Dengue Patients Research Articles

Influence of previous Zika virus infection on acute dengue episode.

The co-circulation of flaviviruses in tropical regions has led to the hypothesis that immunity generated by a previous dengue infection could promote severe disease outcomes in subsequent infections by heterologous serotypes. This study investigated the influence of antibodies generated by previous Zika infection on the clinical outcomes of dengue infection. We enrolled 1,043 laboratory confirmed dengue patients and investigated their prior infection to Zika or dengue. Severe forms of dengue disease were more frequent in patients with previous Zika infection, but not in those previously exposed to dengue. Our findings suggest that previous Zika infection may represent a risk factor for subsequent severe dengue disease, but we did not find evidence of antibody-dependent enhancement (higher viral titer or pro-inflammatory cytokine overexpression) contributing to exacerbation of the subsequent dengue infection.

A Cross-Sectional Study Exploring Mental Health among Patients Suffering from Dengue in Pakistani Tertiary Care Hospitals

Background. Dengue, known as “Tropical flu,” is a widespread disease that has recently become endemic in many Asian countries. Dengue disease still lacks research in many aspects, specifically the impact of patient factors and disease prognosis on mental health. This is a cross-sectional study that evaluated the impact of different patient factors on depression, stress, and anxiety in patients with acute dengue infection. Methods. An interview-based data were collected through a questionnaire containing patient sociodemographic parameters, clinical parameters, and DASS 21 questions. Independent sample T -test, one-way ANOVA test, and post hoc test were performed to determine the degree of association of psychological manifestations with clinical signs and symptoms considering a level of significance of p < 0.05 . Results. The patients from 39 years to 49 years of age had a higher association with stress, depression, and anxiety. The participants at primary and matriculation level education had a higher association with dengue-associated anxiety. Among the three levels of fever, i.e., mild (<102°F), moderate (102-103°F), and severe (>103°F), the participants suffering from severe fever experienced more anxiety and so was those with intense pain and stress. Conclusions. According to the DASS-21 tool, patients with severe pain and high-degree fever during dengue had significant stress and anxiety symptoms, respectively, than the patients with mild or moderate pain and fever. Middle-aged patients with low literacy levels were also found to have significant associations with stress, anxiety, and depression. To our knowledge, this is one of the first studies in Pakistan that in-depth explored the impact of patient factors’ variability on psychological illnesses related to dengue. These findings may warrant practitioners to integrate timely psychological screening and care for dengue patients.

Lambda-free light chain: A serum marker of dengue disease via NS3 protease-mediated antibody cleavage

ABSTRACT Dengue poses a significant global public health threat, with diverse clinical manifestations due to complex interactions between the host and the pathogen. Recent reports have highlighted elevated serum-free light chain (FLC) levels in viral infectious diseases. Hence, our study aimed to investigate serum FLC levels in dengue patients. The findings revealed elevated serum λ FLCs, which were associated with the severity of dengue. Receiver operating characteristic curve (ROC) analysis demonstrated that λ FLCs may serve as a serum marker for identifying dengue disease (AUC: 0.7825, sensitivity: 80, specificity: 71.43) and classifying severe dengue (AUC: 0.8102, sensitivity: 75, specificity: 79.52). The viral protease, Dengue virus (DENV) nonstructural protein 3 (NS3), acts as a protease that cleaves viral polyproteins as well as host substrates. Therefore, we proposed that antibodies might be potential targets of NS3 protease, leading to an increase in FLCs. LC/MS-MS analysis confirmed that λ FLCs were the predominant products after antibody degradation by NS3 protease. Additionally, purified NS3 protease cleaved both human IgG and DENV2-neutralizing antibodies, resulting in the presence of λ FLCs. Moreover, NS3 protease administration in vitro led to a reduction in the neutralizing efficacy of DENV2-neutralizing antibodies. In summary, the elevated serum λ FLC levels effectively differentiate dengue patients from healthy individuals and identify severe dengue. Furthermore, the elevation of serum λ FLCs is, at least in part, mediated through NS3 protease-mediated antibody cleavage. These findings provide new insights for developing diagnostic tools and understanding the pathogenesis of DENV infection.

Dengue virus serotype did not contribute to clinical severity or mortality in Taiwan’s largest dengue outbreak in 2015

BackgroundDengue virus serotype 2 (DENV-2) was the major serotype in the 2015 dengue outbreak in Taiwan, while DENV-1 and DENV-3 were dominant between 2005 and 2014. We aimed to investigate whether DENV-2 contributed to disease severity and mortality in the outbreak in Kaohsiung city, Taiwan.MethodsWe collected serum samples from dengue patients to detect the presence of DENV and determine the serotypes by using quantitative reverse transcription-polymerase chain reaction. Our cohorts comprised 105 DENV-1-infected cases and 1,550 DENV-2-infected cases. Demographic data, DENV serotype, and comorbidities were covariates for univariate and multivariate analyses to explore the association with severity and mortality.ResultsThe results suggested that DENV-1 persisted and circulated, while DENV-2 was dominant during the dengue outbreak that occurred between September and December 2015. However, DENV-2 did not directly contribute to either severity or mortality. Aged patients and patients with diabetes mellitus (DM) or moderate to severe chronic kidney disease (CKD) had a higher risk of developing severe dengue. The mortality of dengue patients was related to a higher Charlson comorbidity index score and severe dengue. Among DENV-2-infected patients and older patients, preexisting anti-dengue IgG, DM, and moderate to severe CKD were associated with severe dengue. Moreover, female sex and severe dengue were associated with a significantly higher risk of death.ConclusionsOur findings highlight the importance of timely serological testing in elderly patients to identify potential secondary infections and focus on the meticulous management of elderly patients with DM or moderate to severe CKD to reduce dengue-related death.

Clinical profiles and predictors of survival in severe dengue cases.

Dengue is endemic in tropical countries. Severe dengue has a high risk of morbidity and mortality. We aimed to identify factors associated with dengue survival among our intensive care unit (ICU) patients. A retrospective study was conducted among dengue cases admitted to the ICU of Hospital Sultan Abdul Halim, Kedah, Malaysia from 2016 to 2019. Out of 1,852 dengue cases admitted to the hospital, 7.2% of patients required ICU admission. Survival rate was 88.6% among severe dengue cases. The majority of severe dengue patients were obese, while other notable comorbidities included hypertension and diabetes mellitus. Also, 73% of patients presented in the critical phase, at a median of Day 4 of illness. All patients admitted to the ICU had a history of fever. The predominant warning signs were lethargy, fluid accumulation and haemoconcentration with rapid platelet reduction. Among nonsurvivors, 69.2% had fulminant hepatitis, 53.8% had massive bleeding or disseminated intravascular coagulation, 38.5% had haemophagocytic lymphohistiocytosis and 30.8% had myocarditis. The predominant serotypes were DENV-3 and DENV-1. The least number of cases was seen in 2017, when all serotypes were equally presented. Multiple logistic regression showed that Sequential Organ Failure Assessment (SOFA) score, peak international normalised ratio, peak partial thromboplastin time and aspartate aminotransferase on admission were independent risk factors for survival. This model had an area under the curve of 0.98, giving an overall 98.2% accuracy. Specific warning signs and blood investigations in dengue patients may aid in early decision for ICU admission. Monitoring of SOFA scores plus coagulation and liver enzyme profiles could improve dengue survival rates.

Enrollment of dengue patients in a prospective cohort study in Umphang District, Thailand, during the COVID-19 pandemic: Implications for research and policy.

Dengue is endemic in Thailand and imposes a high burden on the health system and society. We conducted a prospective cohort study in Umphang District, Tak Province, Thailand, to investigate the share of dengue cases with long symptoms and their duration. Here we present the results of the enrollment process during the COVID-19 pandemic with implications and challenges for research and policy. In a prospective cohort study conducted in Umphang District, Thailand, we examined the prevalence of persistent symptoms in dengue cases. Clinically diagnosed cases were offered free laboratory testing, We enrolled ambulatory dengue patients regardless of age who were confirmed through a highly sensitive laboratory strategy (positive NS1 and/or IgM), agreed to follow-up visits, and gave informed consent. We used multivariate logistic regressions to assess the probability of clinical dengue being laboratory confirmed. To determine the factors associated with study enrollment, we analyzed the relationship of patient characteristics and month of screening to the likelihood of participation. To identify underrepresented groups, we compared the enrolled cohort to external data sources. The 150 clinical cases ranged from 1 to 85 years old. Most clinical cases (78%) were confirmed by a positive laboratory test, but only 19% of those confirmed enrolled in the cohort study. Women, who were half as likely to enroll as men, were underrepresented in the cohort. The Thai physicians' clinical diagnoses at this rural district hospital had good agreement with laboratory diagnoses. By identifying underrepresented groups and disparities, future studies can ensure the creation of statistically representative cohorts to maximize their scientific value. This involves recruiting and retaining underrepresented groups in health research, such as women in this study. Promising strategies for meaningful inclusion include multi-site enrollment, offering in-home or virtual services, and providing in-kind benefits like childcare for underrepresented groups.

Utility of Atypical Lymphocytes and Large Immature Cells in Prediction of Dengue Severity.

Background: There is a clinical imperative to devise metrics to prognosticate dengue severity. Our objective was to determine the association between longitudinal trends in atypical lymphocytes and large immature cell count with platelet count and dengue severity. Materials and methods: Retrospective analysis of longitudinally measured clinical and hematological data from (n = 79) hospitalized dengue patients was done. Results: The cohort consisted of patients with dengue fever without warning signs (DFWOWS) (n = 40, females = 14, and age = 19.9 ± 14.6 years), dengue fever with warning signs (DFWWS) (n = 36, females = 13, and age = 16.1 ± 14.1 years) and severe dengue (n = 3, females = 2, and age = 5.3 ± 4 years). Platelet count increased at a rate of 11,524 cells/mm3/day, with a slower rate of rise as the severity increased (p = 0.001***). Concurrently hematocrit and neutrophil percentage decreased, while the lymphocyte percentage and white blood cell (WBC) count increased during the hospital stay. Every 1% increase in atypical lymphocyte count (ATY) was associated with a fall in platelet count by 16,963 cells/mm3 (p = 0.001***). A similar but weaker trend was found for large immature cells (LICs). Conclusion: The data support the usefulness of longitudinal tracking of atypical lymphocyte and large immature cell count for dengue prognosis. The time trends of the hematological parameters indicate the progression of patients from the critical to the recovery phase. How to cite this article: Peraka R, Koppula A, Muppala BS, et al. Utility of Atypical Lymphocytes and Large Immature Cells in Prediction of Dengue Severity. J Assoc Physicians India 2023;71(11):19-24.

Machine-learning prediction models for any blood component transfusion in hospitalized dengue patients

BackgroundBlood component transfusions are a common and often necessary medical practice during the epidemics of dengue. Transfusions are required for patients when they developed severe dengue fever or thrombocytopenia of 10×109/L or less. This study therefore investigated the risk factors, performance and effectiveness of eight different machine-learning algorithms to predict blood component transfusion requirements in confirmed dengue cases admitted to hospital. The objective was to study the risk factors that can help to predict blood component transfusion needs. MethodsEight predictive models were developed based on retrospective data from a private group of hospitals in India. A python package SHAP (SHapley Additive exPlanations) was used to explain the output of the “XGBoost” model. ResultsSixteen vital variables were finally selected as having the most significant effects on blood component transfusion prediction. The XGBoost model presented significantly better predictive performance (area under the curve: 0.793; 95 % confidence interval: 0.699–0.795) than the other models. ConclusionPredictive modelling techniques can be utilized to streamline blood component preparation procedures and can help in the triage of high-risk patients and readiness of caregivers to provide blood component transfusions when required. This study demonstrates the potential of multilayer algorithms to reasonably predict any blood component transfusion needs which may help healthcare providers make more informed decisions regarding patient care.

PENGETAHUAN, KUALITAS HIDUP DAN BIAYA SAKIT PASIEN DENGUE DI RS PKU MUHAMMADIYAH GAMPING

The incidence of dengue virus infection in the D.I. Yogyakarta reached 3,618 cases in 2020. Based on its clinical manifestations, dengue virus infection is divided into Dengue Fever (DF), Dengue Haemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS). This study aims to identify the level of knowledge, quality of life, and costs of dengue patients at PKU Muhammadiyah Gamping Hospital from March 2021 to October 2021. This study used a cross-sectional design. The measurement of the patient's knowledge level used a questionnaire knowledge of dengue, while the quality of life was assessed using EQ-5D-5L for adult patients and EQ-5D-Y for pediatric patients. The cost of illness data from the hospital finance database. This study involved 31 respondents with the characteristics aged 16-40 years (54.84%), male (87.1%), using BPJS insurance (80.65%), and an average length of stay of 4 days (51.61%). The patient's level of knowledge about dengue, knowledge of dengue prevention, and dengue prevention behavior reached 74.20% (sufficient), 74.20% (sufficient), and 77.42% (sufficient) respectively. The quality of life of dengue patients reached 100% and 85.2% in DF patients, while the DHF patients felt a few anxious/depressed (sad). The average cost of illness in DF patients was Rp. 2,796,386 and Rp. 3,378,537 in DHF patients.

Simultaneous COVID-19 Pandemic and Dengue Epidemic: A Double Challenge to Geriatric Health Security in Bangladesh.

Bangladesh faces distinct challenges as a resource-poor country due to the combined effects of the COVID-19 pandemic and simultaneous dengue outbreaks. Older adults are particularly vulnerable to infection and death from COVID-19. While overall health and life expectancy in the general population have improved substantially in Bangladesh, health services for older adults are still lacking. No specialized geriatric units have been established in hospitals, and no home care programs have been established for older adults. COVID-19 mortality rates were highest among older adults ages 61 to 70 years (35%), and 71 to 80 years (20%) in 2022. Although the country's average COVID-19 mortality rate was low at 1.76%, in older adults, it was much higher (55%), accounting for 14,797 deaths, despite that most cases (55%) were recorded in young adults. During the COVID-19 pandemic, Bangladesh also experienced a dengue epidemic. Around 21,193 dengue patients were admitted to hospitals between January 1 and October 8, 2022. Without a well-established and all-encompassing social care program, the indirect socioeconomic burden of COVID-19 continues to fall on older adults. There is an immediate need for robust healthcare and support services, especially for older adults in Bangladesh, which are particularly susceptible to the dual threats posed by the COVID-19 pandemic and the dengue epidemic. Recommendations are made to protect older adults from the devastating effects of the 2 simultaneous epidemics.

Effectiveness of platelet transfusion in dengue fever: Rangpur community medical college and hospital experience at Rangpur, Bangladesh

Background: Dengue fever, caused by the dengue virus and transmitted by mosquitoes, is a global health concern, causing mild to severe illness. Severe cases lead to thrombocytopenia, a low platelet count that can cause bleeding. Platelet transfusion is debated as a treatment strategy; some studies support its use to prevent bleeding, while others raise concerns about side effects. The aim of the study is to see the effectiveness of platelet transfusion in dengue patients who has a very low platelet count. Methods: This single-center study was conducted at The Department of Medicine, Rangpur Community Medical College and Hospital, Bangladesh. A total of 52 patients were enrolled and analyzed in this study from March to August 2023. Results: Most cases are Dengue Fever (86.54%), followed by Dengue Hemorrhagic Fever Grade 1 (7.69%) and Dengue Shock Syndrome (5.77%). Bleeding occurred in 15.38% of enrollment. Common symptoms include fever (78.85%), headache (57.69%), cough (67.31%), and myalgia (55.77%). Health parameters include blood pressure (110/70 mm Hg), pulse rate (86.5±12.8 bpm), and temperature (100.5±2.8°F). Investigation findings show S. bilirubin (0.61 mg/dl), S. creatinine (0.94 mg/dl), RBS (120.5 mg/dl), HB% (13.78 g/dl), and PCV (39.75). Platelet counts varied in different conditions, with most responders to platelet transfusion (94.23%) showing no deaths but adverse outcomes related to transfusion reactions (5.77%). Conclusions: The prevalence of dengue fever in Bangladesh necessitates a comprehensive understanding of effective treatment modalities. By examining the outcomes and implications of platelet transfusion in this context, the research seeks to shed light on its effectiveness, thereby informing evidence-based medical practices and improving patient care.

Liver Impairment and Elevated Aminotransferase Levels Predict Severe Dengue in Vietnamese Children.

The degree of liver impairment in children with dengue infection varies from mild to severe injury. Aminotransferase levels may be useful in predicting severe dengue. This study aimed to evaluate the degree of liver impairment and determine whether elevated aminotransferases could be used to discriminate between non-severe and severe dengue in Vietnamese children. This was a prospective cohort study of pediatric patients with confirmed dengue infection who were admitted to Can Tho Children's Hospital, Vietnam. The receiver operating characteristic (ROC) curve was used to discriminate the power of Aspartate transaminase (AST) or Alanine transaminase (ALT) to predict severe dengue. Two hundred and thirty confirmed dengue patients were enrolled, including 70% (161) patients with non-severe dengue and 30% (69) with severe dengue. This study indicates that 73.9% of patients had abnormal AST (＞40 U/L), and 34.8% of patients had abnormal ALT (＞40 U/L). The incidence of dengue patients with hepatitis (AST or ALT ≥ 4×ULN) and severe hepatitis (AST or ALT ≥ 10×ULN) were 18.7% and 17.0%, respectively. At a cut-off point of 120 U/L, AST's AUROC, sensitivity, and specificity were 0.93 (95% CI: 0.90-0.96), 82.5%, and 87.3%, respectively. At a cut-off point of 80 U/L, ALT's AUROC, sensitivity, and specificity were 0.89 (95% CI: 0.84-0,93), 87.5%, and 85.2%, respectively, for predicting severe dengue. Elevated aminotransferase levels were associated with severe dengue, and AST/ALT were good markers for predicting severe dengue in Vietnamese children.

Misuse of Antibiotics in Dengue Fever—A Contributor to Antimicrobial Resistance?

Abstract Background Dengue, a vector-borne viral infection, is a concern in the tropical and subtropical regions across the world. The rampant use of antibiotics in dengue patients in India reinforces the anticipated threat of emergence of antimicrobial resistance. Aim We aimed to retrospectively investigate the prescribing pattern of antibiotics and compare the clinical status of dengue patients treated with and without antibiotics. Methods Between January 2016 and December 2020 period, data of patients who tested positive for at least 1 of the 3 screening tests (nonstructural protein 1, immunoglobulin M, or immunoglobulin G) were collected from patient medical chart, and we assessed the clinical outcome of dengue patients treated with and without antibiotics. Results Of 370 patients, 196 (52.97%) were managed with antibiotics and 174 (47.02%) were managed without antibiotics along with other supportive measures. A peak in the percentage of prescriptions with antibiotics was seen in 2019, 168 (85.71%) were prescribed with a single antibiotic with a majority of them, and 56.6% received third generation cephalosporins. Only 46 (23.46%) had bacterial co-infection while 150 (76.53%) had no co-infection. Thirty-five patients (70%) with dengue hemorrhagic fever were clinically managed with antibiotics compared with 50% patients in the “dengue fever” category. Only 8% of patients with mild dengue were given 2 antibiotics, whereas 13% with moderate dengue and 16% with severe dengue were prescribed with 2 antibiotics. Conclusions The increased number of prescriptions with antibiotics for a viral infection when not recommended by the guideline may lead to emergence of antibiotic resistance in hospitals as well as community.

Functional and transcriptional heterogeneity within the massively expanding HLADR+CD38+ CD8 T cell population in acute febrile dengue patients.

CD8 T cells play a crucial role in protecting against intracellular pathogens such as viruses by eliminating infected cells and releasing anti-viral cytokines such as interferon gamma (IFNγ). Consequently, there is significant interest in comprehensively characterizing CD8 T cell responses in acute dengue febrile patients. Previous studies, including our own, have demonstrated that a discrete population of CD8 T cells with HLADR+ CD38+ phenotype undergoes massive expansion during the acute febrile phase of natural dengue virus infection. Although about a third of these massively expanding HLADR+ CD38+ CD8 T cells were also CD69high when examined ex vivo, only a small fraction of them produced IFNγ upon in vitro peptide stimulation. Therefore, to better understand such functional diversity of CD8 T cells responding to dengue virus infection, it is important to know the cytokines/chemokines expressed by these peptide-stimulated HLADR+CD38+ CD8 T cells and the transcriptional profiles that distinguish the CD69+IFNγ+, CD69+IFNγ-, and CD69-IFNγ- subsets.

Kinetics of severe dengue virus infection and development of gut pathology in mice.

Dengue virus, an arbovirus, causes an estimated 100 million symptomatic infections annually and is an increasing threat as the mosquito range expands with climate change. Dengue epidemics are a substantial strain on local economies and health infrastructure, and an understanding of what drives severe disease may enable treatments to help reduce hospitalizations. Factors exacerbating dengue disease are debated, but gut-related symptoms are much more frequent in severe than mild cases. Using mouse models of dengue infection, we have shown that inflammation and damage are earlier and more severe in the gut than in other tissues. Additionally, we observed impairment of the gut mucus layer and propose that breakdown of the barrier function exacerbates inflammation and promotes severe dengue disease. This idea is supported by recent data from human patients showing elevated bacteria-derived molecules in dengue patient serum. Therapies aiming to maintain gut integrity may help to abrogate severe dengue disease.

Overview of microbes in hypertension

High blood pressure (BP), known as hypertension, is a major contributing factor to the development of cardiovascular disease. The development and pathogenesis of hypertension involve a wide array of factors including genetics, environment, hormones, hemodynamics, and inflammation. There is a significantly positive association between higher levels of colonization by Aggregatibacter actinomycetemcomitans , Porphyromonas gingivalis , Tannerella forsythia , and Treponema denticola (etiologic bacterial burden) below the gum line, and the presence of hypertension. The use of antibiotics during pregnancy, which is likely indicative of bacterial infections severe enough to require antibiotic treatment, is associated with a slight increase in average arterial BP. Cytomegalovirus infection is a risk factor for heightened arterial BP and acts as a co-factor in the development of aortic atherosclerosis. The relationship between hypertension and coronavirus disease 2019 involves endothelial dysfunction and dysregulation of the renin-angiotensin system. The effects of gut microbiota on BP, whether beneficial or harmful, are influenced by multiple factors including genetics, epigenetics, lifestyle choices, and antibiotic usage. These variables collectively contribute to overall BP levels and the control of hypertension. Several reports have examined the BP levels of patients infected with the Zika virus. In regions with a high incidence of nasopharyngeal carcinoma, hypertension has been linked to a higher risk of Epstein-Barr virus reactivation. Also, a potential causal link has been found between malaria and elevated BP. Also, the elevated prevalence of hypertension among dengue patients during their initial visit suggests that relying solely on BP measurements to predict severe infection may not be clinically reliable.

Early biomarkers for prediction of severe manifestations of dengue fever: a systematic review and a meta-analysis

Early identification of dengue patients at risk of adverse outcomes is important to prevent hospital overcrowding in low- to middle- income countries during epidemics. We performed a systematic review to identify which biomarkers measured in first 96 h of fever could predict dengue haemorrhagic fever (DHF, World Health Organization 1997 clinical classification) or severe dengue (SD, WHO 2009, clinical classification). PubMed, Scopus, CINAHL, Web of Science, and EMBASE databases were searched for prospective cohort and nested case–control studies published from 1997 to Feb 27, 2022. The protocol for the study was registered in PROSPERO (ID: CRD42021230053). After screening 6747 publications, and analysing 37 eligible studies reporting on 5925 patients, elevated C-reactive protein, aspartate aminotransferase, interleukin-8 and decreased albumin levels were strongly associated with dengue haemorrhagic fever (by meta-analyses of multiple studies, p < 0.05), while elevated vascular cell adhesion protein 1, syndecan-1, aspartate aminotransferase and C-reactive protein levels were strongly associated with severe dengue (by meta-analyses of multiple studies, p < 0.05). Further 44 and 28 biomarkers were associated with the risk of DHF and SD respectively, but only in a single study. The meta-analyses suggest the importance of early acute inflammation with hepatic involvement in determining the subsequent course of illness in dengue.

Complement receptor type 1 and 2 (CR1 and CR2) gene polymorphisms and plasma protein levels are associated with the Dengue disease severity

The pathological outcome of dengue disease results from complex interactions between dengue virus (DENV) and host genetics and immune response. Complement receptor types 1 and 2 (CR1 and CR2) mediate complement activation through the alternative pathway. This study investigated the possible association of genetic polymorphisms and plasma levels of CR1 and CR2 with dengue disease. A total of 267 dengue patients and 133 healthy controls were recruited for this study. CR1 and CR2 gene polymorphisms were analyzed by Sanger sequencing, while plasma CR1 and CR2 levels were measured by ELISA. The frequency of the CR1 minor allele rs6691117G was lower in dengue patients and those with severe dengue compared to healthy controls. Plasma CR1 and CR2 levels were decreased in dengue patients compared to healthy controls (P < 0.0001) and were associated with platelet counts. CR1 levels were lower in dengue patients with warning signs (DWS) compared to those without DWS, while CR2 levels were decreased according to the severity of the disease and after 5 days (T1) and 8 days (T2) of follow-up. CR2 levels were decreased in dengue patients positive for anti-DENV IgG and IgM and patients with bleeding and could discriminate DWS and SD from dengue fever patients (AUC = 0.66). In conclusion, this study revealed a reduction in CR2 levels in dengue patients and that the CR1 SNP rs6691117A/G is associated with the dengue severity. The correlation of CR2 levels with platelet counts suggests that CR2 could be an additional biomarker for the prognosis of severe dengue disease.

Febrile Phase Soluble Urokinase Plasminogen Activator Receptor and Olfactomedin 4 as Prognostic Biomarkers for Severe Dengue in Adults.

Dengue cases continue to rise and can overwhelm healthcare systems during outbreaks. In dengue, neutrophil mediators, soluble urokinase plasminogen activator receptor (suPAR) and olfactomedin 4, and mast cell mediators, chymase and tryptase, have not been measured longitudinally across the dengue phases. The utility of these proteins as prognostic biomarkers for severe dengue has also not been assessed in an older adult population. We prospectively enrolled 99 adults with dengue-40 dengue fever, 46 dengue with warning signs and 13 severe dengue, along with 30 controls. Plasma levels of suPAR, olfactomedin 4, chymase and tryptase were measured at the febrile, critical and recovery phases in dengue patients. The suPAR levels were significantly elevated in severe dengue compared to the other dengue severities and controls in the febrile (P < .001), critical (P < .001), and recovery (P = .005) phases. In the febrile phase, suPAR was a prognostic biomarker of severe dengue, with an AUROC of 0.82. Using a cutoff derived from Youden's index (5.4 ng/mL) and an estimated prevalence of severe dengue (16.5%) in our healthcare institution, the sensitivity was 71.4% with a specificity of 87.9% in the febrile phase, and the positive and negative predictive values were 54.7% and 95.8%, respectively. Olfactomedin 4 was elevated in dengue patients but not in proportion to disease severity in the febrile phase (P = .04) There were no significant differences in chymase and tryptase levels between dengue patients and controls. In adult dengue, suPAR may be a reliable prognostic biomarker for severe dengue in the febrile phase.

Antibody Profiling of Dengue Severities Using Flavivirus Protein Microarrays.

Dengue is a viral disease transmitted by Aedes aegypti mosquitoes. According to the World Health Organization, about half of the world's population is at risk of dengue. There are four serotypes of the dengue virus. After infection with one serotype, it will be immune to such a serotype. However, subsequent infection with other serotypes will increase the risk of severe outcomes, e.g., dengue hemorrhagic fever, dengue shock syndrome, and even death. Since severe dengue is challenging to predict and lacks molecular markers, we aim to build a multiplexed Flavivirus protein microarray (Flaviarray) that includes all of the common Flaviviruses to profile the humoral immunity and cross-reactivity in the dengue patients with different outcomes. The Flaviarrays we fabricated contained 17 Flavivirus antigens with high reproducibility (R-square = 0.96) and low detection limits (172-214 pg). We collected serums from healthy subjects (n = 36) and dengue patients within 7 days after symptom onset (mild dengue (n = 21), hospitalized nonsevere dengue (n = 29), and severe dengue (n = 36)). After profiling the serum antibodies using Flaviarrays, we found that patients with severe dengue showed higher IgG levels against multiple Flavivirus antigens. With logistic regression, we found groups of markers with high performance in distinguishing dengue patients from healthy controls as well as hospitalized from mild cases (AUC > 0.9). We further reported some single markers that were suitable to separate dengue patients from healthy controls (AUC > 0.9) and hospitalized from mild outcomes (AUC > 0.8). Together, Flaviarray is a valuable tool to profile antibody specificities, uncover novel markers for decision-making, and shed some light on early preventions and treatments.