Molecular Insight into Dengue Virus Pathogenesis and Its Implications for Disease Control.

Dengue virus (DENV) is a mosquito-transmitted RNA virus that infects an estimated 390 million humans each year. Here, we review recent advances in our understanding of the biology of DENV and describe knowledge gaps that have impacted the development of effective vaccines and therapeutics.

Structure-Guided Design of an Anti-dengue Antibody Directed to a Non-immunodominant Epitope.

Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue.

Intravenous fluid therapy in hospitalized adult dengue patients without shock: Impact on subsequent severe dengue and potential adverse effects.

There is a lack of evidence on the optimal administration of intravenous (IV) fluids in hospitalized adult dengue patients without compensated and hypotensive shock. This study utilized a well-established cohort of dengue patients to compare risks of progressing to severe dengue (SD) over time for patients who were administered IV fluid versus others who were not. We included adult patients (n = 4781) who were hospitalized for dengue infection from 2005 to 2008. Cases were patients who developed SD (n = 689) and controls were patients who did not up until discharge (n = 4092). We estimated the hazard ratios (HRs) and risk of SD over time between groups administered different volumes of IV fluids versus the no IV fluid comparison group using Cox models with time-dependent covariates. The doubly-robust estimation approach was used to control for the propensity of fluid administration given clinical characteristics of patients. Subgroup analyses by age, sex, and dengue warning signs before IV fluid administration were conducted. High (>2000 mL/day) IV fluids volume was associated with a higher risk of development of SD for those who had warning signs (HR: 1.77 [1.05-2.97], p: 0.0713) and for those below 55 years old (HR: 1.53 [1.04-2.25], p: 0.0713). Low (<1000 mL/day) IV fluids volume was protective against SD for patients without warning signs (HR: 0.757 [0.578-0.990], p: 0.0883), no lethargy (HR: 0.770 [0.600-0.998], p: 0.0847), and females (HR: 0.711 [0.516-0.980], p: 0.0804). Over the course of hospitalization, there were no significant differences in IV fluid administration and SD risk in most subgroups, except in those who experienced lethargy and were administered IV fluid volume or quantity. Administering high volumes of IV fluids may be associated with an increased risk of SD during hospitalization for adult dengue patients without shock. Judicious use of IV fluids as supportive therapy is warranted.

SARS-CoV-2 and dengue virus co-infection: Epidemiology, pathogenesis, diagnosis, treatment, and management.

SARS-CoV-2 and dengue virus co-infection cases have been on the rise in dengue-endemic regions as coronavirus disease 2019 (COVID-19) spreads over the world, posing a threat of a co-epidemic. The risk of comorbidity in co-infection cases is greater than that of a single viral infection, which is a cause of concern. Although the pathophysiologies of the two infections are different, the viruses have comparable effects within the body, resulting in identical clinical symptoms in the case of co-infection, which adds to the complexity. Overlapping symptoms and laboratory features make proper differentiation of the infections important. However, specific biomarkers provide precise results that can be utilised to diagnose and treat a co-infection, whether it is simply COVID-19, dengue, or a co-infection. Though their treatment is distinguished, it becomes more complicated in circumstances of co-infection. As a result, regardless of whatever infection the first symptom points to, confirmation diagnosis of both COVID-19 and dengue should be mandatory, particularly in dengue-endemic regions, to prevent health deterioration in individuals treated for a single infection. There is still a scarcity of concise literature on the epidemiology, pathophysiology, diagnosis, therapy, and management of SARS-CoV-2 and dengue virus co-infection. The epidemiology of SARS-CoV-2 and dengue virus co-infection, the mechanism of pathogenesis, and the potential impact on patients are summarised in this review. The possible diagnosis with biomarkers, treatment, and management of the SARS-CoV-2 and dengue viruses are also discussed. This review will shed light on the appropriate diagnosis, treatment, and management of the patients suffering from SARS-CoV-2 and dengue virus co-infection.

Dengue: A focused review for the emergency clinician.

Dengue is an arbovirus transmitted by the Aedes spp. mosquito. Approximately 390 million infections occur annually per World Health Organization estimates, with significant increases in infections throughout the last decade. The disease is endemic in warmer climates throughout the world, though cases may also be imported to non-endemic regions by returning travelers. Patients experience a wide variety of symptoms ranging from asymptomatic infection to severe disease requiring critical care. Emergency clinicians should consider the diagnosis of dengue in patients from endemic areas presenting with a flu-like illness, rash, and evidence of bleeding.

Structure-guided affinity maturation of a single-chain variable fragment antibody against the Fu-bc epitope of the dengue virus envelope protein.

Dengue is one of the most dominant arthropod-borne viral diseases, infecting at least 390 million people every year throughout the world. Despite this, there is no effective treatment against dengue, and the only available vaccine has already been withdrawn owing to the significant adverse effects. Therefore, passive immunotherapy using monoclonal antibodies is now being sought as a therapeutic option. To date, many dengue monoclonal antibodies have been identified, most of which are serotype-specific, and only a few of which are cross-reactive. Furthermore, antibodies that cross-react within serotypes are weakly neutralizing and frequently induce antibody-dependent enhancement, which promotes viral entry and replication. Therefore, broadly neutralizing antibodies with no risk of antibody-dependent enhancement are required for the treatment of dengue. Here, we developed a single-chain variable fragment (scFv) antibody from an anti-fusion loop E53 antibody (PDB: 2IGF). We introduced previously predicted favorable complementarity-determining region (CDR) mutations into the gene encoding the scFv antibody for affinity maturation, and the resultant variants were tested in vitro against the highly conserved fusion and bc epitope of the dengue virus envelope protein. We show some of these scFv variants with two to three substitution mutations in three different CDRs possess affinity constants (KD) ranging from 20 to 200 nM. The scFv-mutant15, containing D31L, Y105W, and S227W substitutions, showed the lowest affinity constant, (KD = 24 ± 7 nM), approximately 100-fold lower than its parental construct. We propose that the scFv-derivative antibody may be a good candidate for the development of an effective and safe immunotherapy.

Combined Therapeutic Plasma Exchange and Continuous Renal Replacement Therapy in Children With Dengue-Associated Acute Liver Failure and Shock Syndrome: Single-Center Cohort From Vietnam.

OBJECTIVES: Pediatric acute liver failure (PALF) is a fatal complication in patients with severe dengue. To date, clinical data on the combination of therapeutic plasma exchange (TPE) and continuous renal replacement therapy (CRRT) for managing dengue-associated PALF concomitant with shock syndrome are limited. DESIGN: Retrospective cohort study (January 2013 to June 2022). PATIENTS: Thirty-four children. SETTING: PICU of tertiary Children's Hospital No. 2 in Vietnam. INTERVENTIONS: We assessed a before-versus-after practice change at our center of using combined TPE and CRRT (2018 to 2022) versus CRRT alone (2013 to 2017) in managing children with dengue-associated acute liver failure and shock syndrome. Clinical and laboratory data were reviewed from PICU admission, before and 24 h after CRRT and TPE treatments. The main study outcomes were 28-day in-hospital mortality, hemodynamics, clinical hepatoencephalopathy, and liver function normalization. MEASUREMENTS AND MAIN RESULTS: A total of 34 children with a median age of 10 years (interquartile range: 7-11 yr) underwent standard-volume TPE and/or CRRT treatments. Combined TPE and CRRT ( n = 19), versus CRRT alone ( n = 15), was associated with lower proportion of mortality 7 of 19 (37%) versus 13 of 15 (87%), difference 50% (95% CI, 22-78; p < 0.01). Use of combined TPE and CRRT was associated with substantial advancements in clinical hepatoencephalopathy, liver transaminases, coagulation profiles, and blood lactate and ammonia levels (all p values < 0.001). CONCLUSIONS: In our experience of children with dengue-associated PALF and shock syndrome, combined use of TPE and CRRT, versus CRRT alone, is associated with better outcomes. Such combination intervention was associated with normalization of liver function, neurological status, and biochemistry. In our center we continue to use combined TPE and CRRT rather than CRRT alone.

An Extracorporeal Plasma Filtration Column with Specific Binding to Dengue Virions.

INTRODUCTION: Dengue infection is a significant public health concern that no specific treatment is available. Extracorporeal plasmapheresis or plasma filtration is a treatment option for severe cases with complications. However, the commercial adsorption devices mainly contained size-exclusive porous beads to adsorb the plasma proteins nonselectively. METHODS: We developed a 1:50 simulated circuit for dengue virus-specific adsorption using a flavivirus-specific (4G2) antibody entrapped into the alginate bead. RESULTS: The reduction ratios of the viral titer after 3 h of continuous run were 63.00 ± 1.21%, and 93.97 ± 1.27% measured by reverse transcription qPCR, and plaque titration, respectively. No specific adsorption was observed with Enterovirus A71 or Escherichia coli bacteria. CONCLUSION: This study is a proof-of-concept for the potential use of a dengue virus-specific adsorption column in the 1:50 simulated circuit. The system could be applied to various clinical platforms by substituting target-specific antibodies.

Mapping patient pathways and understanding clinical decision-making in dengue management to inform the development of digital health tools.

BACKGROUND: Dengue is a common viral illness and severe disease results in life-threatening complications. Healthcare services in low- and middle-income countries treat the majority of dengue cases worldwide. However, the clinical decision-making processes which result in effective treatment are poorly characterised within this setting. In order to improve clinical care through interventions relating to digital clinical decision-support systems (CDSS), we set out to establish a framework for clinical decision-making in dengue management to inform implementation. METHODS: We utilised process mapping and task analysis methods to characterise existing dengue management at the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. This is a tertiary referral hospital which manages approximately 30,000 patients with dengue each year, accepting referrals from Ho Chi Minh city and the surrounding catchment area. Initial findings were expanded through semi-structured interviews with clinicians in order to understand clinical reasoning and cognitive factors in detail. A grounded theory was used for coding and emergent themes were developed through iterative discussions with clinician-researchers. RESULTS: Key clinical decision-making points were identified: (i) at the initial patient evaluation for dengue diagnosis to decide on hospital admission and the provision of fluid/blood product therapy, (ii) in those patients who develop severe disease or other complications, (iii) at the point of recurrent shock in balancing the need for fluid therapy with complications of volume overload. From interviews the following themes were identified: prioritising clinical diagnosis and evaluation over existing diagnostics, the role of dengue guidelines published by the Ministry of Health, the impact of seasonality and caseload on decision-making strategies, and the potential role of digital decision-support and disease scoring tools. CONCLUSIONS: The study highlights the contemporary priorities in delivering clinical care to patients with dengue in an endemic setting. Key decision-making processes and the sources of information that were of the greatest utility were identified. These findings serve as a foundation for future clinical interventions and improvements in healthcare. Understanding the decision-making process in greater detail also allows for development and implementation of CDSS which are suited to the local context.

An unusual case of dengue fever in aneurysmal subarachnoid haemorrhage: diagnosis and management nuances.

BACKGROUND: Dengue fever is highly prevalent in the Asia-Pacific region. Here we present an unusual case of dengue fever in a patient with a ruptured cerebral aneurysm causing subarachnoid (SAH) and intraventricular haemorrhage (IVH) and discuss the implications of dengue-related thrombopathies on the management of SAH and its complications. CASE REPORT: A 56-year-old female with a two-day history of high-grade pyrexia and myalgia presented with sudden-onset drowsiness (presenting Glasgow Coma Scale, GCS: E1V1M4). Imaging revealed extensive SAH and IVH due to a ruptured right middle cerebral artery (MCA) aneurysm, with extensive vasospasm. Blood test revealed thrombocytopenia and a positive NS-1 antigen. She subsequently suffered from two episodes of re-rupture of the aneurysm and elevated intracranial pressure which required a decompressive craniectomy in addition to coilingof the MCA aneurysm. Cerebral perfusion and rheology were maintained with the triple-H therapy. Her GCS improved to E4V1M6, but remained aphasic. DISCUSSIONS: Thrombocytopenia and deranged platelet functions in dengue infection might affect the stability of clot and increase the risk of re-rupture of aneurysm. Immediate securement of the aneurysm was paramount. In cases of severe dengue, plasma leakage could lead to intravascular depletion, and coupled with haemoconcentration and hypotension would further increase the risk for vasospasm.

Dengue Fever Presenting As Acute Febrile Illness In Neonates: A Case Series From Pakistant.

Dengue fever is a mosquito-borne disease caused by flavivirus. It primarily infects people living in tropical and subtropical areas and can be transmitted vertically or horizontally to new-borns. We discuss the clinical spectrum, treatment, and outcomes of five neonates who presented with dengue fever at Aga Khan Hospital for Women in Karimabad, Karachi, Pakistan, during the 2021 post- monsoon season (October to December). Dengue infection was confirmed via positive NS1 antigen test. All new-borns had fever, flushing, and thrombocytopenia. Capillary leak syndrome and haemorrhagic complications occurred in one case. Two babies required oxygen support, with one mortality. Due to the severity of the disease in this population, we suggest that dengue fever should be evaluated as a differential diagnosis in neonates with sepsis and thrombocytopenia, especially in high-risk or endemic areas. Critical management strategies for neonatal dengue fever are the same as those for other paediatric patients and include judicious use of intravenous fluids and inotropes.

A rare case of acute liver failure with intrahepatic cholestasis due to dengue hemorrhagic fever: CytoSorb® and plasma exchange aided in the recovery: case report.

BACKGROUND: Dengue haemorrhagic fever is a severe form of acute dengue infection characterized by leakage of plasma through capillaries into body spaces resulting in circulatory insufficiency leading to shock. Despite varying degrees of liver involvement occurring in acute dengue infection, intrahepatic cholestasis is very rare in the literature with only two cases reported so far. We report a challenging case of a middle-aged woman with DHF complicated by acute liver failure, coagulopathy, acute renal failure and prolonged intrahepatic cholestasis. She was successfully managed in the intensive care unit with supportive therapy, Cytosorb® and therapeutic plasma exchange. CASE PRESENTATION: A 54-year-old Sri Lankan obese woman with multiple comorbidities presented with fever, headache, vomiting and generalized malaise for 3 days and was diagnosed with dengue haemorrhagic fever. Despite the standard dengue management, she clinically deteriorated due to development of complications such as, acute liver injury, intrahepatic cholestasis and acute renal injury. Acute liver failure was evidenced by transaminitis, lactic acidosis, coagulopathy with pervaginal bleeding and severe encephalopathy necessitating elective intubation and mechanical ventilation. She was immediately transferred to intensive care facilities where she underwent supportive management for liver failure, continuous renal replacement therapy coupled with cytosorb and therapeutic plasma exchange with which she made a remarkable recovery. CONCLUSION: Acute liver failure with a prolonged phase of intrahepatic cholestasis is a very rare complication of acute dengue illness which is sparsely documented in medical literature so far. This patient was managed successfully with supportive therapy, aided by cytoSorb hemo-adsorption and therapeutic plasma exchange.

Dengue and Plasmodium falciparum Coinfection With Secondary Hemophagocytic Lymphohistiocytosis in a 3-Year-old Boy: A Clinical Conundrum.

Hemophagocytic lymphohistiocytosis (HLH) is a multisystem disease wherein there is an exaggerated immune system activation following a trigger such as infection, malignancy, or autoimmune diseases. Here we report a case of a 3-year-old boy who presented to us with fever, was diagnosed with dengue fever, and treatment started for the same. Clinical response was poor to treatment and high-grade fever persisted. Subsequent evaluation showed Plasmodium falciparum malaria and treatment was initiated with antimalarial drugs. Further clinical deterioration with poor trend of laboratory values over the next few days prompted evaluation for HLH; workup was positive satisfying the HLH-2004 criteria and IV dexamethasone was started. The child gradually improved and was discharged with normal counts on follow-up over the next 3 months. This article emphasizes on the importance of high degree of suspicion, early workup, and initiation of treatment for HLH for a better outcome.

Direct and indirect costs for hospitalized patients with dengue in Southern Sri Lanka.

BACKGROUND: The Southern Province of Sri Lanka is endemic with dengue, with frequent outbreaks and occurrence of severe disease. However, the economic burden of dengue is poorly quantified. Therefore, we conducted a cost analysis to assess the direct and indirect costs associated with hospitalized patients with dengue to households and to the public healthcare system. METHODS: From June 2017-December 2018, we prospectively enrolled children and adults with acute dengue hospitalized at the largest, public tertiary-care (1800 bed) hospital in the Southern Province, Sri Lanka. We administered a structured questionnaire to obtain information regarding direct costs spent by households on medical visits, medications, laboratory testing, and travel for seeking care for the illness. Indirect costs lost by households were estimated by identifying the days of work lost by patients and caregivers and school days lost by children. Direct hospital costs were estimated using gross costing approach and adjusted by multiplying by annual inflation rates in Sri Lankan rupees and converted to US dollars. RESULTS: A total of 1064 patients with laboratory-confirmed dengue were enrolled. The mean age (SD) was 35.9 years (15.6) with male predominance (66.2%). The mean durations of hospitalization for adults and paediatric patients were 3.86 (SD = 1.51) and 4 (SD = 1.32) days, respectively. The per-capita direct cost borne by the healthcare system was 233.76 USD, and was approximately 14 times greater than the per-capita direct cost borne by households (16.29 USD, SD = 14.02). The per-capita average number of loss of working days was 21.51 (SD = 41.71), with mean per-capita loss of income due to loss of work being 303.99 USD (SD = 569.77), accounting for over 70% of average monthly income. On average, 10.88 days (SD = 10.97) of school days were missed due to the dengue episode. School misses were expected to reduce future annual income of affected children by 0.44%. CONCLUSIONS: Dengue requiring hospitalization had a substantial economic burden on the public healthcare system in Sri Lanka and the affected households. These findings emphasize the importance of strengthening dengue control activities and improved use of hospital-based resources for care to reduce the economic impact of dengue in Sri Lanka.

Matrix metalloproteinases in the pathogenesis of dengue viral disease: Involvement of immune system and newer therapeutic strategies.

Globally, the burden due to dengue infection is increasing with a recent estimate of 96 million progressing to the disease every year. Dengue pathogenesis and the factors influencing it are not completely known. It is now widely speculated that there is an important role of matrix metalloproteinases (MMPs) in the initiation and progression of dengue pathogenesis; however, their exact roles are not fully understood. Overactivation of matrix metalloproteinases may contribute to the severity of dengue pathogenesis. Cytokines and various other mediators of inflammation interact with the vascular endothelium and matrix metalloproteinases may be one of the components among them. Extensive plasma leakage into tissue spaces may result in a shock. It is evident in the literature that MMP2 and MMP9 increase in dengue patients is correlated with the severity of the disease; however, the underlying mechanism is still unknown. Activation of innate cells and adaptive immune cells which include, B and T cells, macrophages or monocytes and dendritic cells also contribute to the dengue pathology. Newer therapeutic strategies include microRNAs, such as miR-134 (targets MMP3 and MMP1) and MicroRNA-320d, (targets MMP/TIMP proteolytic system). The use of antibodies-based therapeutics like (Andecaliximab; anti-matrix metalloproteinase-9 antibody) is also suggested against MMPs in dengue. In this review, we summarize some recent developments associated with the involvement of immune cells and their mediators associated with the matrix metalloproteinases mediated dengue pathogenesis. We highlight that, there is still very little knowledge about the MMPs in dengue pathogenesis which needs attention and extensive investigations.

Serological and molecular epidemiology of the Dengue, Zika and Chikungunya viruses in a risk area in Brazil.

BACKGROUND: The co-circulation of types of arbovirus in areas where they are endemic increased the risk of outbreaks and limited the diagnostic methods available. Here, we analyze the epidemiological profile of DENV, CHIKV and ZIKV at the serological and molecular level in patients with suspected infection with these arboviruses in the city of Juazeiro do Norte, Ceará, Brazil. METHODS: In 2016, the Central Public Health Laboratory (LACEN) of Juazeiro do Norte received 182 plasma samples from patients who visited health facilities with symptoms compatible with arbovirus infection. The LACEN performed serological tests for detection of IgM/IgG to DENV and CHIKV. They then sent these samples to the Retrovirology Laboratory of the Federal University of São Paulo and Faculty of Medical of the ABC where molecular analyses to confirm the infection by DENV, ZIKV and CHIKV were performed. The prevalence of IgM/IgG antibodies and of infections confirmed by RT-qPCR were presented with 95% confidence interval. RESULTS: In serologic analysis, 125 samples were positive for antibodies against CHIKV and all were positive for antibodies against DENV. A higher prevalence of IgG against CHIKV (63.20% with 95% CI: 45.76-70.56) than against DENV (95.05% with 95% CI: 78.09-98.12) was observed. When the samples were submitted to analysis by RT-qPCR, we observed the following prevalence: mono-infection by ZIKV of 19.23% (95% CI: 14.29-34.82) patients, mono-infection by CHIKV of 3.84% (95% CI: 2.01-5.44) and co-infection with ZIKV and CHIKV of 1.09% (95% CI: 0.89-4.56). CONCLUSION: The serologic and molecular tests performed in this study were effective in analyzing the epidemiological profile of DENV, CHIKV and ZIKV in patients with suspected infection by these arboviruses in the city of Juazeiro do Norte, Ceará/Brazil.

Neonatal Dengue With HLH: Perks of Early Diagnosis and Management.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, aggressive syndrome. It can be primary, which involves genetic mutation with an early presentation, or secondary to infections, malignancies, etc., due to absence of immune downregulation. It is a very rare condition in newborns. Dengue is a potential virus causing HLH, but, in newborns, there are only few case reports and limited clinical literature. OBSERVATION: Herein, in this report, we highlight a case of neonatal HLH, triggered by perinatal dengue. The neonate manifested clinically within the first week of life, the earliest reported timeline so far in the literature. CONCLUSION: HLH should be excluded in neonates especially when multisystem involvement cannot be explained by sepsis alone.

Identification of predictors and model for predicting prolonged length of stay in dengue patients.

PURPOSE: Our objective is to identify the predictive factors and predict hospital length of stay (LOS) in dengue patients, for efficient utilization of hospital resources. METHODS: We collected 1360 medical patient records of confirmed dengue infection from 2012 to 2017 at Max group of hospitals in India. We applied two different data mining algorithms, logistic regression (LR) with elastic-net, and random forest to extract predictive factors and predict the LOS. We used an area under the curve (AUC), sensitivity, and specificity to evaluate the performance of the classifiers. RESULTS: The classifiers performed well, with logistic regression (LR) with elastic-net providing an AUC score of 0.75 and random forest providing a score of 0.72. Out of 1148 patients, 364 (32%) patients had prolonged length of stay (LOS) (> 5 days) and overall hospitalization mean was 4.03 ± 2.44 days (median ± IQR). The highest number of dengue cases belonged to the age group of 10-20 years (21.1%) with a male predominance. Moreover, the study showed that blood transfusion, emergency admission, assisted ventilation, low haemoglobin, high total leucocyte count (TLC), low or high haematocrit, and low lymphocytes have a significant correlation with prolonged LOS. CONCLUSION: Our findings demonstrated that the logistic regression with elastic-net was the best fit with an AUC of 0.75 and there is a significant association between LOS greater than five days and identified patient-specific variables. This method can identify the patients at highest risks and help focus time and resources.

The Double Burden of COVID-19 and Dengue in Nepal: The challenges ahead.

Coronavirus disease 2019 (COVID-19) pandemic has caused significant impact on the health care system. As a consequence, diagnosis and treatment of vector borne diseases including dengue has been equally affected. Nepal is no exception to this, where COVID-19 cases is exponentially increased and all resources are concentrated on its prevention, control and management. Dengue, one of the major vector-borne diseases in Nepal, is apparently overlooked despite approaching the peak season of the disease. The aim of this paper is to describe the double burden of COVID-19 and dengue in Nepal, particularly highlighting the co-circulation and possible coinfections. This has posed higher risk of increased severity, more severe cases and deaths in Nepal. Moreover, potential misdiagnosis of these viral diseases may lead to delayed or, inappropriate treatment and poor allocation of resources.

Predictors and Clinical Outcomes of Poor Platelet Recovery in Adult Dengue With Thrombocytopenia: A Multicenter, Prospective Study.

BACKGROUND: Platelet transfusion is common in dengue patients with thrombocytopenia. We previously showed in a randomized clinical trial that prophylactic platelet transfusion did not reduce clinical bleeding. In this study, we aimed to characterize the predictors and clinical outcomes of poor platelet recovery in transfused and nontransfused participants. METHODS: We analyzed patients from the Adult Dengue Platelet Study with laboratory-confirmed dengue with ≤20 000 platelets/µL and without persistent mild bleeding or any severe bleeding in a post hoc analysis. Poor platelet recovery was defined as a platelet count of ≤20 000/µL on Day 2. We recruited 372 participants from 5 acute care hospitals located in Singapore and Malaysia between 29 April 2010 and 9 December 2014. Of these, 188 were randomly assigned to the transfusion group and 184 to the control group. RESULTS: Of 360 patients, 158 had poor platelet recovery. Age, white cell count, and day of illness at study enrollment were significant predictors of poor platelet recovery after adjustment for baseline characteristics and platelet transfusion. Patients with poor platelet recovery had longer hospitalizations but no significant difference in other clinical outcomes, regardless of transfusion. We found a significant interaction between platelet recovery and transfusion; patients with poor platelet recovery were more likely to bleed if given a prophylactic platelet transfusion (odds ratio 2.34, 95% confidence interval 1.18-4.63). CONCLUSIONS: Dengue patients with thrombocytopenia who were older or presented earlier and with lower white cell counts were more likely to have poor platelet recovery. In patients with poor platelet recovery, platelet transfusion does not improve outcomes and may actually increase the risk of bleeding. The mechanisms of poor platelet recovery need to be determined. CLINICAL TRIALS REGISTRATION: NCT01030211.