Peptide-ligand conjugate based immunotherapeutic approach for targeted dismissal of non-structural protein 1 of dengue virus: A novel therapeutic solution for mild and severe dengue infections.

Dengue virus infection has significantly increased, with reported cases soaring from 505,430 in 2000 to 2,809,818 in 2022, emphasizing the need for effective treatments. Among the eleven structural and non-structural proteins of DENV, Non-structural protein 1 (NS1) has emerged as a promising target due to its diverse role in modulating the immune response, inducing vascular leakage, and facilitating viral replication and assembly. Monoclonal antibodies are the sole therapeutics to target NS1, but concerns about their cross-reactivity persist. Given these concerns, our study focuses on designing a novel Peptide Ligand Conjugate (PLC) as a potential alternative immunotherapeutic agent against NS1. This PLC aims to mediate the immune elimination of soluble NS1 and NS1-presenting DENV-infected host cells by pre-existing vaccine-induced immunity. By employing the High Throughput Virtual Screening (HTVS) method, QikProp analysis, and Molecular Dynamics studies, we identified three hits from Asinex Biodesigned Ligands out of 220,177 compounds that show strong binding affinity towards the monoclonal binding site of NS1 protein. After a rigorous analysis of physicochemical characteristics, antigenicity, allergenicity, and toxicity using various servers, we selected two peptides: the minimum epitopic region of the Diphtheria and Tetanus toxins as the peptide components of the PLCs. A non-cleavable, non-reactive oxime linker connected the ligand with the peptide through oxime and amide bonds. DPT vaccine is widely used in dengue-endemic countries, and it has been reported that antibodies titer against MER of Diphtheria toxin and Tetanus toxins persist lifelong in DPT-vaccinated people. Therefore, once the rationally designed PLCs bind to NS1 through the ligands, the peptide will induce an immune response against NS1 by triggering pre-existing DPT antibodies and activating memory cells. This orchestrated immune response will destroy soluble NS1 and NS1-expressing DENV-infected cells, thereby reducing the illness of severe dengue hemorrhagic fever and the DENV infection, respectively. Given the increasing demand for new therapeutics for DENV treatment, further investigation into this novel immune-therapeutic strategy may offer a new avenue for treating mild and severe dengue infections.

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.

Economic Evaluation of Novel Models of Care for Patients With Acute Medical Problems.

Importance: During COVID-19, Singapore simultaneously experienced a dengue outbreak, and acute hospitals were under pressure to lower bed occupancy rates. This led to new models of care to treat patients with acute, low-severity medical conditions either at home, in a hospital-at-home (HaH) model, or in a clinic-style setting sited at the emergency department in an ambulatory care team (ACT) model, but a reliable cost analysis for these models is lacking. Objective: To compare personnel costs of HaH and ACT with inpatient care. Design, Setting, and Participants: In this economic evaluation study, time-driven activity-based costing was used to compare the personnel cost of inpatient care with treating dengue via HaH and treating chest pain via ACT. Participants were patients with nonsevere dengue and chest pain unrelated to a coronary event admitted via the emergency department to the internal medicine service of a tertiary hospital in Singapore. Exposures: HaH for dengue and ACT for chest pain. Main Outcomes and Measures: A process map was created for the patient journey for a typical patient with each condition. The amount of time personnel spent on delivering care was estimated and the cost per minute determined based on their wages in 2022. The total cost of care was calculated by multiplying the time spent by the per-minute cost of the personnel resource and summing all costs. Results: Compared with inpatient care, HaH used 50% less nursing time (418 minutes, 95% uncertainty interval [UI], 370 to 465 minutes) but 80% more medical time (303 minutes, 95% UI, 270 to 338 minutes) per case of dengue. If implemented nationally, HaH would save an estimated 56 828 SGD per year (95% UI, -169 497 to 281 412 SGD [US $41 856; 95% UI, -$124 839 to $207 268]). The probability that HaH is cost saving was 69.2%. Compared with inpatient care, ACT used 15% less nursing time (296 minutes, 95% UI, 257 to 335 minutes) and 50% less medical time (57 minutes, 95% UI, 46 to 69 minutes) per case of chest pain. If implemented nationally, ACT would save an estimated 1 561 185 SGD per year (95% UI, 1 040 666 to 2 086 518 SGD [US $1 149 862; 95% UI, $766 483 to $1 536 786]). The probability that ACT is cost saving was 100%. Conclusions and Relevance: This economic evaluation found that the HaH and ACT models decreased the overall personnel cost of care. Reorganizing hospital resources may help hospitals reap the benefits of reduced hospital-acquired infections, improved patient recovery, and reduced hospital bed occupancy rates.

Dengue overview: An updated systemic review.

Dengue is caused by the dengue virus (DENVs) infection and clinical manifestations include dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). Due to a lack of antiviral drugs and effective vaccines, several therapeutic and control strategies have been proposed. A systemic literature review was conducted according to PRISMA guidelines to select proper references to give an overview of DENV infection. Results indicate that understanding the virus characteristics and epidemiology are essential to gain the basic and clinical knowledge as well as dengue disseminated pattern and status. Different factors and mechanisms are thought to be involved in the presentation of DHF and DSS, including antibody-dependent enhancement, immune dysregulation, viral virulence, host genetic susceptibility, and preexisting dengue antibodies. This study suggests that dissecting pathogenesis and risk factors as well as developing different types of therapeutic and control strategies against DENV infection are urgently needed.

Dengue: updates for dermatologists on the world's fastest-growing vector-borne disease.

Dengue is the world's fastest-growing vector borne disease and has significant epidemic potential in suitable climates. Recent disease models incorporating climate change scenarios predict geographic expansion across the globe, including parts of the United States and Europe. It will be increasingly important in the next decade for dermatologists to become familiar with dengue, as it commonly manifests with rashes, which can be used to aid diagnosis. In this review, we discuss dengue for general dermatologists, specifically focusing on its cutaneous manifestations, epidemiology, diagnosis, treatment, and prevention. As dengue continues to spread in both endemic and new locations, dermatologists may have a larger role in the timely diagnosis and management of this disease.

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.

Self-care practices and health-seeking behaviours in patients with dengue fever: A qualitative study from patients' and physicians' perspectives.

INTRODUCTION: Outpatient management for dengue fever is the mainstay of treatment for most dengue cases. However, severe dengue can develop rapidly while patients are at home. Understanding the self-care practices and healthcare-seeking behaviours among dengue patients managed as outpatients will help improve the delivery of care to these patients. OBJECTIVE: This study aimed to explore the self-care practices, health-seeking behaviour and outpatient management of dengue fever from the perspectives of patients and primary care physicians. METHODOLOGY: This qualitative study used in-depth interviews and focus group discussions to obtain information from laboratory-confirmed dengue patients who received outpatient care and primary care physicians who cared for them. Patients and physicians shared their experiences and perceptions of self-care practices, decisions to seek urgent care, and outpatient management procedures and visit frequency. Data were coded and analysed using thematic analysis. RESULTS: 13 patients and 11 physicians participated. We discovered that the use of traditional remedies was common with patients perceiving no harm from it, whereas physicians did not see a benefit. Dengue patients' knowledge of warning signs was inadequate despite the information being provided by physicians during clinical follow-up visits. Regarding the decision to seek urgent medical care, physicians assumed patients would seek help immediately once they experienced warning signs. However, for the patients, other factors influenced their health-seeking behaviour, such as their personal perceptions of symptom severity and often more importantly, their social circumstances (e.g., availability of childcare). Patients also described regular outpatient follow-up for dengue as inconvenient. There was variation in the prescribed outpatient follow-up interval recommended by participating physicians who complained about the lack of clear guidelines. CONCLUSION: Perceptions around self-care practices, health-seeking behaviour and outpatient management of dengue often differed between physicians and patients, especially on comprehension of dengue warning signs. Addressing these gaps between patient and physician perceptions and recognition of patient drivers of health-seeking behaviour are needed to improve the safety and delivery of outpatient care for dengue patients.

Clinical Profile of Pediatric Cases of Dengue during the 2019 Epidemic in Bangladesh: A Multicenter Cross-Sectional Study.

Bangladesh experienced the largest dengue epidemic during 2019, with more than 100,000 confirmed cases and 164 deaths. Almost one-third of these cases were children. The present study aimed to investigate the clinical and hematological manifestations of pediatric dengue cases during the epidemic. This was a multicenter cross-sectional study conducted in Dhaka Medical College Hospital, Dhaka, Dr. Sirajul Islam Medical College Hospital and Tangail Sadar Hospital, Tangail, Bangladesh between the period of June 2019 and September 2019. The study included 208 pediatric patients (age <18 years) with confirmed dengue fever. Patient's demographics, clinical and laboratory features of dengue were collected through patients' interview, clinical examination and laboratory investigations. Descriptive statistics were used to represent the patients' socio-demographic information, clinical presentations and hematological parameters. The majority of the patients were aged between 6 and 17 years with male predominance. The most commonly presented clinical manifestations were fever (100.0%), headache (59.0%), myalgia (42.0%), rash (36.0%), retro-orbital pain (28.0%) and diarrhea (24.0%). Warning signs abdominal pain (40.0%) and persistent vomiting (29.0%), bleeding manifestations such as melena (17.0%), gum bleeding (7.0%) and epistaxis (6.0%) and evidence of plasma leakage such as oliguria (3.4%), ascites (2.4%), pleural effusion (1.4%), and shock (1.0%) were also present in the patients. Raised HCT levels, leucopenia and thrombocytopenia were present in almost 23.0%, 43.0% and 28.0% of children, respectively. Warning signs and plasma leakage were present in a substantial number of patients indicating potential risk of severe dengue. Prompt diagnosis and management based on best clinical judgment might prevent severe dengue at an early stage.

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.

Blood transfusion in severe dengue infection: a case series.

BACKGROUND: Dengue is still a recurrent challenge to the global population, without specific antiviral therapy. Clinical management strategies are aimed to mitigate the deaths. The use of blood products in dengue is recommended mainly in cases of bleeding. CASE PRESENTATION: We prospectively collected data on Sri Lankan dengue cases in the Teaching Hospital, Peradeniya, Sri Lanka from 2017, and selected ten severe cases where blood transfusions were involved in the management. The series comprises seven females and three males, with a median age of 36 years (range 12-53 years). All patients were critically ill at the time of blood transfusion, with dramatic stabilization of vital parameters after the transfusions. Only one patient had detectable bleeding, while five patients had occult blood loss as indicated by dropping hematocrit. Even though four patients had stable hematocrit, they had metabolic acidosis. Two patients had a very high increase of hepatic transaminases along with acidosis. Two patients had myocarditis with dropping hematocrit, suggestive of occult bleeding. CONCLUSIONS: Clinical deterioration despite fluid management commonly occurs due to occult bleeding in dengue infection. Blood transfusion is lifesaving in such cases of blood loss, acidosis, and severe hepatic damage. The mechanism of this effect needs an explanation, such as enhanced oxygen delivery to the tissues and hemostasis to hypothesize a few possibilities.

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.

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.

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.

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.

Clinical features and management of children with dengue-associated obstructive shock syndrome: A case report.

RATIONALE: Dengue obstructive shock syndrome is a fatal complication commonly observed in the late critical phase of dengue infection and is associated with a high mortality rate. The main pathogenesis involves a dramatic increase in chest pressure, owing to severe plasma leakage and mechanical respiratory support, hampering the heart's ability to pump effectively and impeding adequate blood venous return to the heart chambers. To date, there is a paucity of clinical data about Dengue obstructive shock syndrome reported. PATIENT CONCERNS: The 2 reported patients presented with prolonged and decompensated dengue shock with critical multi-organ failures and mechanical ventilation. The patients' hemodynamics were profoundly affected by high pressure in the thoracic and abdominal cavities resulting from Dengue-induced severe plasma leakage and mechanical ventilation. DIAGNOSES: Clinical presentations, laboratory data, mini-fluid challenge test, and point-of-care (POCUS) were used to make diagnoses and guide management. INTERVENTIONS: Clinical monitoring, judicious fluid (colloids and blood products) administration guided by repeated POCUS to properly assess the adequacy of the intravascular volume, homeostasis adjustments by plasma exchange, and continuous renal replacement therapies. OUTCOMES: The patients had favorable outcomes. LESSONS: Our study highlights the clinical manifestations and management of children with dengue obstructive shock syndrome and underscores the importance of monitoring hemodynamics by consecutive POCUS at the bedside in order to make a timely diagnosis and assess intravascular fluid volume inadequacy accurately as well as closely monitor the fluid management responses.

Direct Medical Costs of Tetanus, Dengue, and Sepsis Patients in an Intensive Care Unit in Vietnam.

Background: Critically ill patients often require complex clinical care by highly trained staff within a specialized intensive care unit (ICU) with advanced equipment. There are currently limited data on the costs of critical care in low-and middle-income countries (LMICs). This study aims to investigate the direct-medical costs of key infectious disease (tetanus, sepsis, and dengue) patients admitted to ICU in a hospital in Ho Chi Minh City (HCMC), Vietnam, and explores how the costs and cost drivers can vary between the different diseases. Methods: We calculated the direct medical costs for patients requiring critical care for tetanus, dengue and sepsis. Costing data (stratified into different cost categories) were extracted from the bills of patients hospitalized to the adult ICU with a dengue, sepsis and tetanus diagnosis that were enrolled in three studies conducted at the Hospital for Tropical Diseases in HCMC from January 2017 to December 2019. The costs were considered from the health sector perspective. The total sample size in this study was 342 patients. Results: ICU care was associated with significant direct medical costs. For patients that did not require mechanical ventilation, the median total ICU cost per patient varied between US$64.40 and US$675 for the different diseases. The costs were higher for patients that required mechanical ventilation, with the median total ICU cost per patient for the different diseases varying between US$2,590 and US$4,250. The main cost drivers varied according to disease and associated severity. Conclusion: This study demonstrates the notable cost of ICU care in Vietnam and in similar LMIC settings. Future studies are needed to further evaluate the costs and economic burden incurred by ICU patients. The data also highlight the importance of evaluating novel critical care interventions that could reduce the costs of ICU care.