4 | 81 | 2009 WHO classification | No association was found. Intriguingly, the findings indicated that co-infection of chronic HBV did not change the risk of SD, albeit the slight increase in ALT level | Low |
| Vaughn et al., 2000, Thailand [79] | Retrospective | 18 mths–14 yrs | Less than 3 days after fever onset | Viremia titer | NR | NR | 1997 WHO classification | High viremia titers during the first 3 days of fever onset were associated with severe dengue | High |
| Vuong et al., 2016, Vietnam§ [80] | Prospective | 14 (11–19) yrs | Less than 3 days after fever onset | Vomiting | 12 | 67 | 2009 WHO classification | Vomiting was more prevalent in SD than in NSD. At the cutoff of two episodes per day, the discriminative ability yielded high sensitivity, 92%, but low specificity, 52% | High |
| Vuong et al., 2020, multi-country study§ [81] | Prospective | 15 (10–25) yrs | Less than 3 days after fever onset | CRP, viremia titer, AST, ALT, albumin, CK, WBC, RNC, RLC | 28–38 | 984–1075 | 2009 WHO classification | Although high CRP level was suggestive of severe dengue, the variation of CRP levels between those with and without severe outcomes was not substantial | Low |
| Wills et al., 2009, Vietnam [82] | Prospective | 12 (7–14) yrs | Day 1–3 after fever onset | PT, APTT, fibrinogen, FDP, platelet counts | 14–26 | 156–212 | 1997 WHO classification | Although PT increased proportionally to the degrees of plasma leak, the association was weak and not discerned from non-dengue controls, while platelet counts were strongly associated with the extravasation | Low |
| Zhao et al., 2016, China [83] | Prospective | 46.0 ± 20.9 yrs | Day 1–3 after fever onset | Urine IgA level | 3 | 16 | 2009 WHO classification | No association found | High |
NR = not reported. SD = severe dengue. NSD = non-severe dengue. DSS = dengue shock syndrome. NS1 = non-structural protein 1. LDL = low-density lipoprotein protein cholesterol. HDL = high-density lipoprotein cholesterol. WBC = white blood cell. sTM = soluble thrombomodulin. sICAM-1 = soluble intercellular adhesion molecule-1. sE-selectin = soluble E-selectin. CECs = circulating endothelial cells. AAL = absolute atypical lymphocyte. ANC = absolute neutrophil count. ALC = absolute lymphocyte count. IL = interleukin. IFN = interferon. TNF = tumour necrosis factor. MCP-1 = monocyte chemoattractant protein-1. VEGF = vascular endothelial growth factor. EGF = epidermal growth factor. CRP = C-reactive protein. AST = aspartate aminotransferase. ALT = alanine aminotransferase. GGT = gamma-glutamyl transferase. ALP = alkaline phosphatase. sTNFR = soluble tumour necrosis factor receptors. PTX-3 = pentraxin 3. TGF = transforming growth factor. sVCAM-1 = soluble vascular cell adhesion molecule-1. RBC = red blood cell. MPs = microparticles. cfDNA = cell-free DNA. Hgb = hemoglobin. MDA = malondialdehyde. TAS = total antioxidant status. PCOs = protein carbonyls. APTT = activated partial thromboplastin time. PT = prothrombin time. TT = thrombin time. FDP = fibrinogen degradation products. ECL = euglobulin clot lysis time. FM = fibrin monomer. BTG = beta-thromboglobulin. PF4 = platelet factor 4. CK = creatinine kinase. RNC = relative neutrophil count. RLC = relative lymphocyte count.
*Age was presented in mean ± SD, median (IQR), and range. For Trung et al., 2010 and Wills et al., 2009, age was presented in median and 90% range.
†Some studies had observations longer than 3 days of the disease course, but we limited data reporting to the first 3 days only.
‡For data reported by individual markers or day of illness, we presented the number of participants ranging from minimum–maximum sizes.
§Studies for meta-analysis.
¶For a genetic association study, we performed the additional assessment yielding a single score of 49, in other words, a good study design.