Capillary Leak Research Articles

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.

Usefulness of an Ultrasound-guided Prehospital Care for SCUBA Diving Accidents.

The incidence of diving accidents is increasing. Point-of-care ultrasound is the only imaging tool available in the field for the military physician who practices in isolated conditions. While ultrasound is integrated in the pre-hospital evaluation protocols of severe trauma patients, few applications are described for diving accident victims. Through a clinical case, we propose an algorithm of ultrasound triage for diving accidents with pulmonary symptoms. Point-of-care ultrasound makes it possible to avoid a risky transfer, by supporting a diagnosis and the treatment on the spot, to rule out contraindications to recompression, and to detect and monitor the treatment of high-risk complications such as the capillary leak syndrome.

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill.

Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

Hypersensitive blood vessels in Clarkson disease.

Idiopathic systemic capillary leak syndrome (ISCLS) is a rare, recurrent condition with dramatically increased blood vessel permeability and, therefore, induction of systemic edema, which may lead to organ damage and death. In this issue of the JCI, Ablooglu et al. showed that ISCLS vessels were hypersensitive to agents known to increase vascular permeability, using human biopsies, cell culture, and mouse models. Several endothelium-specific proteins that regulate endothelial junctions were dysregulated and thereby compromised the vascular barrier. These findings suggest that endothelium-intrinsic dysregulation underlies hyperpermeability and implicate the cytoplasmic serine/threonine protein phosphatase 2A (PP2A) as a potential drug target for the treatment of ISCLS.

Tocilizumab in the treatment of hyperferritinemic syndrome and capillary leak syndrome secondary to rheumatoid arthritis: Case report and literature review.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which is mainly characterized by joint swelling, pressure pain and joint destruction. Some patients may suffer from a variety of serious complications, which require prompt diagnosis and treatment. Otherwise, the patient condition may deteriorate rapidly, leading to premature death. We reported a case of RA combined with hyperferritinemic syndrome and capillary leak syndrome (CLS) that was successfully treated with tocilizumab (TCZ), with the aim of improving diagnostic ideas for clinicians and consequently improving the diagnosis and treatment of the hyperferritinemic syndrome and CLS. A 55-year-old female patient was admitted to the Department of Infectious Diseases of our hospital due to "recurrent fever for more than 1 month and aggravation for 3 days." The patient was diagnosed with fever of unknown origin (lung infection?) and received anti-infective therapy with large encirclement of anti-bacterial, antifungal and empirical anti-tuberculosis successively during hospitalization in the Department of Infectious Diseases. Yet her condition continues to progress. The patient was eventually diagnosed with RA combined with hyperferritinemic syndrome and CLS. Then she received glucocorticoids (GC) (160 mg qd) combined with intravenous immunoglobulin (IVIG, 20 g/d, for 3 days). We considered that the patient also had an overwhelming proinflammatory cytokine storm, so she received a strong anti-inflammatory treatment with TCZ (400 mg qm). The patient symptoms and follow-up chest CT showed significant improvement following treatment. TCZ has good efficacy in the treatment of RA combined with hyperferritinemic syndrome and CLS and is expected to be a promising treatment.

Gallbladder Wall Thickening for Early Detection of Plasma Leakage Among Children with Dengue Fever Admitted in a Tertiary Care Hospital

Background: Plasma leakage is defined as e”20% elevation of hematocrit from baseline or evidence of plasma leakages such as pleural effusion, ascites, or hypoalbuminemia. In the early phase, these signs of plasma leakage are usually difficult to ascertain by physical examination and laboratory tests. Objective: This study aimed to investigate whether gallbladder wall thickening (GBWT) in the febrile phase of the disease can be used to detect the occurrence of plasma leakage in dengue patients. Methods: A cross-sectional analytical study was conducted during a 4-month period in Dr. M R Khan Shishu Hospital and ICH from September 2021 to December 2021. Children from 6 months to 14 years who were admitted with acute onset of fever less than 3 days with NS1 positivity were included consecutively. Laboratory tests and abdominal Ultrasonography were also performed to confirm the occurrence of plasma leakage. Result: Out of 114 patients, the majority were male (64%), in the 5-&lt;10-year age group(48.25%). Common presentations include fever (100%), flushed appearance (66.7%), abdominal pain (66.7%), vomiting (44.7%), bodyache (39.5%), During the febrile phase, 56patients were presented with GBWT, 49 of which showed plasma leakage during treatment. The sensitivity and specificity of GBWT during fever were 89% and 88%. PPV and NPV were 87% and 90% respectively. In risk factor analysis, Gallbladder wall thickening was found statistically significant (&lt;.009) predictor of plasma leakage in dengue. Conclusion: Gallbladder wall thickening during the febrile phaseis a predictor of plasma leakage in Dengue. BANGLADESH J CHILD HEALTH 2022; VOL 46 (3) : 138-143

Modulation of the capillary leakage by exogenous albumin in a rat model of endothelial glycocalyx damage.

Endothelial glycocalyx (EG) plays a crucial role in maintaining the plasma proteins within the intravascular space. We studied whether exogenous albumin protects the EG in an experimental model of EG enzymatic damage in rats. Rats were divided into three groups of 10 animals that received (1) Evans blue (2) Evans blue + hyaluronidase, or (3) Evans blue + hyaluronidase + 20% human albumin via the tail vein. Spectrophotometric analysis was performed 2 h later to quantify the leakage of Evans blue-labeled albumin into the heart, lungs, brain, kidneys, liver, small intestine, spleen, and skeletal muscle. Administration of hyaluronidase numerically increased the capillary leakage of Evans blue in all examined tissues. Co-administration of albumin decreased the leakage of albumin in all tissues except the heart. In the lungs, the ratio between the absorbance and dry organ weight decreased from 5.3 ± 2.4 to 1.7 ± 0.5 (mean ± SD) (P < 0.002), and in the liver, the absorbance decreased from 2.2 ± 0.7 to 1.5 ± 0.4 (P < 0.011). Exogenous albumin decreased the capillary leakage of albumin which was interpreted as a sign of maintained EG integrity.