The aim of the meta-analysis was to provide more solid evidence for the reliability of the new classification. A systematic literature search was performed using PubMed, Armed Forces Pest Management Board Literature Retrieval System, and Google Scholar up to August 2012. A pooled odds ratio (OR) was calculated using either a random-effect or a fixed-effect model. A total of 16 papers were identified. Among the 11 factors studied, five symptoms demonstrated an increased risk for SDD, including bleeding [OR: 13.617; 95% confidence interval (CI): 3.281, 56.508], vomiting/nausea (OR: 1.692; 95% CI: 1.256, 2.280), abdominal pain (OR: 2.278; 95% CI: 1.631, 3.182), skin rashes (OR: 2.031; 95% CI: 1.269, 3.250), and hepatomegaly (OR: 4.751; 95% CI: 1.769, 12.570). Among the four bleeding-related symptoms including hematemesis, melena, gum bleeding, and epistaxis, only hematemesis (OR: 6.174; 95% CI: 2.66, 14.334;
Dengue is an infectious disease caused by dengue virus (DENV). It is endemic in many tropical and subtropical areas. Patients infected with DENV have a wide spectrum of clinical manifestation, ranging from silent infections with no symptoms to a mild flu-like syndrome, dengue fever (DF), or severe dengue disease (SDD), including dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) [
Several methods have been used for the diagnoses of DF. However, there lacks an accurate means to predict the severity of disease at early stages of the infection. Since patients with mild or classical DF can develop SDD later [
Published studies about symptoms/signs that are associated with SDD have been inconclusive. For instance, Khan et al. found that male DF patients were more likely to progress into DHF (OR: 2.3, 95% CI: 1.1–4.5,
Because of these inconsistent reports, more accurate methods to predict SDD are needed. We conducted the meta-analysis to identify which clinical symptoms/signs are associated with SDD and to help find better methods to predict the development of SDD in patients with DF.
Our study was performed according to the recommendations of the PRISMA Statement [
Studies were eligible for inclusion if they met the following criteria: (1) retrospective, prospective, or cross-sectional studies providing the details of symptoms/signs as well as any information regarding gender, vomiting/nausea, abdominal pain, skin rashes, bleeding, headache, lethargy, retroorbital pain, diarrhea, hepatomegaly, or tourniquet test; (2) the symptoms/signs of DF and SDD were distinguished; (3) cases with DF in the study were confirmed by laboratory tests; cases with SDD were defined by one or more of the following: plasma leakage that may lead to shock (dengue shock) and/or fluid accumulation, with or without respiratory distress, and/or severe bleeding, and/or severe organ impairment. When two or more publications reported the same study, we chose the most recent one. Reports providing inadequate information were excluded.
The quality of the selected studies was assessed independently by two authors using the Newcastle-Ottawa Scale (NOS) [
For each eligible manuscript, the following information was extracted: (1) first author’s name and year of publication; (2) study design (prospective, retrospective, or cross-sectional); (3) study populations (children, adults, or both); (4) distinctive numbers of patients with specific symptoms in DF and SDD groups.
The prevalence rates of specific symptoms/signs in DF and SDD groups were compared by calculating an odds ratio (OR) with a 95% confidence interval (CI) using either a fixed-effect model or a random-effect model. Predictive factors of interest included gender, vomiting/nausea, abdominal pain, skin rashes, bleeding (hematemesis, melena, gum bleeding, and epistaxis), headache, lethargy, retroorbital pain, diarrhea, hepatomegaly, and tourniquet test.
Heterogeneity between studies was assessed using both the Chi-square test with a
Potential publication bias was comprehensively assessed by Begg’s funnel plot and Egger’s rank correlation test of asymmetry. Publication bias was determined present when the
The search strategy identified 446 citations. Sixteen articles published between 2000 and 2012 were ultimately included in this meta-analysis based on the inclusion and exclusion criteria (Figure
Basic features of the eligible studies.
Author (publication year) | Study design | Population | Gender | Vomiting/nausea | Bleeding | Headache | Abdominal pain | Retroorbital pain | Rashes | Diarrhea | Hepatomegaly | Lethargy | Tourniquet test | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
DF (M/F) | SD (M/F) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | DF (Y/N) | SD (Y/N) | |||
Ahmed et al. (2001) [ |
Prospective | Children | — | — | 4/22 | 5/41 | 16/10 | 46/0 | 22/4 | 34/12 | — | — | 7/19 | 10/36 | 3/23 | 24/22 | 6/20 | 8/38 | 0/26 | 36/10 | — | — | — | — |
Narayanan et al. (2002) [ |
Prospective | Children | 22/21 | 9/7 | 34/9 | 15/1 | 23/20 | 16/0 | 13/30 | 4/12 | 10/33 | 4/12 | 3/40 | 4/12 | 4/39 | 1/15 | — | — | 19/24 | 12/4 | 11/32 | 3/13 | 5/38 | 9/7 |
Endy et al. (2002) [ |
Prospective | Children | — | — | 44/89 | 14/5 | 2/130 | 1/18 | 82/50 | 14/5 | 20/111 | 6/13 | — | — | 6/125 | 1/18 | 5/127 | 1/18 | — | — | 43/89 | 6/13 | — | — |
Phuong et al. (2004) [ |
Prospective | Children | — | — | 178/134 | 234/85 | 56/256 | 36/283 | 140/167 | 88/230 | 156/156 | 234/84 | — | — | — | — | — | — | — | — | — | — | 106/166 | 128/145 |
Carlos et al. (2005) [ |
Prospective | Children | 143/96 | 72/48 | — | — | 11/221 | 6/105 | — | — | 69/168 | 51/68 | — | — | — | — | — | — | — | — | 0/238 | 4/115 | — | — |
Shah et al. (2006) [ |
Prospective | Children | — | — | 11/0 | 87/2 | 0/11 | 68/21 | 11/0 | 87/2 | 9/2 | 87/2 | 11/0 | 87/2 | — | — | — | — | 0/11 | 77/12 | 11/0 | 87/2 | 10/1 | 15/15 |
Malavige et al. (2006) [ |
Prospective | Adult | — | — | 18/15 | 51/24 | 5/28 | 37/38 | 26/7 | 45/30 | 3/30 | 14/61 | — | — | — | — | 7/26 | 24/51 | 10/23 | 39/36 | — | — | — | — |
Lee et al. (2006) [ |
Retrospective | Both | 177/235 | 119/113 | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — | — |
Riaz et al. (2009) [ |
Cross-sectional | Both | — | — | 134/35 | 83/26 | 6/163 | 89/20 | 23/146 | 13/96 | 85/84 | 61/48 | 0/169 | 1/108 | 55/114 | 37/72 | 10/159 | 2/107 | 1/168 | 1/108 | — | — | — | — |
Lee et al. (2009) [ |
Retrospective | Adult | 1183/672 | 53/29 | 604/1251 | 29/53 | — | — | 606/1249 | 16/66 | 252/1603 | 14/68 | 5/1850 | 0/82 | 887/968 | 49/33 | — | — | — | — | — | — | — | — |
Priyadarshini et al. (2010) [ |
Prospective | Both | — | — | 90/69 | 44/18 | — | — | 101/58 | 33/29 | 29/130 | 31/31 | 34/125 | 2/60 | 31/128 | 26/36 | — | — | — | — | — | — | — | — |
Khan et al. (2010) [ |
Retrospective | Both | 99/62 | 30/10 | 93/68 | 27/13 | 6/155 | 29/11 | 21/140 | 2/38 | 6/80 | 1/10 | — | — | 44/117 | 31/9 | 26/135 | 5/35 | — | — | — | — | — | — |
Giraldo et al. (2011) [ |
Retrospective | Children | 77/74 | 16/14 | 96/55 | 23/7 | 51/100 | 14/16 | 92/59 | 17/13 | 78/73 | 22/8 | 18/133 | 4/26 | 63/88 | 16/14 | 29/122 | 5/25 | 27/124 | 7/23 | 54/97 | 20/10 | — | — |
Falconar et al. (2012) [ |
Prospective | Both | — | — | 13/15 | 4/1 | 13/28 | 5/0 | — | — | 0/28 | 5/0 | 22/6 | 4/1 | — | — | — | — | 0/28 | 2/3 | — | — | 8/20 | 5/0 |
Karoli et al. (2012) [ |
Cross-sectional | Both | — | — | — | — | 13/83 | 42/0 | 77/19 | 28/14 | — | — | — | — | 26/70 | 12/30 | — | — | 47/49 | 25/17 | — | — | — | — |
Sirivichayakul et al. (2012) [ |
Prospective | Children | — | — | 95/28 | 32/2 | — | — | 107/16 | 25/9 | 59/64 | 25/9 | 35/88 | 13/21 | 53/70 | 18/16 | 21/102 | 17/17 | — | — | 23/100 | 6/28 | — | — |
Note: “M”: male; “F”: female; “Y”: yes, the group has the symptom; “N”: no, the group has no symptom. “—”: no statistics.
Flow diagram of selection and disposition of studies.
In this meta-analysis, the fix-effect model was analyzed in gender, hematemesis, melena, and headache, while the random-effect model was used in vomiting/nausea, abdominal pain, skin rashes, bleeding (gum bleeding and epistaxis), lethargy, retroorbital pain, diarrhea, hepatomegaly, and tourniquet. According to the meta-analysis results, there were no significant differences between the DF and SDD groups in association with the following factors (
Results of meta-analysis for the clinical manifestations between DF and SDD.
Clinical manifestation | Number of studies | Odds ratio (95% CI) | Test for OR | Test of heterogeneity | Publication bias | ||
---|---|---|---|---|---|---|---|
|
|
|
Egger’s test | Begg’s test | |||
|
6 | 1.230 (0.999, 1.513) | 0.051 | 0 | 0.686 | 0.991 | 0.707 |
Vomiting/nausea* | 13 | 1.692 (1.256, 2.280) | 0.001 | 39.7 | 0.069 | 0.455 | 0.428 |
Abdominal pain* | 13 | 2.278 (1.631, 3.182) | <0.001 | 55.5 | 0.008 | 0.343 | 0.669 |
Skin rashes* | 10 | 2.031 (1.269, 3.250) | 0.003 | 69.7 | <0.001 | 0.581 | 0.592 |
Bleeding* | 12 | 13.617 (3.281, 56.508) | 0.001 | 94.0 | <0.001 | 0.033 | 0.373 |
|
5 | 6.174 (2.66, 14.334) | <0.001 | 0 | 0.476 | 0.137 | 0.211 |
|
4 | 10.351 (3.065, 34.956) | <0.001 | 0 | 0.955 | 0.36 | 0.734 |
Gum bleeding | 7 | 2.518 (0.463, 13.685) | 0.285 | 90.5 | <0.001 | 0.058 | 0.548 |
Epistaxis | 5 | 2.319 (0.599, 8.976) | 0.562 | 86.9 | <0.001 | 0.981 | 0.462 |
|
13 | 0.555 (0.455, 0.676) | <0.001 | 0 | 0.594 | 0.177 | 0.583 |
Lethargy | 6 | 1.552 (0.714, 3.370) | 0.267 | 49.6 | 0.078 | 0.864 | 1 |
Retroorbital pain | 9 | 1.096 (0.531, 2.261) | 0.804 | 45.2 | 0.067 | 0.810 | 0.602 |
Diarrhea | 7 | 1.149 (0.555, 2.380) | 0.708 | 64.1 | 0.010 | 0.185 | 0.230 |
Hepatomegaly* | 8 | 4.751 (1.769, 12.570) | 0.002 | 72.5 | 0.001 | 0.014 | 0.063 |
Tourniquet | 4 | 2.194 (0.395, 12.206) | 0.369 | 82.4 | 0.001 | 0.715 | 1 |
Note: “Italics”: using the fixed-effect model, the other symptoms/signs: using the random-effect model; *significantly different between DF and SDD.
Forrest plots of the relationship between DF and the risk of SDD. (a)–(e) Pooled ORs of SDD are greater than one in 5 symptoms and signs with vomiting/nausea, abdominal pain, skin rashes, bleeding, and hepatomegaly; (f) pooled OR of SDD is smaller than one in headache.
Vomiting/nausea
Abdominal pain
Skin rashes
Bleeding
Hepatomegaly
Headache
Forrest plots of four kinds of bleeding. (a)-(b) Pooled ORs of SDD are greater than one in hematemesis and melena; (c)-(d) pooled ORs of SDD are not significantly different from one in epistaxis and gum bleeding.
Hematemesis
Melena
Gum bleeding
Epistaxis
Metaregression analysis was conducted to examine which factors could have brought heterogeneity across the studies, and 11 clinical symptoms/signs were analyzed, including vomiting/nausea, abdominal pain, skin rashes, bleeding (epistaxis and gum bleeding), lethargy, retroorbital pain, diarrhea, hepatomegaly, and tourniquet test. It turned out that two factors, study design and population, contributed to the heterogeneity in the studies of gum bleeding (
Funnel plots showed no publication bias in the studies covering vomiting/nausea, abdominal pain, skin rashes, bleeding, or retroorbital pain (Figure
The present study is the meta-analysis to comprehensively evaluate the correlation of clinical symptoms/signs with the development of SDD in patients with DF. The results showed that a total of five symptoms/signs significantly predict dengue patients progressing into SDD: vomiting/nausea, abdominal pain, skin rashes, bleeding, and hepatomegaly. The other five factors were not associated with the disease progression, including tourniquet versus nontourniquet, female versus male patients, lethargy, retroorbital pain, and diarrhea. We found that patients with bleeding after DENV infection had approximately a 14-fold increased risk for progression into SDD (including DHF and DSS). When compared with the frequencies of leucopenia and thrombocytopenia, haemorrhagic manifestations, such as gum bleeding, epistaxis, and gastrointestinal bleeding, are less frequent, but not rare [
The most accepted hypothesis for progression of DF is that subneutralizing levels of DENV-specific antibodies exacerbate the disease by means of an antibody-dependent enhancement of infection (ADE) [
The unassociated factors/manifestations were gender, lethargy, retroorbital pain, diarrhea, and positivity of a tourniquet test. However, the World Health Organization (WHO) has published guidelines stating that positivity of a tourniquet test may be included in the clinical case definition of dengue haemorrhagic fever [
Furthermore, headache was a protective factor against SDD after DENV infection (OR: 0.555; 95% CI: 0.455, 0.676), implying that dengue patients with headache had a lower probability to develop into SDD. The protective effect has been proved by a retrospective cohort study [
There are limitations in the present study. Firstly, the results will not apply to multicenter prospective studies, since the present meta-analysis only included retrospective and single-center prospective studies. These designs could not eliminate recall and selection biases. Hence, the true associations between these symptoms/signs and the development of SDD might have been distorted. Secondly, the definitions of DF and SDD within these studies may have varied, which brought uncertainty into determining cases. Lastly, some of the results were based on a random-effect model that might weaken the validity of the analysis. Nonetheless, this study explored a new approach to identify the correlations of the symptoms/signs after DENV infection with the risk of progression into SDD, which can greatly facilitate the prevention of SDD.
This meta-analysis identified clinical symptoms and signs that significantly predicted DF patients progressing into severe dengue. DF patients with vomiting/nausea, abdominal pain, skin rashes, bleeding (hematemesis/melena), and hepatomegaly were more likely to develop SDD, while patients with headache had a lower risk of progression into SDD. Other factors such as gender, lethargy, retroorbital pain, diarrhea, and positive tourniquet test are not associated with SDD. Further studies, especially ones with larger sample sizes and prospective, are warranted to confirm the findings.
Dengue virus
Dengue fever
Severe dengue disease
Dengue haemorrhagic fever
Dengue shock syndrome
The Newcastle-Ottawa Scale
Antibody-dependent enhancement of infection
The World Health Organization.
On behalf of all authors, the corresponding author states that there is no conflict of interests.
All authors were involved in the study design, including developing the search strategies and project protocol. H. Zhang, H. J. Peng, X. H. Zhang, F. Y. Zhou, Z. H. Liu, and X. G. Chen were responsible for supervising the project and performing the literature search and data extraction. H. J. Peng, F. Y. Zhou, and Z. H. Liu assessed the quality of studies. H. Zhang performed data analysis and drafted the paper. X. H. Zhang was responsible for the language editorial. Y. P. Zhou and X. G. Chen revised the paper.
This work was supported by Grants from the National Natural Science Foundation of China (30771899) to Y. P. Zhou and NIH (AI083202-02) to X. G. Chen.