Evaluation of the traditional and revised WHO classifications of Dengue disease severity.
ABSTRACT: Dengue is a major public health problem worldwide and continues to increase in incidence. Dengue virus (DENV) infection leads to a range of outcomes, including subclinical infection, undifferentiated febrile illness, Dengue Fever (DF), life-threatening syndromes with fluid loss and hypotensive shock, or other severe manifestations such as bleeding and organ failure. The long-standing World Health Organization (WHO) dengue classification and management scheme was recently revised, replacing DF, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS) with Dengue without Warning Signs, Dengue with Warning Signs (abdominal pain, persistent vomiting, fluid accumulation, mucosal bleeding, lethargy, liver enlargement, increasing hematocrit with decreasing platelets) and Severe Dengue (SD; dengue with severe plasma leakage, severe bleeding, or organ failure). We evaluated the traditional and revised classification schemes against clinical intervention levels to determine how each captures disease severity using data from five years (2005-2010) of a hospital-based study of pediatric dengue in Managua, Nicaragua. Laboratory-confirmed dengue cases (n?=?544) were categorized using both classification schemes and by level of care (I-III). Category I was out-patient care, Category II was in-patient care that did not meet criteria for Category III, which included ICU admission, ventilation, administration of inotropic drugs, or organ failure. Sensitivity and specificity to capture Category III care for DHF/DSS were 39.0% and 75.5%, respectively; sensitivity and specificity for SD were 92.1% and 78.5%, respectively. In this data set, DENV-2 was found to be significantly associated with DHF/DSS; however, this association was not observed with the revised classification. Among dengue-confirmed cases, the revised WHO classification for severe dengue appears to have higher sensitivity and specificity to identify cases in need of heightened care, although it is no longer as specific for a particular pathogenic entity as was the traditional schema.
Project description:<h4>Background</h4>In view of the long term discussion on the appropriateness of the dengue classification into dengue fever (DF), dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), the World Health Organization (WHO) has outlined in its new global dengue guidelines a revised classification into levels of severity: dengue fever with an intermediary group of "dengue fever with warning sings", and severe dengue. The objective of this paper was to compare the two classification systems regarding applicability in clinical practice and surveillance, as well as user-friendliness and acceptance by health staff.<h4>Methods</h4>A mix of quantitative (prospective and retrospective review of medical charts by expert reviewers, formal staff interviews), semi-quantitative (open questions in staff interviews) and qualitative methods (focus group discussions) were used in 18 countries. Quality control of data collected was undertaken by external monitors.<h4>Results</h4>The applicability of the DF/DHF/DSS classification was limited, even when strict DHF criteria were not applied (13.7% of dengue cases could not be classified using the DF/DHF/DSS classification by experienced reviewers, compared to only 1.6% with the revised classification). The fact that some severe dengue cases could not be classified in the DF/DHF/DSS system was of particular concern. Both acceptance and perceived user-friendliness of the revised system were high, particularly in relation to triage and case management. The applicability of the revised classification to retrospective data sets (of importance for dengue surveillance) was also favourable. However, the need for training, dissemination and further research on the warning signs was highlighted.<h4>Conclusions</h4>The revised dengue classification has a high potential for facilitating dengue case management and surveillance.
Project description:BACKGROUND:Epidemic dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) are overwhelming public health capacity for diagnosis and clinical care of dengue patients throughout the tropical and subtropical world. The ability to predict severe dengue disease outcomes (DHF/DSS) using acute phase clinical specimens would be of enormous value to physicians and health care workers for appropriate triaging of patients for clinical management. Advances in the field of metabolomics and analytic software provide new opportunities to identify host small molecule biomarkers (SMBs) in acute phase clinical specimens that differentiate dengue disease outcomes. METHODOLOGY/PRINCIPAL FINDINGS:Exploratory metabolomic studies were conducted to characterize the serum metabolome of patients who experienced different dengue disease outcomes. Serum samples from dengue patients from Nicaragua and Mexico were retrospectively obtained, and hydrophilic interaction liquid chromatography (HILIC)-mass spectrometry (MS) identified small molecule metabolites that were associated with and statistically differentiated DHF/DSS, DF, and non-dengue (ND) diagnosis groups. In the Nicaraguan samples, 191 metabolites differentiated DF from ND outcomes and 83 differentiated DHF/DSS and DF outcomes. In the Mexican samples, 306 metabolites differentiated DF from ND and 37 differentiated DHF/DSS and DF outcomes. The structural identities of 13 metabolites were confirmed using tandem mass spectrometry (MS/MS). Metabolomic analysis of serum samples from patients diagnosed as DF who progressed to DHF/DSS identified 65 metabolites that predicted dengue disease outcomes. Differential perturbation of the serum metabolome was demonstrated following infection with different DENV serotypes and following primary and secondary DENV infections. CONCLUSIONS/SIGNIFICANCE:These results provide proof-of-concept that a metabolomics approach can be used to identify metabolites or SMBs in serum specimens that are associated with distinct DENV infections and disease outcomes. The differentiating metabolites also provide insights into metabolic pathways and pathogenic and immunologic mechanisms associated with dengue disease severity.
Project description:Dengue virus (DENV) infection usually presents with mild self-limiting dengue fever (DF). Few however, would present with the more severe form of the disease, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). In the present study, the association between IL-12B, IL-10 and TNF-? gene polymorphisms and dengue severity was investigated.A case-control study was performed on a total of 120 unrelated controls, 86 DF patients and 196 DHF/DSS patients. The polymorphisms in IL-12B, IL-10 and TNF-? genes were genotyped using PCR-RFLP and PCR-sequencing methods.A protective association of TNF-? -308A allele and -308GA genotype against DHF/DSS was observed, while TNF-? -238A allele and -238GA genotype were associated with DHF/DSS. A combination of TNF-? -308GA+AA genotype and IL-10 non-GCC haplotypes, IL-12B pro homozygotes (pro1/pro1, pro2/pro2) and IL-12B 3'UTR AC were significantly correlated with protective effects against DHF/DSS. An association between the cytokine gene polymorphisms and protection against the clinical features of severe dengue including thrombocytopenia and increased liver enzymes was observed in this study.The overall findings of the study support the correlation of high-producer TNF-? genotypes combined with low-producer IL-10 haplotypes and IL-12B genotypes in reduced risk of DHF/DSS.
Project description:BACKGROUND:The World Health Organization (WHO) proposed guidelines on dengue clinical classification in 1997 and more recently in 2009 for the clinical management of patients. The WHO 1997 classification defines three categories of dengue infection according to severity: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Alternative WHO 2009 guidelines provide a cross-sectional classification aiming to discriminate dengue fever from dengue with warning signs (DWWS) and severe dengue (SD). The primary objective of this study was to perform a comparison of two dengue classifications. The secondary objective was to describe the changes of hematological and biochemical parameters occurring in patients presenting with different degrees of severity during the course of the disease, since progression to more severe clinical forms is unpredictable. METHODOLOGY/PRINCIPAL FINDINGS:We performed a prospective, monocentric, cross-sectional study of hospitalized children in Cambodia, aged from 2 to 15 years old with severe and non-severe dengue. We enrolled 243 patients with acute dengue-like illness: 71.2% were dengue infections confirmed using quantitative reverse transcription PCR or NS1 antigen capture ELISA, of which 87.2% and 9.0% of DF cases were respectively classified DWWS and SD, and 35.9% of DHF were designated SD using an adapted WHO 2009 classification for SD case definition. Systematic use of ultrasound at patient admission was crucial for detecting plasma leakage. No difference was observed in the concentration of secreted NS1 protein between different dengue severity groups. Lipid profiles were different between DWWS and SD at admission, characterized by a decrease in total cholesterol, HDL cholesterol, and LDL cholesterol, in SD. CONCLUSIONS/SIGNIFICANCE:Our results show discrepancies between the two classifications, including misclassification of severe dengue cases as mild cases by the WHO 1997 classification. Using an adapted WHO 2009 classification, SD more precisely defines the group of patients requiring careful clinical care at a given time during hospitalization.
Project description:PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed to examine whether serum PUFA concentrations in patients diagnosed with dengue fever (DF) were related to the risk of progression to dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). A secondary aim was to assess correlations between fatty acids (FA) and inflammatory biomarkers in patients with DF. We conducted a prospective case-control study nested within a cohort of patients who were diagnosed with DF and followed during the acute episode. We compared the distribution of individual FA (% of total FA) at onset of fever between 109 cases who progressed to DHF/DSS and 235 DF non-progressing controls using unconditional logistic regression. We estimated correlations between baseline FA and cytokine concentrations and compared FA concentrations between the acute episode and >1 year post-convalescence in a subgroup. DHA was positively related to progression to DHF/DSS (multivariable adjusted OR (AOR) for DHA in quintile 5 v. 1=5·34, 95 % CI 2·03, 14·1; P trend=0·007). Dihomo-?-linolenic acid (DGLA) was inversely associated with progression (AOR for quintile 5 v. 1=0·30, 95 % CI 0·13, 0·69; P trend=0·007). Pentadecanoic acid concentrations were inversely related to DHF/DSS. Correlations of PUFA with cytokines at baseline were low. PUFA were lower during the acute episode than in a disease-free period. In conclusion, serum DHA in patients with DF predicts higher odds of progression to DHF/DSS whereas DGLA and pentadecanoic acid predict lower odds.
Project description:Dengue illness has been a major health concern in Pakistan during the last decade. Dengue infection can result in a spectrum of clinically distinct outcomes, ranging from asymptomatic infection to potentially life-threatening forms of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). A single-nucleotide polymorphism in Fc?RIIa (rs1801274) results in altered affinity of the receptor for different subclasses of immunoglobulin G, and is a key player in determining the susceptibility to or protection from severe clinical infection of dengue. In this study, we analyzed the allelic and genotypic distribution of rs1801274 in subjects of Pakistani origin with subclinical dengue infection (n = 40), dengue fever (DF) (n = 40), and DHF/DSS (n = 30). We found that HH homozygotes and heterozygotes were significantly more likely to develop clinical dengue (odds ratio [OR] = 3.21, 95% confidence interval [CI] = 1.29-7.97, P = 0.009), either DF (OR = 2.82, 95% CI = 1.00-7.97, P = 0.045) or DHF/DSS (OR = 3.90, 95% CI = 1.13-13.07, P = 0.024) than the asymptomatic dengue infection. Results of allelic distribution comparisons and logistic regression analysis also supported the same relationship. The results suggest complex nature of interacting factors in determining the course for severe dengue illness.
Project description:<h4>Background</h4>Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations.<h4>Methods</h4>We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls.<h4>Findings</h4>The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other.<h4>Interpretation</h4>There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries.
Project description:The four dengue virus serotypes (DENV1-4) are responsible for the most prevalent mosquito-borne viral illness in humans. DENV causes a spectrum of disease from self-limiting dengue fever (DF) to severe, life-threatening dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Antibodies from one infection can contribute to either protection or increased disease severity in a subsequent infection with a distinct DENV serotype. The effectiveness of the antibody response is modulated by both the affinity and avidity of the antibody/antigen interaction.We investigated how antibody avidity developed over time following secondary DENV2 infection across different disease severities.We analyzed sera from 42 secondary DENV2-infected subjects (DF, n=15; DHF, n=16; DSS, n=11) from a pediatric hospital-based dengue study in Nicaragua. IgG avidity against DENV2 virions was measured in samples collected during acute and convalescent phases as well as 3, 6, and 18 months post-illness using a urea enzyme-linked immunosorbent assay.The data show a significant increase in avidity from acute to convalescent phase followed by a decrease from convalescent phase to 3 months post-symptom onset, then a plateau. Linear regression analysis comparing antibody avidity between disease severity groups over time indicate that individuals with more severe disease (DHF/DSS) experienced greater decay in antibody avidity over time compared to less severe disease (DF), and ROC curve analysis showed that at 18 months post-illness, lower avidity was associated with previously having experienced more severe disease.These data suggest that increased dengue disease severity is associated with lower antibody avidity at later time-points post-illness.
Project description:Dengue virus (DENV) can cause diseases ranging from dengue fever (DF) to more severe dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Whether antiviral T cells contribute to the protection against or pathogenesis of severe disease is not well defined. Here, we identified antigen-specific IL-10+IFN-?+ double-positive (DP) CD4 T cells during acute DENV infection. While the transcriptomic signatures of DP cells partially overlapped with those of cytotoxic and type 1 regulatory CD4 T cells, the majority of them were non-cytotoxic/Tr1 and included IL21, IL22, CD109, and CCR1. Although we observed a higher frequency of DP cells in DHF, the transcriptomic profile of DP cells was similar in DF and DHF, suggesting that DHF is not associated with the altered phenotypic or functional attributes of DP cells. Overall, this study revealed a DENV-specific DP cell subset in patients with acute dengue disease and argues against altered DP cells as a determinant of DHF.
Project description:<h4>Background</h4>Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels.<h4>Methods</h4>Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS.<h4>Results</h4>An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF.<h4>Conclusions</h4>These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.