Capillary Leak Research Articles

Effect of rigorous fluid management using monitoring of ECW ratio by bioelectrical impedance analysis in critically ill postoperative patients: A prospective, single-blind, randomized controlled study

Background & AimsPrecise assessment of postoperative volume status is important to administrate optimal fluid management. Bioelectrical impedance analysis (BIA) which measures the body composition using electric character. Extracellular water (ECW) ratio by BIA represented as the ratio of ECW to total body water (TBW) and is known to reflect the hydration status. Based on this, we aimed to determine whether aggressive fluid control using ECW ratio could improve clinical outcomes through a single blind, randomized controlled trial. MethodsFrom November 2021 to December 2022, intensive care unit (ICU) patients admitted after surgery were randomly assigned to an intervention group or a control group whether postoperative fluid management was controlled via BIA. Among patients in the intervention group, dehydrated patients received a bolus infusion with crystalloid fluid whereas diuretics were administrated to overhydrated patients until the value of ECW ratio fell within its normal setting range (0.390–0.406). Contrarily, BIA was performed once a day for the control group. Patients in the control group received traditional fluid treatment regardless of BIA results. Primary outcome was in-hospital mortality in two groups. The secondary outcomes were postoperative morbidities, 28-day mortality. Results77 patients of the intervention group and 90 patients of the control group were finally analyzed. The in-hospital mortality (0 in intervention, 4.4% in control, p = 0.125) and 28-day mortality (1.3% in intervention, 14.4% in control, p = 0.002) showed lower incidence in the intervention group than in the control group. In multivariate analysis, the overhydrated status whose ECW ratio exceeding 0.406 [odds ratio (OR): 2.731, 95% confidence interval (CI): 1.001-7.663, p = 0.049] and high capillary leak index (CLI) value at ICU admission (OR: 1.024, 95% CI: 1.008-1.039, p = 0.002) were risk factors of postoperative morbidities. Regarding the 28-day mortality, high CLI value (OR: 1.025, 95% CI: 1.002-1.050, p = 0.037) and traditional strategy without BIA monitoring (OR: 9.903, 95% CI: 1.095-89.566, p = 0.041) were the significant predisposing factors. ConclusionOur results revealed the rigorous fluid treatment with volume control based on ECW ratio by BIA failed to achieve significant improvement in in-hospital mortality, but it could reduce 28-day mortality of ICU patients. Monitoring of ECW ratio may help establish optimal fluid treatment strategies for postoperative ICU patients who are susceptible to fluid imbalances with fluid overload. Trial registrationClinicalTrials.gov, NCT06097923, retrospectively registered on October 16, 2023, https://clinicaltrials.gov/study/NCT06097923?term=NCT06097923&rank=1

Pathogenesis, Symptoms and Diagnosis, and Prevention of Dengue Hemorrhagic Fever in Adults

Dengue Hemorrhagic Fever (DHF) is an infectious disease caused by the dengue virus, characterized by symptoms such as fever, muscle or joint pain, leukopenia, rash, lymphadenopathy, thrombocytopenia, and hemorrhagic tendencies. In DHF, there is plasma leakage leading to fluid accumulation in body cavities, and in severe cases, it can progress to Dengue Shock Syndrome, characterized by shock. The illness is mainly spread by Aedes aegypti and Aedes albopictus mosquitoes, presenting a substantial worldwide health issue. The diagnosis of DHF requires the presence of several criteria: fever or recent history of acute fever lasting 2-7 days, often biphasic; at least one hemorrhagic manifestation such as positive tourniquet test, ecchymosis, mucosal bleeding, hematemesis, or thrombocytopenia; and evidence of plasma leakage. Young adults are particularly susceptible to dengue fever due to their frequent outdoor activities. In Padang City, West Sumatra Province, in 2020, the age group most affected by the disease was adults aged 15 to 44 years.

Importance of IgE-Induced Unique Plasma Leakage in the Skin for Urticaria-Like Symptoms in an Anaphylaxis-Dependent Spotted Distribution of Immune Complex in Skin (ASDIS) Mouse Model

Plain Language SummaryUrticaria, a skin allergy causing itchy bumps, is often treated with antihistamines. However, these treatments may not always be effective. To address this, researchers aim to develop new anti-allergic drugs. While several methods to induce urticaria-like symptoms in experimental animals have been explored, few are currently available. In a previous study, we successfully induced anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS) in hairless mice, resembling human urticaria. In this study, we investigated and clarified several key aspects using this method. First, we found that ASDIS in mice is mediated by an increase in vascular permeability, similar to human urticaria. This discovery supports the idea of considering mouse ASDIS as a model for human urticaria. Second, we demonstrated that ASDIS could be induced by IgE but not by histamine, a key mediator of vascular permeability increase. The unique plasma leakage induced by IgE was identified as a contributing factor to the urticaria-like symptoms in ASDIS. Third, a comparison of ASDIS and histamine-induced anaphylaxis in haired and hairless mice revealed that hairless mice were more sensitive. This suggests that hairless mice possess a unique mechanism induced by IgE, partially associated with histamine function. Finally, the inhibition of ASDIS by applying an adrenaline α1 receptor agonist to the skin strongly suggested the potential of this drug as an anti-allergic ointment. In summary, our mouse ASDIS model can be utilized as an urticaria model. Further detailed clarification of the underlying mechanisms of ASDIS induction will expedite the development of new anti-allergic drugs.

Assessment of acute toxicity, genotoxicity, and anti-inflammatory activity of SteLL, a lectin from Schinus terebinthifolia Raddi. Leaves, in mice

Ethnopharmacology relevanceSchinus terebinthifolia Raddi (Anacardiaceae), known as Brazilian pepper tree, stands out as a medicinal plant widely used in traditional medicine. The leaves are popularly used as anti-inflammatory agent and to relieve inflammatory conditions such as bronchitis, ulcers, and wounds, for example. Aim of the studyThe present study evaluated the acute toxicity, genotoxicity, and anti-inflammatory activity of S. terebinthifolia leaf lectin (SteLL) in mice (Mus musculus). Materials and methodsIn the acute toxicity assay, the animals were treated intraperitoneally (i.p.) or orally (per os) with a single dose of 100 mg/kg. Genotoxicity was assessed by the comet and micronucleus assays. Carrageenan-induced peritonitis and paw edema models were used to evaluate the anti-inflammatory effects of SteLL (1, 5 and 10 mg/kg, i.p.). ResultsNo animal died and no signs of intoxication or histopathological damage were observed in the acute toxicity assay. Genotoxic effect was not detected. In peritonitis assay, SteLL reduced in 56–69% leukocyte migration to the peritoneal cavity; neutrophil count decreased by 25–32%, while mononuclear cell count increased by 67–74%. SteLL promoted a notable reduction of paw edema after 4 h (61.1–63.4%). Morphometric analysis showed that SteLL also decreased the thickness of epidermal edema (30.2–40.7%). Furthermore, SteLL decreased MPO activity, plasma leakage, NO release, and modulated cytokines in both peritoneal fluid and paw homogenate. ConclusionSteLL did not induce acute toxicity or genotoxicity in mice and stands out as a promising candidate in the development of new phytopharmaceuticals with anti-inflammatory action.

A Case Report on Heart Failure in Dengue Patients with Concurrent Capillary Leakage Syndrome: Unveiling a “Leakage-Failure” Co-existence

This case report describes a rare and compelling presentation of Massive Tubercular Pericardial Effusion (MTPE) concomitant with Heart Failure (HF) and Diabetes Mellitus (DM). Tuberculosis, once thought to be a disease of the past, continues to manifest in diverse clinical scenarios, emphasizing the importance of maintaining a high index of suspicion, particularly in endemic regions. The patient, a 60 year old male with a known history of DM and HF, presented with symptoms of worsening dyspnea, fatigue, and peripheral edema. Diagnostic workup revealed a massive pericardial effusion with characteristics suggestive of tubercular etiology, subsequently confirmed by pericardial fluid analysis. The challenges in managing this triad of conditions: MTPE, HF, and DM were addressed through a multidisciplinary approach involving cardiology, infectious disease, and endocrinology specialists. This case underscores the significance of a comprehensive diagnostic evaluation and collaborative management in optimizing outcomes for patients with complex cardiovascular and infectious comorbidities. KYAMC Journal Volume: 14, No: 04, January 2024: 246-248.

A case report: Maternal complications from severe dengue. What can happen?

Dengue fever (DHF) is an acute infectious disease caused by dengue virus. Thrombocytopenia results from viral suppression in the bone marrow, and platelet destruction occurs. Damaged platelets worsen plasma leakage. When the amount of filtration fluid exceeds the ability and fluid trapped in the interstitium eventually enters the alveoli, there is an increase in alveolar capillaries, resulting in pulmonary oedema. The patient was referred with complaints of fever for 5 days, dizziness (+), shortness of breath (+), nausea (+), and vomiting (+). Laboratory examination showed platelets 109 x 103/µL, positive Ig G DHF Immuno Serology, and thorax X-ray with pulmonary oedema. Cesarean section and IUD insertion were performed. During and after surgery, there were no complications.

Biomimetic nanoporous oxygenation membranes with high hemocompatibility and fast gas transport property

Membrane technology holds great potential for separation applications and also finds critical needs in biomedical fields, such as blood oxygenation. However, the bottlenecks in gas permeation, plasma leakage, and especially hemocompatibility hamper the development of membrane oxygenation. It remains extremely challenging to design efficient membranes and elucidate underlying principles. In this study, we report biomimetic decoration of asymmetric nanoporous membranes by ultrathin FeIII-tannic acid metal–ligand networks to realize fast gas exchange with on plasma leakage and substantially enhance hemocompatibility. Because the intrinsic nanopores facilitate gas permeability and the FeIII-catechol layers enable superior hydrophilicity and electronegativity to original surfaces, the modified membranes exhibit high transport properties for gases and great resistances to protein adsorption, platelet activation, coagulation, thrombosis, and hemolysis. Molecular docking and density functional theory simulations indicate that more preferential adsorption of metal–ligand networks with water molecules than proteins is critical to anticoagulation. Moreover, benefiting from the better antiaging property gave by biomimetic decoration, the membranes after four-month aging present gas permeances similar to or even larger than those of pristine ones, despite the initial permeation decline. Importantly, for blood oxygenation, the designed membranes after aging show fast O2 and CO2 exchange processes with rates up to 28–17 and 97–47 mL m−2 min−1, respectively, accompanied with no detectable thrombus and plasma leakage. We envisage that the biomimetic decoration of nanoporous membranes provide a feasible route to achieve great biocompatibility and transport capability for various applications.

Dengue viremia kinetics and effects on platelet count and clinical outcomes: An analysis of 2340 patients from Vietnam.

Viremia is a critical factor in understanding the pathogenesis of dengue infection, but limited data exist on viremia kinetics. This study aimed to investigate the kinetics of viremia and its effects on subsequent platelet count, severe dengue, and plasma leakage. We pooled data from three studies conducted in Vietnam between 2000 and 2016, involving 2340 dengue patients with daily viremia measurements and platelet counts after symptom onset. Viremia kinetics were assessed using a random effects model that accounted for left-censored data. The effects of viremia on subsequent platelet count and clinical outcomes were examined using a landmark approach with a random effects model and logistic regression model with generalized estimating equations, respectively. The rate of viremia decline was derived from the model of viremia kinetics. Its effect on the clinical outcomes was assessed by logistic regression models. Viremia levels rapidly decreased following symptom onset, with variations observed depending on the infecting serotype. DENV-1 exhibited the highest mean viremia levels during the first 5-6 days, while DENV-4 demonstrated the shortest clearance time. Higher viremia levels were associated with decreased subsequent platelet counts from day 6 onwards. Elevated viremia levels on each illness day increased the risk of developing severe dengue and plasma leakage. However, the effect size decreased with later illness days. A more rapid decline in viremia is associated with a reduced risk of the clinical outcomes. This study provides comprehensive insights into viremia kinetics and its effect on subsequent platelet count and clinical outcomes in dengue patients. Our findings underscore the importance of measuring viremia levels during the early febrile phase for dengue studies and support the use of viremia kinetics as outcome for phase-2 dengue therapeutic trials. Wellcome Trust and European Union Seventh Framework Programme.

Ipilimumab- and pembrolizumab-related risk of capillary leak syndrome

Ipilimumab- and pembrolizumab-related risk of capillary leak syndrome

Dengue Shock Syndrome with Recurrent Shock and Obesity in Children: A Case Report

Introduction: Dengue fever remains a major global health problem that is widespread in tropical and subtropical regions. DSS is one of the dangerous clinical manifestations of dengue infection, characterized by severe plasma leakage due to increased vascular permeability leading to a progressive decrease in intravascular volume. Obesity has been proposed as a potential risk factor for the development of DSS in children. Management with proper fluid resuscitation is essential to prevent worsening in patients with Dengue Shock Syndrom. Case Presentation: This study reports a 5-year-old obese pediatric patient with a body mass index of 31 kg/m2 who developed Dengue Shock Syndrome and recurrent shock. Vital signs examination at the initial examination obtained a pulse rate of 99x / min palpable weak, not strong lift with a temperature of 36oCand extremities acral palpable was cold with Capillary Refill Time (CRT) elongated > 2 seconds. The patient was given initial management in the ER in the form of oxygenation with a 2 lpm nasal cannula, then given lactate ringer (RL) as a fluid teraphy 10cc/kgBB, which was 310cc finished in 30 minutes. Initial complete blood hematological examination showed a leukopenia result of 3.1 x103/uL. The patient had an increased hematocrit of 51% with a haemoglobin level of 17g/dL. Platelet levels were found to be below normal levels at 60 x103/uL. The patient experienced recurrent shock during treatment. The patient was given several rounds of fluid resuscitation but worsened during treatment. The patient had seizures leading to respiratory arrest and cardiac arrest. The patient was later pronounced dead after cardiopulmonary resuscitation was unsuccessful. Conclusion: Dengue infection with obesity has a higher risk of Dengue Shock Syndrome in children. Management with proper fluid resuscitation is important in the hope of reducing morbidity and mortality of Dengue Shock Syndrome in children.

Cut-off Value of HSPG for Early Marker of Plasma Leakage in Adult Dengue Patient

Plasma leakage is a state of increased vascular permeability due to loss of interendothelial junction and focal adhesion. Endothelium glycocalyx plays a major role in the pathogenesis of plasma leakage. Proteoglycans glycocalyx consists of heparan sulfate (HSPG) around 50-90%. Plasma leakage in dengue infection can be fatal and early detection is essential. This study aimed to determine the optimal cut-off value of HSPG levels for early marker of plasma leakage in dengue infection. The study was a retrospective cohort study as a part of the Community Based Dengue Study of the Faculty of Medicine, University of Indonesia, which was conducted between February 2010 and January 2011. Subjects were recruited by consecutive sampling. Dengue infection was confirmed by conventional PCR serotyping. Subjects were categorized into 2 groups, i.e. those with and without plasma leakage. Plasma leakage was confirmed by hemoconcentration or hypoalbuminemia or USG results. The level of HSPG was measured using the ELISA method from the first until the third day of the hospital admission. A total of 40 subjects were involved in this study, consisting of 21 with leakage and 19 without leakage. The optimal cut-off level of HSPG as a marker of early plasma leakage in dengue infection patients on the 1st day, 2nd day, and 3rd day was was 2179.73 pg/mL, 2538.66 pg/mL, and 1294.06 pg/mL, respectively. HSPG could as an early marker of plasma leakage in dengue infection with an optimal cut-off value for each of the first 3 days of the patient's fever. A pediatric study was recommended to obtain the optimal cut-off value for HSPG.

The 2023 Dengue Outbreak in Bangladesh: Exploring the Epidemiology in Hospitalized Patients.

For the past two decades, Bangladesh has faced recurrent dengue outbreaks, with the most recent occurring in 2023. We investigated the socioeconomic, clinical, and laboratory aspects of patients diagnosed with dengue during this outbreak. This observational study was conducted from July to September 2023 at Dhaka Medical College Hospital and Chittagong Medical College Hospital, and included 450 confirmed cases of dengue. Sociodemographic information was collected via face-to-face interviews, clinical examinations, and laboratory testing, which was done within 24 hours of admission. Dengue severity was classified according to the 2009 WHO dengue guidelines. Notably, 17% of patients experienced severe dengue, and 89% of those with nonsevere cases exhibited at least one warning sign. Most patients were young adults (mean age, 33 years), with a nearly equal male-to-female ratio. Common clinical presentations included fever (95%), myalgia (62%), and headache (58%), whereas warning signs such as vomiting (54%) and abdominal pain (39%) were prevalent. Plasma leakage indicators, including ascites, pleural effusion, and edema, were found predominantly in severe cases. Laboratory findings revealed leukopenia, thrombocytopenia, and elevated hepatic enzymes (alanine aminotransferase and aspartate aminotransferase) in nearly half the patients. An elevated hematocrit level was associated with severe dengue. We report that a substantial number of patients developed severe dengue during the epidemic in 2023, and provide detailed clinical-epidemiological profiles of the patients, offering valuable insight into management of dengue cases.

Complement-dependent virion lysis mediated by dengue-Zika virus cross-reactive antibodies correlates with protection from severe dengue disease.

Primary infection with one of four dengue virus serotypes (DENV1-4) may generate antibodies that protect or enhance subsequent secondary heterotypic infections. However, the characteristics of heterotypic cross-reactive antibodies associated with protection from symptomatic infection and severe disease are not well-defined. We selected plasma samples collected before a secondary DENV heterotypic infection that was classified either as dengue fever (DF, n = 31) or dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS, n = 33) from our longstanding pediatric cohort in Nicaragua. We screened various antibody properties to determine the features correlated with protection from DHF/DSS. Protection was associated with high levels of binding of various antibody isotypes, IgG subclasses and effector functions, including antibody-dependent complement deposition, ADCD. Although the samples were derived from DENV-exposed, Zika virus (ZIKV)-naïve individuals, the protective ADCD association was stronger when assays were conducted with recombinant ZIKV antigens. Further, we showed that a complement-mediated virion lysis (virolysis) assay conducted with ZIKV virions was strongly associated with protection, a finding reproduced in an independent sample set collected prior to secondary heterotypic inapparent versus symptomatic DENV infection. Virolysis was the main antibody feature correlated with protection from DHF/DSS and severe symptoms, such as thrombocytopenia, hemorrhagic manifestations, and plasma leakage. Hence, anti-DENV antibodies that cross-react with ZIKV, target virion-associated epitopes, and mediate complement-dependent virolysis are correlated with protection from secondary symptomatic DENV infection and DHF/DSS. These findings may support the rational design and evaluation of dengue vaccines and development of therapeutics.

Real world (RW) study of patients (pts) with relapsed or refractory (RR) blastic plasmacytoid dendritic cell neoplasm (BPDCN) treated with tagraxofusp (TAG).

e18533 Background: BPDCN is characterized by clonal expansion of plasmacytoid dendritic malignant cells that express CD123 and other markers. TAG, a CD123-directed therapy, is the only drug approved to treat BPDCN (US/EU). In August 2019, a European Named Patient Program (NPP) started to ensure pt access to TAG. To assess RW safety and efficacy of TAG treatment in RR BPDCN, a pt population with a very poor prognosis, we retrospectively analyzed data from pts enrolled in the NPP. Methods: Pts with RR BPDCN received TAG 12 mcg/kg qd on days 1-5 (or by day 10) of each 21-day cycle. The first TAG cycle was given inpatient with outpatient treatment allowed thereafter. Clinicians received training on capillary leak syndrome (CLS) monitoring and management guidelines. Primary endpoints were complete response (CR) after 2-3 cycles and CLS incidence and grade (G). Secondary endpoints included number of pts bridged to stem cell transplantation (SCT), progression-free survival (PFS), overall survival (OS), best overall response rate (ORR), duration of response (DOR), and safety. Results: Of 18 pts with RR BPDCN (median age 66 y [29–83]; 89% male), 67% had received 1 prior line of therapy and 28% 2 prior lines. At initial diagnosis, pts had disease involvement in bone marrow (89%), skin (67%), and lymph nodes (61%). Median time from initial diagnosis to TAG was 7.4 mo (1–27). At a median follow-up of 8 mo, pts received a median of 2 (1–5) TAG cycles. In 15 pts with ≥1 tumor assessment, the ORR was 67% (40% CR and 27% partial response [PR]) with a median DOR of 5 mo (95% CI, 3.0–not estimable [NE]). All 18 pts had a median PFS of 4.3 mo (95% CI, 1.4–12.9) and median OS of 8.6 mo (95% CI, 3.6–NE). In 15 pts with ≥1 tumor assessment, 6 (40%) pts were bridged to SCT and had durable posttransplant responses (CR 83%; PR 17%) with median DOR, PFS, and OS not reached. CLS was mostly mild to moderate in severity; 61% of pts had CLS in cycle 1 and only 1 pt had an event in cycle 2. The median time to CLS resolution was 4 days. Other than CLS, TAG-related nonhematologic G3-4 adverse events (AEs) and serious AEs (SAEs) occurred in 44% of pts, all during cycle 1, with hepatic cytolysis, pneumonia and tumor lysis syndrome reported in 2 (11%) pts each. Grade 3-4 thrombocytopenia and pancytopenia were reported in 2 (11%) pts each. Median time to resolution was 5 days for the nonhematologic G3-4 AEs/SAEs and 18 days for thrombocytopenia. Two (11%) pts had G3-4/SAE infections. There were no treatment-related deaths. Conclusions: TAG induced fast and durable responses, and a high response rate, in RR BPDCN pts, with prolonged survival in a poor prognosis population, where historic treatments show limited efficacy. There were no new safety signals. With proper selection, monitoring, and directed intervention, CLS is manageable, usually mild, limited to the first cycle, and does not recur. These RW results support the use of TAG in pts with RR BPDCN.

Overexpression of Plakophilin2 Mitigates Capillary Leak Syndrome in Severe Acute Pancreatitis by Activating the p38/MAPK Signaling Pathway.

Capillary leak syndrome (CLS) is an intermediary phase between severe acute pancreatitis (SAP) and multiple organ failure. As a result, CLS is of clinical importance for enhancing the prognosis of SAP. Plakophilin2 (PKP2), an essential constituent of desmosomes, plays a critical role in promoting connections between epithelial cells. However, the function and mechanism of PKP2 in CLS in SAP are not clear at present. We detected the expression of PKP2 in mice pancreatic tissue by transcriptome sequencing and bioinformatics analysis. PKP2 was overexpressed and knocked down to assess its influence on cell permeability, the cytoskeleton, tight junction molecules, cell adhesion junction molecules, and associated pathways. PKP2 expression was increased in the pancreatic tissues of SAP mice and human umbilical vein endothelial cells (HUVECs) after lipopolysaccharide (LPS) stimulation. PKP2 overexpression not only reduced endothelial cell permeability but also improved cytoskeleton relaxation in response to acute inflammatory stimulation. PKP2 overexpression increased levels of ZO-1, occludin, claudin1, β-catenin, and connexin43. The overexpression of PKP2 in LPS-induced HUVECs counteracted the inhibitory effect of SB203580 (a p38/MAPK signaling pathway inhibitor) on the p38/MAPK signaling pathway, thereby restoring the levels of ZO-1, β-catenin, and claudin1. Additionally, PKP2 suppression eliminated the enhanced levels of ZO-1, β-catenin, occludin, and claudin1 induced by dehydrocorydaline. We predicted that the upstream transcription factor PPARγregulates PKP2 expression, and our findings demonstrate that the PPARγactivator rosiglitazone significantly upregulates PKP2, whereas its antagonist GW9662 down-regulates PKP2. Administration of rosiglitazone significantly reduced the increase in HUVECs permeability stimulated by LPS. Conversely, PKP2 overexpression counteracted the GW9662-induced reduction in ZO-1, phosphorylated p38/p38, and claudin1. The activation of the p38/MAPK signaling pathway by PKP2 mitigates CLS in SAP. PPARγactivator rosiglitazone can up-regulate PKP2. Overall, directing efforts toward PKP2 could prove to be a feasible treatment approach for effectively managing CLS in SAP.

A phase 1/1b, first-in-human, multi-part study of DF6215, an engineered IL-2Rα-active agonist, to investigate the safety, tolerability, pharmacokinetics, and biological and clinical activity in patients with advanced solid tumors.

TPS2704 Background: IL-2 is a pleiotropic cytokine that stimulates strong anti-tumor responses by promoting expansion and activation of cytotoxic tumor-infiltrating immune cells including CD8 + T cells and NK cells (1). Aldesleukin is an approved rhIL-2; however, it has clinical limitations due to short half-life, requirement for 5 days of hospitalization per cycle, and high toxicity [eg, cytokine-related toxicity, capillary leak syndrome (CLS)] that limits its use [aldesleukin USPI]. DF6215 is a modified monovalent human IL-2 that binds to the IL2R. Preclinically, DF6215 administration results in sustained and modulated IL-2 pharmacology, leading to protracted pharmacodynamic (PD) effects and enhanced anti-tumor activity without observation of CLS in murine and primate toxicology studies. In response to the limitations of previous IL-2 therapeutics, DF6215 was designed as an IL-2Rα-active agonist with increased IL-2Rβγ stimulation to improve the benefit-to-risk ratio of historic IL-2 drugs. An additional design element is a prolonged elimination half-life due to Fc fusion, allowing for less frequent dosing. Methods: This is a first-in-human, open-label, multipart, Phase 1/1b clinical trial to characterize the initial safety, tolerability, pharmacokinetics, and preliminary efficacy of DF6215 in patients with advanced solid tumors. The Phase 1 dose escalation (DE) starting dose is 10 ug/kg IV every 2 weeks (up to 42 subjects expected to be enrolled), and the Safety/PK/PD will be explored at doses already characterized as safe in dose escalation and potentially efficacious (max of 40 subjects). Phase 1b includes an efficacy expansion (EE) cohort in subjects with advanced melanoma who have received prior anti-PD-1 agents and, if the tumor harbors a BRAF-activating mutation, a BRAF inhibitor. Key inclusion criteria include ≥ 18 years of age; ECOG PS of 0 or 1; adequate organ function, and locally advanced or metastatic solid tumors for which standard therapy options have been exhausted; and availability of baseline tumor biopsy. Primary objectives include determination of the MTD of DF6215 in DE and demonstration of clinical activity of DF6215 in the EE. Secondary objectives include assessment of safety and tolerability, pharmacokinetics, and immunogenicity of DF6215. This study plans to enroll up to 102 subjects across ~30 global centers in the US, European, and the Asia/Pacific regions, and is currently open to enrollment. 1. Arenas-Ramirez N, et al. 2015. Trends Immunol. Clinical trial information: NCT06108479 .

Analgesic and anti-inflammatory activity of Cotinus coggygria Scop. extracts in vivo

Objective: To assess the analgesic and anti-inflammatory effects of standardized extract of Cotinus coggygria (C. coggygria) in different animal models. Methods: C. coggygria extracts (25, 50, and 100 mg/kg) were administered to rats and mice (n=6) during hot plate, tail-flick, acetic acid-induced writhing, and formalin tests to determine its analgesic efficacy. The anti-inflammatory activity of C. coggygria extracts was evaluated by histamine and carrageenan-induced paw edema, cotton pellet-induced granuloma, and acetic acid-induced peritoneal capillary dye leakage tests. Results: C. coggygria extracts (50 and 100 mg/kg) significantly alleviated thermal and chemical-induced pain in rodents (P<0.05). It also demonstrated notable anti-inflammatory properties by mitigating histamine and carrageenan-induced paw edema, granuloma deposits, and vascular permeability (P<0.05). Moreover, C. coggygria extracts remarkably reduced TNF-α, IL-1β, IL-6, COX-2, and oxidative stress in rat paws (P<0.05). Carrageenan-induced histological aberrations in hind paw tissues were effectively (P<0.05) mitigated by treatment with C. coggygria extracts. Conclusions: C. coggygria Scop. extracts show analgesic and anti-inflammatory effects via inhibition of COX-2 and inflammatory and oxidative mediators.

Intramyocardial edema as an atypical manifestation of capillary leak syndrome

Intramyocardial edema as an atypical manifestation of capillary leak syndrome

IOV-3001, a modified interleukin-2 fusion protein, for potential use in tumor-infiltrating lymphocyte cell therapy regimens.

2552 Background: Tumor-infiltrating lymphocyte (TIL) cell therapy has shown promising efficacy in patients with solid tumor malignancies. Interleukin-2 (IL-2) administration after TIL infusion supports persistence and survival of infused TIL. Aldesleukin is a synthetic IL-2 with a short half-life administered every 8–12 hours, to support the expansion and persistence of the TIL in vivo. IOV-3001 is a modified dimeric IL-2 fused to palivizumab that has a longer half-life and potentially better safety profile, compared with aldesleukin. Here, we describe the preclinical activity, pharmacokinetics (PK), pharmacodynamics (PD), and in vivo safety profile of IOV-3001. Methods: Binding of IOV-3001 and aldesleukin to the IL-2 receptor (IL-2R), IL-2R-mediated activation via STAT5 phosphorylation, and T cell proliferation were assessed. Pharmacological activities of IOV-3001 and aldesleukin were evaluated in B16-F10 mice infused with pmel-1 T cells. Safety after a single dose of IOV-3001 (0.01–9.0 mg/kg) was assessed in cynomolgus monkeys across 3 independent studies. PK and PD parameters, clinical pathology, hematology, and histopathology were assessed. Results: Both IOV-3001 and aldesleukin induced comparable STAT5 phosphorylation and proliferation of T-cell subsets. Mice infused with pmel-1 T cells and subsequently treated with IOV-3001 or aldesleukin showed similar reductions in tumor burden. The half-life of IOV-3001 in cynomolgus monkeys ranged from 5–8 hours. IOV-3001 was well tolerated in monkeys across the dose range studied except for 1 animal administered IOV-3001 at the highest tested dose level, with recovery by Day 29. Inflammatory cytokines (IL-12 p40, IL-6, MCP-1) increased from 4 hours to ≤3 days after dosing and returned to baseline by Day 29. Fibrinogen, bilirubin, and triglycerides increased on Day 3 and returned to baseline by Day 29. No signs of capillary leak were observed. Increased numbers of hematopoietic cells were found in the bone marrow, spleen, and lymph nodes 3 days post dosing. During the 4-week recovery, these changes diminished or resolved, while bone marrow showed differential dose-dependent effects. IL-2–induced proinflammatory PD effects were observed, including >10-fold peak CD8+ T cell expansion in peripheral blood mononuclear cells at Day 5 versus preacclimation in most cynomolgus monkeys treated with IOV-3001. Conclusions: IOV-3001 exhibited a similar mechanism of action (MoA) to that of aldesleukin in vitro and has a longer half-life in vivo. PD effects were consistent with the MoA of IL-2. IOV-3001 showed a favorable preclinical safety profile. These results suggest a potentially improved safety profile for IOV-3001 with less frequent dosing compared with aldesleukin. These features of IOV-3001 strongly advocate for its development in TIL cell therapy regimens.

Lung Manifestation of Dengue Fever: A Retrospective Study.

Introduction Dengue fever, caused by the dengue virus transmitted by Aedes aegypti mosquitoes, is a significant public health concern globally. Its resurgence in recent years, particularly in low- and middle-income countries, has led to increased morbidity and mortality rates. Atypical manifestations, involving the cardiac, liver, gut, renal, blood, bone, nervous, and respiratory systems, in dengue, can complicate both diagnosis and management. This study aimed to investigate the incidence of lung manifestations in dengue-infected individuals and their correlation with patient outcomes. Background The prevalence of dengue fever has risen dramatically over the past two decades, with Asia bearing the brunt of the burden, particularly India. The pathophysiology of lung complications in dengue remains unclear but is thought to be related to capillary leak syndrome and thrombocytopenia. Studies suggest that respiratory symptoms may be associated with severe cases and increased mortality rates. Despite limited research in India, understanding lung manifestations in dengue is crucial for improving diagnostic accuracy and patient care. Methods A retrospective study was conducted at K.S. Hegde Hospital, a tertiary care facility located in Mangalore, India, involving patients aged 18 years and above diagnosed with dengue fever between January and December 2019. Data gathered comprised patient demographics, clinical symptoms, laboratory findings, imaging results including radiographs, computed tomography (CT) scans of the chest (if accessible), ultrasound examinations of the chest and abdomen, and 2D echocardiograms, as well as patient outcomes. Diagnosis of lung manifestation was established through clinical assessment, chest X-ray interpretation, and ultrasound of the chest. Statistical analysis was conducted using SPSS Statistics (version 20), with a significance set at p<0.05. Results Out of 255 dengue cases, 10.19% (n=26) exhibited pulmonary manifestations, with pleural effusion being the most common. Older age (>50 years) and comorbidities were associated with a higher incidence of lung involvement. Respiratory symptoms, such as breathlessness, were more prevalent in patients with pulmonary complications. Laboratory parameters indicated distinct profiles in patients with lung manifestations, including elevated total count, urea, bilirubin, and liver enzymes, and reduced platelet counts. Mortality rates were higher in patients with lung involvement, older age, and comorbidities. Discussion The study findings highlight the importance of recognizing respiratory symptoms in dengue fever, particularly in older patients and those with underlying health conditions. The association between pulmonary involvement and adverse outcomes underscores the need for early detection and appropriate management strategies. Future research should focus on elucidating the pathophysiology of lung complications in dengue and developing targeted interventions to improve patient outcomes. Conclusion Lung manifestations in dengue fever represent a significant clinical challenge and are associated with increased morbidity and mortality. Early recognition of respiratory symptoms, along with prompt diagnostic evaluation and appropriate management, is essential for improving patient prognosis. Further studies are warranted to deepen our understanding of lung involvement in dengue and optimize therapeutic approaches to mitigate its impact on patient outcomes.