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Fulltext Vascular leakage in dengue - clinical spectrum and influence of parenteral fluid therapy

Rosenberger KD, Lum L, Alexander N, Junghanss T, Wills B, Jaenisch T, et al.

Trop Med Int Health, 2016 Mar;21(3):445-53.
PMID: 26752720 DOI: 10.1111/tmi.12666

OBJECTIVE: Clinical management of dengue relies on careful monitoring of fluid balance combined with judicious intravenous (IV) fluid therapy. However, in patients with significant vascular leakage, IV fluids may aggravate serosal fluid accumulation and result in respiratory distress.
METHODS: Trained physicians followed suspected dengue cases prospectively at seven hospitals across Asia and Latin America, using a comprehensive case report form that included daily clinical assessment and detailed documentation of parenteral fluid therapy. Applying Cox regression, we evaluated risk factors for the development of shock or respiratory distress with fluid accumulation.
RESULTS: Most confirmed dengue patients (1524/1734, 88%) never experienced dengue shock syndrome (DSS). Among those with DSS, 176/210 (84%) had fluid accumulation, and in the majority (83%), this was detectable clinically. Among all cases with clinically detectable fluid accumulation, 179/447 (40%) were diagnosed with shock or respiratory distress. The risk for respiratory distress with fluid accumulation increased significantly as the infused volume over the preceding 24 h increased (hazard ratio 1.18 per 10 ml/kg increase; P < 0.001). Longer duration of IV therapy, use of a fluid bolus in the preceding 24 h, female gender and poor nutrition also constituted independent risk factors.
CONCLUSIONS: Shock and respiratory distress are relatively rare manifestations of dengue, but some evidence of fluid accumulation is seen in around 50% of cases. IV fluids play a crucial role in management, but they must be administered with caution. Clinically and/or radiologically detectable fluid accumulations have potential as intermediate severity endpoints for therapeutic intervention trials and/or pathogenesis studies.
KEYWORDS: IV fluid therapy; clinical spectrum; dengue; espectro clínico; fluidothérapie IV; fuga vascular; fuite vasculaire; prospectif; prospective; prospectivo; spectre clinique; terapia IV de fluidos; vascular leakage
Fulltext Severe dengue categories as research endpoints-Results from a prospective observational study in hospitalised dengue patients

Rosenberger KD, Alexander N, Martinez E, Lum LCS, Dempfle CE, Junghanss T, et al.

PLoS Negl Trop Dis, 2020 Mar;14(3):e0008076.
PMID: 32130212 DOI: 10.1371/journal.pntd.0008076

Severe dengue was perceived as one clinical disease entity until the WHO 2009 classification stratified it into severe vascular leakage, severe bleeding, and severe organ dysfunction. The objectives of this study were to investigate the potential use of severe dengue categories as endpoints for intervention research. 271 patients with severe dengue among 1734 confirmed dengue patients were followed prospectively in this hospital-based observational study in Latin America and Asia. We compared the distribution of severe dengue categories according to gender and age (below/above 15y), and determined the relative frequency and the overlap of severe dengue categories in the same patients. In a next step, we extended the analysis to candidate moderate severity categories, based on recently suggested definitions which were adapted for our purposes. Severe vascular leakage occurred in 244 (90%), severe bleeding in 39 (14%), and severe organ dysfunction in 28 (10%) of 271 severe dengue patients. A higher frequency of severe leakage was seen in children or adolescents (<15y) compared to adults. More than 80% of the severe leakage cases, and 30-50% of the cases with severe bleeding or severe organ dysfunction, were defined as severe on the basis of that feature alone. In 136 out of 213 patients with severe leakage alone, neither moderate bleeding manifestation nor hepatic involvement was recorded. On the other hand, moderate leakage manifestations were detected in 4 out of 12 cases that were classified as severe based on bleeding alone. A major proportion of severe dengue patients exhibited clinical manifestations of severe vascular leakage only, which may constitute a useful endpoint for intervention research or pathophysiology studies. Severe bleeding and severe organ manifestation were recorded less frequently and exhibited a higher degree of overlap with severe leakage. Severe bleeding without leakage may be associated with individual predisposition or the presence of comorbidities. More detailed assessments are needed to explore this hypothesis. Candidate moderate disease endpoints were investigated and need to be further validated.
Fulltext C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study

Vuong NL, Le Duyen HT, Lam PK, Tam DTH, Vinh Chau NV, Van Kinh N, et al.

BMC Med, 2020 02 17;18(1):35.
PMID: 32063229 DOI: 10.1186/s12916-020-1496-1

BACKGROUND: Dengue infection can cause a wide spectrum of clinical outcomes. The severe clinical manifestations occur sufficiently late in the disease course, during day 4-6 of illness, to allow a window of opportunity for risk stratification. Markers of inflammation may be useful biomarkers. We investigated the value of C-reactive protein (CRP) measured early on illness days 1-3 to predict dengue disease outcome and the difference in CRP levels between dengue and other febrile illnesses (OFI).
METHOD: We performed a nested case-control study using the clinical data and samples collected from the IDAMS-consortium multi-country study. This was a prospective multi-center observational study that enrolled almost 8000 participants presenting with a dengue-like illness to outpatient facilities in 8 countries across Asia and Latin America. Predefined severity definitions of severe and intermediate dengue were used as the primary outcomes. A total of 281 cases with severe/intermediate dengue were compared to 836 uncomplicated dengue patients as controls (ratio 1:3), and also 394 patients with OFI.
RESULTS: In patients with confirmed dengue, median (interquartile range) of CRP level within the first 3 days was 30.2 mg/L (12.4-61.2 mg/L) (uncomplicated dengue, 28.6 (10.5-58.9); severe or intermediate dengue, 34.0 (17.4-71.8)). Higher CRP levels in the first 3 days of illness were associated with a higher risk of severe or intermediate outcome (OR 1.17, 95% CI 1.07-1.29), especially in children. Higher CRP levels, exceeding 30 mg/L, also associated with hospitalization (OR 1.37, 95% CI 1.14-1.64) and longer fever clearance time (HR 0.84, 95% CI 0.76-0.93), especially in adults. CRP levels in patients with dengue were higher than patients with potential viral infection but lower than patients with potential bacterial infection, resulting in a quadratic association between dengue diagnosis and CRP, with levels of approximately 30 mg/L associated with the highest risk of having dengue. CRP had a positive correlation with total white cell count and neutrophils and negative correlation with lymphocytes, but did not correlate with liver transaminases, albumin, or platelet nadir.
CONCLUSIONS: In summary, CRP measured in the first 3 days of illness could be a useful biomarker for early dengue risk prediction and may assist differentiating dengue from other febrile illnesses.
Fulltext Development of standard clinical endpoints for use in dengue interventional trials

Tomashek KM, Wills B, See Lum LC, Thomas L, Durbin A, Leo YS, et al.

PLoS Negl Trop Dis, 2018 10;12(10):e0006497.
PMID: 30286085 DOI: 10.1371/journal.pntd.0006497

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.
Fulltext Clinical evaluation of dengue and identification of risk factors for severe disease: protocol for a multicentre study in 8 countries

Jaenisch T, Tam DT, Kieu NT, Van Ngoc T, Nam NT, Van Kinh N, et al.

BMC Infect Dis, 2016 Mar 11;16:120.
PMID: 26968374 DOI: 10.1186/s12879-016-1440-3

The burden of dengue continues to increase globally, with an estimated 100 million clinically apparent infections occurring each year. Although most dengue infections are asymptomatic, patients can present with a wide spectrum of clinical symptoms ranging from mild febrile illness through to severe manifestations of bleeding, organ impairment, and hypovolaemic shock due to a systemic vascular leak syndrome. Clinical diagnosis of dengue and identification of which patients are likely to develop severe disease remain challenging. This study aims to improve diagnosis and clinical management through approaches designed a) to differentiate between dengue and other common febrile illness within 72 h of fever onset, and b) among patients with dengue to identify markers that are predictive of the likelihood of evolving to a more severe disease course.
Fulltext The influence of fluid resuscitation strategy on outcomes from dengue shock syndrome: a review of the management of 691 children in 7 Southeast Asian hospitals

Trieu HT, Vuong NL, Hung NT, Nguyen Minh T, Nguyen Van VC, Phan TQ, et al.

BMJ Glob Health, 2025 Mar 11;10(3).
PMID: 40068930 DOI: 10.1136/bmjgh-2024-017538

INTRODUCTION: The pathognomonic feature of dengue shock syndrome (DSS) is a transient capillary leak syndrome resulting in profound intravascular volume depletion. WHO management guidelines recommend particular parenteral fluid regimens during the critical leakage phase, including synthetic colloid solutions in certain circumstances. We set out to describe the actual fluid management strategies employed in different settings and to investigate relationships with clinical outcomes.
METHODS: We performed a retrospective review of paediatric DSS cases managed at seven hospitals across Malaysia, Myanmar and Vietnam. We explored the effects of both initial resuscitation (crystalloid alone or mixed crystalloid/colloid in the first 2 hours) and general management: group 1 (conservative-colloid, crystalloid only), group 2 (intermediate-colloid, colloid for 1-4 hours) or group 3 (liberal-colloid, continuous colloid for more than 4 hours) categorised according to the fluid given over the first 6 hours in clinically stable patients. We incorporated an inverse probability weighting score to adjust for potential differences in baseline severity.
RESULTS: Among all 691 patients, respiratory compromise (HR 2.08, p=0.022), requirement for nasal continuous positive airway pressure (NCPAP)/ventilation (OR 2.34, p<0.045) and days in hospital after DSS onset (risk ratio, RR 1.33, p=0.032) were significantly worse for mixed crystalloid/colloid versus crystalloid-only initial resuscitation regimens, after adjusting for baseline severity. Among the 547/691 children who stabilised within 2 hours, although a liberal-colloid general management strategy (group 3) was associated with a reduction in recurrent shock episodes (RR 0.13, p=0.043) when compared with a conservative-colloid strategy (group 1), the risks for respiratory compromise (OR 8.84, p<0.001) and requirement for NCPAP/ventilation (OR 8.16, p<0.001) were markedly increased. Additionally, the respective costs for group 3 vs group 1 were significantly higher.
CONCLUSIONS: The study highlights the potential benefits and risks of using colloid solutions in children with DSS. Formal randomised trials could help determine the most effective and safe parenteral fluid regimens for paediatric DSS. In the meantime, prolonged use of colloid solutions may be inappropriate, especially in settings without access to respiratory support.