Search Results (211)

Background and Clinical Significance: Hemophagocytic lymphohistiocytosis (HLH) and autoimmune hemolytic anemia (AIHA) are both life-threatening hematologic syndromes that rarely present together outside of malignancy. Advanced acquired immunodeficiency syndrome (AIDS) creates a milieu of profound immune dysregulation and hyperinflammation, predisposing patients to atypical overlaps of these disorders. Case Presentation: A 30-year-old woman with poorly controlled AIDS presented with three weeks of jaundice, fever, and fatigue. Initial labs revealed pancytopenia, hyperbilirubinemia, and elevated ferritin level. Direct anti-globulin testing confirmed warm AIHA (IgG⁺/C3d⁺) with transient cold agglutinins. Despite intravenous immunoglobulin (IVIG), rituximab, and transfusions, she developed hepatosplenomegaly, extreme hyperferritinemia, and sIL-2R > 10,000 pg/mL, meeting HLH-2004 criteria. Bone marrow biopsy excluded malignancy; further work-up revealed Epstein–Barr virus (EBV) viremia and cytomegalovirus (CMV) reactivation. Dexamethasone plus reduced-dose etoposide transiently reduced soluble interleukin-2 receptor (sIL-2R) but precipitated profound pancytopenia, Acute respiratory distress syndrome (ARDS) from CMV/parainfluenza pneumonia, bilateral deep vein thrombosis (DVT), and an ST-elevation myocardial infarction (STEMI). She ultimately died of hemorrhagic shock after anticoagulation despite maximal supportive measures. Conclusions: This case underscores the diagnostic challenges of HLH-AIHA overlap in AIDS, where cytopenias and hyperferritinemia mask the underlying cytokine storm. Pathogenesis likely involved IL-6/IFN-γ overproduction, impaired cytotoxic T-cell function, and molecular mimicry. While etoposide remains a cornerstone of HLH therapy, its myelotoxicity proved catastrophic in this immunocompromised host, highlighting the urgent need for cytokine-targeted agents to mitigate treatment-related mortality. Full article

Hemorrhage is the leading cause of preventable death in trauma care, requiring rapid and accurate detection to guide effective interventions. Hemorrhagic shock can be masked by underlying compensatory mechanisms, which may lead to delayed decision-making that can compromise casualty care. In this proof-of-concept study, we aimed to develop and evaluate machine learning models to predict Percent Estimated Blood Loss from a photoplethysmography waveform, offering non-invasive, field deployable solutions. Different model types were tuned and optimized using data captured during a hemorrhage and resuscitation swine study. Through this optimization process, we evaluated different time-lengths of prediction windows, machine learning model architectures, and data normalization approaches. Models were successful at predicting Percent Estimated Blood Loss in blind swine subjects with coefficient of determination values exceeding 0.8. This provides evidence that Percent Estimated Blood Loss can be accurately derived from non-invasive signals, improving its utility for trauma care and casualty triage in the pre-hospital and emergency medicine environment. Full article

Plasmodium falciparum malaria remains a major cause of morbidity and mortality, particularly in endemic regions. We report the case of a 21-year-old male with recent travel to an endemic area (Guapi, Colombia), who presented with febrile symptoms, severe respiratory distress, and oxygen saturation below 75%, necessitating orotracheal intubation. During the procedure, he developed pulseless electrical activity cardiac arrest, achieving return of spontaneous circulation after advanced resuscitation. Diagnosis was confirmed by thick blood smear, demonstrating P. falciparum infection. The patient progressed to multiorgan failure, including acute respiratory distress syndrome with capillary leak pulmonary edema, refractory distributive shock, acute kidney injury with severe hyperkalemia, and consumptive thrombocytopenia. Management included invasive mechanical ventilation, vasopressor support, sedation-analgesia, neuromuscular blockade, methylene blue, unsuccessful hemodialysis due to hemorrhagic complications, and platelet transfusions. Despite these interventions, the patient experienced a second cardiac arrest and died. This case highlights the severity and rapid progression of severe malaria with multisystem involvement, underscoring the critical importance of early diagnosis and intensive multidisciplinary management. It also emphasizes the need for preventive strategies for travelers to endemic areas and the development of clinical protocols to improve outcomes in complicated malaria. Full article

Fluid resuscitation after thermal injury is paramount to avoid burn shock and restore organ perfusion. Both over- and under-resuscitation can lead to unintended consequences affecting patient outcomes. While many studies have examined systemic effects, limited data exist on how fluid resuscitation impacts burn wound progression in the acute period. Furthermore, the mechanisms underlying burn wound progression remain not fully understood. This study used a swine model to investigate how varying resuscitation levels affect peri-burn wound dynamics. Twenty-seven female Yorkshire pigs were anesthetized, subjected to 40% total body surface area burn and 15% hemorrhage, then randomized (n = 9) to receive decision-support-driven (adequate, 2–4 mL/kg/%TBSA), fluid-withholding (under, <1 mL/kg/%TBSA), or high-constant-rate (over, >>4 mL/kg/%TBSA) resuscitation. Pigs were monitored for 24 h in an intensive care setting prior to necropsy. Laser Doppler Imaging (LDI) was conducted pre-burn and at 2, 6, 12, and 24 h post burn to assess perfusion. Biopsies were taken from burn, peri-burn (within 2 cm), and normal skin. RNA was isolated at 24 h for the qRT-PCR analysis of IL-6, CXCL8, and IFN-γ. At hour 2, LDI revealed increased peri-burn perfusion in over-resuscitated animals vs. under-resuscitated animals (p = 0.0499). At hour 24, IL-6 (p = 0.0220) and IFN-γ (p = 0.0253) were elevated in over-resuscitated peri-burn skin. CXCL8 showed no significant change. TUNEL staining revealed increased apoptosis in over- and under-resuscitated peri-burn skin. Differences in perfusion and cytokine expression based on resuscitation strategy suggest that fluid levels may influence burn wound progression. Full article

Background and Clinical Significance: Spontaneous renal hematoma, also known as Wunderlich syndrome (WS), is a rare disease characterized by the acute onset of spontaneous renal hemorrhage into the subcapsular, perirenal, and/or pararenal spaces without a history of prior trauma. WS can be a life-threatening condition due to hemorrhagic shock; consequently, prompt diagnosis and a therapeutic approach are essential for favorable outcomes. Treatment ranges from conservative management to surgical intervention. The most common etiologies are neoplasms and vascular diseases, but WS can also be observed in patients undergoing hemodialysis. In patients with end-stage renal disease (ESRD), especially those on hemodialysis, acquired cystic kidney disease and renal cell carcinoma are among the primary causes of WS. Although less common, WS can develop in dialysis patients even in the absence of traditional (primary) risk factors. In general, patients with chronic kidney disease (CKD) have a paradoxical hemostatic profile, likely explaining their higher tendency to bleed, so WS can occur without existing predisposing factors. The multifactorial pathogenesis in these patients includes functional platelet abnormalities, intimal arterial fibrosis, chronic inflammation, and oxidative stress associated with ESRD. The use of hemodialysis-related antithrombotic medications could serve as another contributing factor increasing the risk of bleeding. Case Presentation: We present a case report of a 62-year-old male on chronic dialysis who developed sudden right-sided lumbar pain and hematuria during dialysis without evidence of prior trauma. Imaging revealed a large subcapsular hematoma of the right kidney. Further investigations did not reveal additional risk factors in this instance; however, his routinely used hemodialysis-related antithrombotic medications were potentially a contributing factor. Despite conservative treatment, his condition worsened, and the hematoma enlarged, requiring emergency nephrectomy. Postoperatively, his condition gradually improved. Conclusions: This case highlights the importance of considering WS in hemodialysis patients, even without the presence of traditional risk factors, as well as including WS in the differential diagnosis of acute abdominal pain. Full article

Background: PP-007 (SANGUINATE^®, PEGylated carboxyhemoglobin, bovine) is under development to treat conditions of ischemia/hypoxia. Hemorrhagic/hypovolemic shock (H/HVS) becomes a life-threatening comorbidity due in part to hypotension and hypoxia. Blood transfusions are indicated, but supply and compatibility issues may limit subject access or when blood is not an option due to religious restriction or concern for clinical complications. PP-007 is universally compatible with an effective hydrodynamic radius and colloidal osmotic pressure facilitating perfusion without promoting extravasation. Methods: A review of previous clinical trials was performed and revealed an Open-Label Phase 1 safety study of acute severe anemia (hemoglobin ≤ 5 g/dL) in adult (≥18 y) patients unable to receive red blood cell transfusion (NCT02754999). Primary outcomes included safety events with secondary efficacy measures of organ function and survival at 1, 14, and 28 days. Additionally, a retrospective review of published, peer-reviewed case reports was performed, evaluating the administration of Sanguinate for Expanded Access in those patient populations where blood was not an option over the past 12 years. Results: A total of 103 subjects were enrolled in the Phase I safety study with significant co-morbidities that most commonly included hypertension (n = 43), acute and chronic kidney disease (n = 38), diabetes mellitus (n = 29), gastrointestinal bleeds (n = 18), and sickle cell disease (n = 13). Enrollment characteristics included decreased hemoglobin and severe anemia (mean baseline hemoglobin of 4.2 g/dL). Treatments included an average of three infusions [range 1–17]. Secondary efficacy measures were mean Hb levels, respiratory support, and vasopressor requirements, all demonstrating clinically relevant improvements. Fourteen additional cases were identified in the literature. Though one patient died due to pre-treatment conditions, all patients but one were discharged home in stable condition. Conclusion: Collectively, these observations are encouraging and provide support for the continued evaluation of PP-007 in advanced clinical trials in severe anemia including H/HVS. The review of published case reports underscored the potential of Sanguinate to reduce early mortality. Adverse effects included transient hypertension, lethargy, dizziness, and troponin elevation. These findings highlight the need for continued research and funding of blood alternatives to improve outcomes when standard blood transfusions are unavailable or contraindicated. Full article

Yellow fever (YF) is an acute hemorrhagic zoonotic disease that causes severe liver damage, renal failure, and hemorrhagic shock. No antiviral treatment is available; thus, vaccination is a critical preventive measure. Although the World Health Organization (WHO) revised the guidelines regarding the need for booster vaccination for YF with the rationale that a single vaccination provides sufficient long-term immunogenicity, no studies have evaluated long-term immunity in Japanese adults who received a single dose of YF vaccine. This study evaluated the long-term persistence of immunogenicity in Japanese adults vaccinated with the YF vaccine. This observational study enrolled Japanese adults who received a single YF vaccination >5 years previously. Blood samples were collected after confirming eligibility for the study. The serum levels of anti-yellow fever virus (YFV)-neutralizing antibodies were measured using the 50% plaque reduction neutralization test (PRNT₅₀). The 65 participants comprised 35 males and 30 females, with a median age at vaccination of 34 years. The time between YF vaccination and registration was between 5 and 26 years. All participants remained seropositive even after a long time. Statistical analysis showed no correlation between the time elapsed since YF vaccination and PRNT₅₀. Our results indicate that a single dose of YF vaccine provides adequate long-term immunity in Japanese adults and that booster vaccinations are not routinely required. These findings strongly aid in the development of travel medicine guidelines and the optimization of vaccination strategies by reducing the usage of medical resources and simplifying the health requirements for travelers. Full article

Dengue virus (DENV) infection is strongly associated with dengue hemorrhagic fever and dengue shock syndrome, both of which carry mortality risks. Addressing the urgent need for effective dengue therapeutics, we identified sofalcone, a gastroprotective agent with antioxidant and anti-inflammatory properties, as a potential inhibitor of DENV replication. Sofalcone demonstrated efficacy against all four DENV serotypes, with the dose inhibiting 50% (IC50) value of 28.1 ± 0.42 μM against viral replication of DENV serotype 2, without significant cytotoxicity. Additionally, sofalcone significantly improved survival rates and reduced viral titers in DENV-infected ICR-suckling mice. Mechanistically, sofalcone induced heme oxygenase-1 (HO-1) expression via the nuclear factor-erythroid 2-reated factor 2 (Nrf2) pathway, which in turn suppressed viral protease activity and restored antiviral interferon (IFN) responses. This included dose-dependent stimulation of IFN downstream antiviral genes such as 2′-5′-oligoadenylate synthetase 1 (OAS1), OAS2, and OAS3. Given its established clinical use as an anti-gastric ulcer drug, sofalcone offers promising potential for rapid application in treating DENV infection. Full article

Severe dengue is a global health threat, affecting 4 billion people, with nearly 1 million hospitalizations during epidemics and around 25,000 annual deaths. Severe dengue presentations are characterized by vascular leakage, hemorrhagic manifestations, and shock, which can lead to multiorgan failure. Recent studies highlight the crucial role of extracellular vesicles (EVs) in the pathogenesis of dengue, influencing immune response and disease progression. EVs, nanometric structures secreted by cells, mediate viral dissemination, immune modulation, and endothelial dysfunction by transporting biomolecules such as microRNAs (miRNAs) and viral proteins. Infected cell-derived EVs carry viral components, including NS protein and miRNAs like miR-21 and miR-126-5p, which compromise endothelial integrity and activate immune pathways such as Toll-like receptor, NF-κB, and JAK-STAT signaling. This, together with the immune response, leads to the release of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IFN-γ. EVs also facilitate viral immune evasion by suppressing antiviral responses. Recent analyses of miRNAs within EVs suggest their potential as biomarkers for disease progression. Differentially expressed miRNAs in circulating EVs correlate with severe outcomes, providing tools for risk stratification and therapeutic monitoring. Advanced techniques, such as nanoparticle tracking analysis and flow cytometry, allow precise EV characterization, supporting their integration into clinical applications. Full article

Background/Objectives: We reported previously that antagonists at chemokine receptors CCR2 and CCR3 have fluid-sparing effects during resuscitation from hemorrhagic shock. Because CCR1 shares several chemokine ligands with CCR2/3, we tested whether the CCR1 antagonist BX471 also reduces fluid requirements to maintain hemodynamics. Methods: Sprague Dawley rats were hemorrhaged for 30 min, followed by fluid resuscitation to maintain blood pressure for 60 min (series 1) and 180 min (series 2). Series 1: Animals received vehicle (n = 5), 0.05 μmol/kg (n = 5), or 0.5 μmol/kg (n = 4) BX471 at t = 30 min. Series 2: Animals received vehicle (n = 8) or 0.5 μmol/kg (n = 7) BX471 at t = 30 min. Hemodynamics, fluid requirements, blood gases, and lactate were monitored. Serum concentrations of CCR1 ligands (CCL3/4/5/7) were determined at baseline and at the conclusion of the experiments. Tissue (small/large intestine, lung) wet/dry (W/D) weight ratios, lung myeloperoxidase activity, and a panel of inflammation markers in tissue extracts were measured. Results: All animals could be resuscitated to target blood pressures. Series 1: A total of 0.5 μmol/kg BX471 reduced fluid requirements by more than 60% (p < 0.05 vs. vehicle and 0.05 μmol/kg BX471). Series 2: Systemic CCL3/5/7 levels increased during the experiment (p < 0.05). BX471-treatment reduced fluid requirements by more than 60% (p < 0.05) and prevented increases in CCL3/7. W/D ratios of large intestine and of the sum of all tissues were lower with BX471 treatment (p < 0.05). BX471-treatment reduced TNFα and IL6 concentrations in large intestine extracts (p < 0.05). Conclusions: Our findings suggest CCR1 as a new therapeutic target to reduce fluid requirements during resuscitation from hemorrhagic shock. Full article

Hemoglobin-based oxygen carriers (HBOCs) represent a promising alternative to traditional blood transfusions, offering the advantages of extended shelf life and avoiding blood compatibility limitations and infection risks. Positive effects of hemoglobin-based oxygen carriers (HBOCs) on hemorrhagic shock have been researched across various animal species, including swine, rats, rabbits, guinea pigs, and dogs. As previously described, HBOCs based on ovine hemoglobin display better efficiency in the context of hemorrhagic shock compared to those based on the more commonly used bovine hemoglobin. This was evidenced through higher survival rates and more favorable histopathological and immunological outcomes. The vascular effects of ovine hemoglobin polymerized with glutaraldehyde exposure included the absence of hypertension, minimal endothelial damage with slight alterations in inducible nitric oxide synthase (iNOS), and reduced vascular inflammation mediated by interleukin-10 (IL-10). Ovine hemoglobin has emerged as a particularly promising raw material for the development of HBOCs, surpassing bovine and human hemoglobin due to its advantages in availability and efficacy. Furthermore, reducing oxidative stress by polymerizing hemoglobin with glutaraldehyde is most effective with ovine hemoglobin compared to bovine hemoglobin. This study evaluates the effectiveness of ovine hemoglobin polymerized with glutaraldehyde in managing hemorrhagic shock in rabbits, with a focus on its ability to maintain blood pressure, support oxygen transport, and assess potential systemic and oxidative responses. Fifteen adult New Zealand white rabbits, divided into three equal groups, were included in this study: a negative control group transfused with colloid solutions, a positive control group treated with autotransfusion, and a group receiving HBOCs. All groups underwent a hemorrhagic shock protocol, with 40% of their total blood volume withdrawn under deep anesthesia, followed by transfusions 30 min later. Vital parameters, including invasive arterial blood pressure, heart rate, and end-tidal CO₂, were measured throughout the experimental procedures. Arterial blood gas samples were collected before the procedures, after hemorrhagic shock induction, and at the conclusion of the transfusion. In summary, HBOCs offer a promising solution for oxygen delivery, but their effects on blood chemistry, particularly CO₂ and lactate levels, must be considered. Although no direct oxygenation issues were observed in experimental models, elevated CO₂ levels and the interference of HBOCs with lactate measurements emphasize the importance of vigilant clinical monitoring. Polymerized hemoglobin provides a non-nephrotoxic alternative, but challenges persist in preventing nitric oxide scavenging and ensuring effective oxygen delivery. Full article

Background/Objectives: The benefits of liberal transfusion strategies for neurological outcomes in critically ill patients with acute brain injuries (ABIs) remain uncertain due to conflicting evidence and potential risks. This study aimed to evaluate the efficacy and safety of a liberal transfusion strategy in adults with ABI. Methods: A systematic review of PubMed, Scopus, and the Cochrane Library was conducted from inception until 18 December 2024. Randomized clinical trials (RCTs) comparing liberal and restrictive transfusion strategies in adult patients admitted to intensive care units with ABI were included. The primary outcome was unfavorable neurological function at the last follow-up, defined as Glasgow Outcome Scale (GOS) score <4, Extended GOS score <5, or modified Rankin Scale score >3. Results: Among 5859 screened records, five RCTs (2385 patients) met the inclusion criteria. Liberal transfusion significantly reduced unfavorable neurological outcomes (RR, 0.88; 95% CI, 0.82–0.95; p = 0.0009) without affecting mortality (RR, 0.97; 95% CI, 0.84–1.11; p = 0.66). A meta-analysis of two studies (n = 1465 patients) showed improved functional independence with liberal strategies (MD, 6.70; 95% CI, 2.07–11.33; p = 0.005) but no difference in quality of life (p = 0.30). Sepsis or septic shock occurred less frequently in the liberal group (RR, 0.68; 95% CI, 0.50–0.92; p = 0.01). Subgroup analysis indicated that liberal strategies improved neurological outcome in traumatic brain injury (TBI) patients (RR, 0.89; 95% CI, 0.82–0.97; p = 0.01) but did not yield significant differences in spontaneous subarachnoid hemorrhage (p = 0.09). Conclusions: Liberal transfusion strategies safely improve neurological outcomes in adults with ABI, specifically in the subgroup of TBI, whereas further studies are needed in patients with SAH. Full article

Dengue virus is the most prevalent arthropod-borne viral disease in humans. Severe dengue, defined by hemorrhagic fever and dengue shock syndrome, can develop quickly in people who have warning indications such as abdominal pain, mucosal bleeding, and a significant decrease in platelet count. Laboratory markers such as hematocrit, platelet count, liver enzymes, and coagulation tests are critical for early diagnosis and prognosis. This retrospective study was carried out from January 2023 to December 2024 at a super-specialty tertiary care hospital. There were 283 adult patients with dengue with warning signs, who were categorized into 102 with platelet transfusion and 181 with no platelet transfusion. Data on patient demographics, clinical history, laboratory values, and radiological findings were systematically obtained from hospital records at the time of admission. Laboratory parameters such as white blood cell (OR = 2.137), hemoglobin (OR = 2.15), aPTT (OR = 5.815), AST²/ALT (OR = 2.431), platelet count (OR = 26.261) and NS1 (OR = 4.279) were found to be significantly associated (p < 0.01) with platelet transfusion. Similarly, an increased prothrombin time (OR = 2.432) contributed to prolonged hospital stays and the presence of ascites (OR = 5.059), gallbladder wall thickening (OR = 4.212), and pleural effusion (OR = 2.917), contributing to the severity of the dengue infection. These significant laboratory markers help with identifying patients with dengue who may develop severe dengue, requiring platelet transfusion, thereby prioritizing patient care and enabling the implementation of targeted interventions. Full article

Extracellular cold-inducible RNA-binding protein (eCIRP) is a critical damage-associated molecular pattern (DAMP) that drives inflammation and tissue injury in hemorrhagic and septic shock, and has emerged as a promising therapeutic target. Since then, extensive research using preclinical models of diseases and patient materials has explored eCIRP’s role in driving inflammatory responses and its potential as a biomarker. The main objective of this comprehensive review is to provide a detailed overview of eCIRP, covering its discovery, role in disease pathophysiology, mechanisms of release and action, potential as a biomarker, and therapeutic strategies targeting eCIRP in preclinical models of inflammatory and ischemic diseases. We examine the molecular, cellular, and immunological mechanisms through which eCIRP contributes to disease progression, and explore both well-established and emerging areas of research. Furthermore, we discuss potential therapeutic strategies targeting eCIRP across a broad spectrum of inflammatory conditions, including shock, ischemia–reperfusion injury, neurodegenerative diseases, and radiation injury. Full article

Background: In trauma, the shock index (SI) is commonly used to assess the presence of significant blood loss. Prior studies have shown that the SI has a fair predictive ability for clinical outcomes such as massive transfusion (MT) or mortality in adult trauma patients. We hypothesized that the relatively lower predictive power of the SI in older adult patients compared to that of younger adult patients results in the overall fair predictive ability of the SI for clinical outcomes in adult trauma patients. Methods: This retrospective observational study analyzed adult trauma patients who presented to a single regional trauma center between 2019 and 2023, categorizing them into younger (18–64 years) and older (≥65 years) cohorts. The association between SI and MT was evaluated using simple logistic regression, while the modifying effect of age on this association was evaluated through an interaction model. The predictive performance was compared between the groups using the area under the receiver operating characteristic curve (AUC). Age-stratified AUC trends were visualized using cubic spline analysis. Results: A total of 2404 trauma patients met the inclusion criteria, including 1531 younger adults and 873 older adults. The SI was identified as an independent predictor of MT, with a stronger association in younger adults. The AUC for predicting MT was significantly higher in younger adults compared to older adults (0.801 vs. 0.666; p < 0.001), with optimal SI cut-off values of 1.18 and 0.88, respectively. Age-stratified analysis showed the highest AUC in the 41–50 age group (AUC 0.880; 95% CI, 0.836–0.916) and the lowest in the 71–80 age group (AUC 0.624; 95% CI, 0.573–0.674). Conclusions: The predictive performance of the SI for MT was influenced by age, demonstrating a lower predictive ability in older adult patients compared to younger adults. Full article