Search Results (326)

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

Background: Influenza B usually causes mild illness in children. Severe and fatal cases can occur when complicated by secondary Staphylococcus aureus (S. aureus) pneumonia, including community-acquired methicillin-resistant Staphylococcus aureus (MRSA). We present a rare, rapidly progressive fatal case in an adolescent with no known medical history to highlight diagnostic and therapeutic pitfalls. Case Presentation: A 16-year-old boy with no known underlying conditions (unvaccinated for influenza) presented critically ill at “Sf. Ioan” Clinical Emergency Pediatric Hospital in Galați after one week of high fever and cough. He was in respiratory failure with septic shock, requiring immediate intubation and vasopressors. Chest X-ray (CXR) showed diffuse bilateral infiltrates (acute respiratory distress syndrome, ARDS). Initial laboratory tests revealed leukopenia, severe thrombocytopenia, disseminated intravascular coagulation (DIC), rhabdomyolysis, and acute kidney injury (AKI). Reverse transcription polymerase chain reaction (RT-PCR) confirmed influenza B, and blood cultures grew MRSA. Despite maximal intensive care, including mechanical ventilation, antibiotics (escalated for MRSA), antiviral therapy, and cytokine hemoadsorption therapy, the patient developed refractory multi-organ failure and died on hospital day 6. Autopsy revealed bilateral necrotizing pneumonia (NP) without radiographic cavitation, underscoring the diagnostic challenge. Discussion: The initial chest radiography showed diffuse bilateral pulmonary infiltrates, predominantly in the lower zones, with an ill-defined, patchy, and confluent appearance. Such appearance, in our case, was more suggestive of rapid progressive NP caused by MRSA rather than the typical pneumococcal one. This is one of the few reported cases of influenza B–MRSA coinfection with fulminant rhabdomyolysis and autopsy-confirmed necrosis. Our fulminant case illustrates the synergistic virulence of influenza and MRSA. Toxin-producing MRSA strains can cause NP and a “cytokine storm,” causing capillary leak, ARDS, shock, and DIC. Once multi-organ failure ensues, the prognosis is grim despite aggressive care. The absence of early radiographic necrosis and delayed anti-MRSA therapy (initiated after culture results) likely contributed to the poor outcome. Conclusions: Influenza B–MRSA co-infection, though rare, demands urgent empiric anti-MRSA therapy in severe influenza cases with leukopenia or shock, even without radiographic necrosis. This fatal outcome underscores the dual imperative of influenza vaccination and early, aggressive dual-pathogen targeting in high-risk presentations. Full article

Background and Objectives: Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory condition characterized by excessive activation of cytotoxic lymphocytes and macrophages, resulting in a cytokine storm, multiorgan damage, and high mortality. HLH is classified into primary (genetic) and secondary (acquired) forms, with diagnosis often challenging due to nonspecific symptoms. Macrophage activation syndrome (MAS) refers to the secondary HLH triggered by rheumatic diseases. In this study, we retrospectively analyzed the clinical and laboratory features of patients with secondary HLH to enhance understanding of this life-threatening condition and summarize emerging management strategies. Materials and Methods: This single-center retrospective study analyzed medical records of patients hospitalized with HLH at the University Hospital in Kraków, Poland, from 2013 to 2024, based on HLH-2009 criteria and HScore > 169 points. Diagnostic criteria included clinical, laboratory, and histological findings, e.g., hemophagocytosis in bone marrow, circulating cytopenia, and elevated ferritin levels. Results: A total of 21 patients met the criteria for HLH diagnosis, with a median age of 35 (range: 19–67) years, including 12 women (57.1%). The median HScore among the patients was 244 (range: 208–304) points. Fever was the most common presenting symptom, occurring in all cases. High ferritin, hypertriglyceridemia, and hypofibrinogenemia in peripheral blood were also prevalent. Bone marrow hemophagocytosis was confirmed in 66.7% of cases (n = 12/18 of available data). Regarding immunosuppressive therapy, glucocorticosteroids were the most frequently used (used in all cases). Four (19.0%) patients died during HLH (cases triggered by lymphoma [twice], Epstein–Barr virus infection, unknown reason). Compared to survivors, these patients had lower counts of white blood cells, neutrophils, and lymphocytes at diagnosis (p < 0.05 for all). Conclusions: Secondary HLH is a severe syndrome requiring rapid diagnosis and timely intervention to improve patient outcomes. Lower white blood cell, neutrophil, and lymphocyte counts present worse prognostic factors. Full article

Background/Objectives: Proinflammatory cytokines have been associated with poor prognosis in community-acquired and COVID-19 pneumonia. There is a paucity of reports on the cytokine release syndrome, also called cytokine storm in the Mexican population with pneumonia and COVID-19; therefore, our objective was to compare proinflammatory cytokine levels in Mexican patients without COVID-19 (non-COVID-19) and those with moderate, severe, and critical COVID-19 pneumonia. Methods: This study included 30 patients with non-COVID-19 pneumonia and 57 with COVID-19 pneumonia. Disease diagnosis and severity were determined using the radiographic pulmonary edema assessment (RALE) score. Quantification of IL-6, IL-10, and TNF-α was performed using multiplex immunoassays. A receiver operating characteristic curve was constructed to classify subjects with elevated cytokine levels. Logistic regression was used to find associations between elevated cytokine levels and the presence of COVID-19 pneumonia. Results: The severity classification of patients with COVID-19 pneumonia was as follows: moderate (n = 20), severe (n = 19), and critical (n = 18). The proinflammatory cytokines IL-6 and IL-10 were significantly increased in COVID-19 patients compared to non-COVID-19 patients (p < 0.005), while TNF-α levels were lower in critically ill patients with COVID-19 pneumonia. High levels of IL-6 and IL-10, adjusted for age, sex, the presence of comorbidities, and the neutrophil-to-lymphocyte ratio (NLR), showed an elevated risk (OR IL-6 = 4.02; OR IL-10 = 9.36) of presenting pneumonia and COVID-19 compared to pneumonia without COVID-19 in patients. Likewise, 61% of COVID-19 patients with elevated proinflammatory cytokines (IL-6 and IL-10) had a fatal outcome. Conclusions: Elevated levels of both IL-6 and IL-10 are a differential risk factor for developing COVID-19 pneumonia. These elevated levels were more frequently observed in Mexican COVID-19 pneumonia patients who died at the onset of the COVID-19 pandemic. It is important that they are monitored from initial diagnosis as they may be markers of a fatal outcome in severe and critical COVID-19 patients. Full article

Background: The COVID-19 (coronavirus disease 2019) pandemic has presented a serious challenge to nephrologists, since it can lead to severe kidney injury in the form of acute tubular necrosis, with many patients requiring renal replacement therapy. This is predominantly seen in people who develop severe respiratory manifestations like ARDS (acute respiratory distress syndrome) from the viral infection, a cytokine storm or septic shock with unstable hemodynamics. It also presents with various glomerular injuries, mainly collapsing glomerulopathy in high-risk APOL1 (Apolipoprotein L1) genotype patients, thrombotic microangiopathy-related renal failure due to hyper coagulopathy and occasionally pauci-immune glomerulonephritis due to immune dysregulation. All the glomerular disorders that are caused by COVID-19 infection have been described under the designation COVAN (COVID-19-associated nephropathy). Proteinuria is a predominant presentation in glomerular disorders. Gross hematuria and AKI without any respiratory symptoms from COVID-19 infection have not been described so far in the literature. We are presenting one such rare case here. Methods: We have encountered a rare case of gross hematuria and severe acute renal failure. His serological work up was negative for all autoimmune etiologies that can cause Glomerulonephritis. He was found to have infection-related crescentic glomerulonephritis due to active COVID-19 infections discovered via kidney biopsy. He tested positive for SARS-CoV-2 but didn’t have any clinical respiratory symptoms. He has responded well to treatment with a steroid taper and antiviral medication (Remdesivir). This is a very rare renal manifestation of COVID-19 infection. Results: COVID-19 infection can result in crescentic glomerulonephritis. This can be diagnosed by kidney biopsy which shows extensive c3 deposits, tubuloreticular inclusion bodies along with crescentic lesions. This responds to treatment with steroids and Antiviral agents. Conclusions: Crescentic Glomerulonephritis should be considered as a possible etiology for severe acute kidney injury with hematuria in patients with active covid-19 infection without any respiratory symptoms. Kidney biopsy helps in diagnosing it and responds to treatment with steroids and antivirals. Full article

Acute surgical abdomen is characterized by intense, sudden abdominal pain due to intra-abdominal conditions requiring prompt surgical intervention. The coronavirus disease 2019 (COVID-19) pandemic has led to various complications related to the disease’s complex pathophysiological mechanisms, hence the hypothesis of COVID-19-induced acute abdominal surgical pathologies. The connection between acute surgical abdomen and COVID-19 involves two primary mechanisms. First, there is the presence of angiotensin-converting enzyme 2 (ACE2) receptors in multiple abdominal organs. This facilitates the cytokine storm through direct viral injury and inflammation. Second, the hypercoagulable state induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) increases the thrombotic risk within abdominal vessels, which can subsequently lead to ischemia. ACE2 receptors are notably expressed in the gastric, duodenal, and rectal epithelium, with SARS-CoV-2 viral RNA and nucleocapsid proteins detected in these tissues. The inflammatory response results in significant endothelial damage, activating coagulation pathways that cause monocellular infiltration, lymphocytic inflammation, and uncontrolled coagulation. These findings highlight the need for further research to clarify how COVID-19 leads to acute abdominal pathologies. Understanding these mechanisms is vital for improving clinical management and patient outcomes during future health crises and in the aftermath of the pandemic. Full article

Pediatric sepsis presents a unique clinical challenge due to the distinct characteristics of the developing immune system. The immune response in children differs significantly from that in adults, exhibiting a unique combination of resistance, disease tolerance, and resilience. These factors influence the clinical presentation and prognosis of pediatric patients with sepsis. Over the past few years, various studies have explored the role of immunomodulatory therapies in managing sepsis, including the use of immunoglobulins, corticosteroids, monoclonal antibodies, and immunostimulatory treatments. However, the heterogeneity of the clinical presentations and individual responses makes it difficult to identify universally effective treatments. Recent research has highlighted the importance of a personalized approach based on specific biomarkers and patient phenotyping. Extracorporeal blood purification techniques have emerged as promising strategies for the modulation of hyperinflammation. However, strong evidence supporting their routine use in pediatric sepsis is lacking. This review provides a comprehensive overview of the current knowledge of the immune response in pediatric sepsis and discusses the main immunomodulatory strategies and future perspectives for personalized therapy. A deeper understanding of the immunological differences between children and adults could improve the prognosis and treatment efficacy, paving the way for new approaches to pediatric sepsis management. Full article

Although the acute phase of the COVID-19 pandemic has subsided, the emergence of the post-COVID-19 condition presents a new and complex public health challenge, characterized by persistent, multisystem symptoms that can endure for weeks or months after the initial infection with the SARS-CoV-2 virus, significantly affecting survivors’ quality of life. Among the most concerning sequelae are cardiovascular complications, which encompass a broad spectrum of conditions, including arrhythmias, myocardial damage, or postural orthostatic tachycardia syndrome. This narrative review explores the burden of the SARS-CoV-2 infection on cardiovascular health by reviewing the latest and most relevant findings in the literature and highlighting different aspects of COVID-19’s cardiovascular involvement. This review investigates the pathophysiological mechanisms underlying cardiovascular involvement in the post-COVID-19 condition, with a focus on direct viral invasion via ACE2 receptors, immune-mediated cardiovascular injury, cytokine storm, systemic inflammation, endothelial dysfunction, and mitochondrial injury. The interplay between pre-existing cardiovascular diseases, such as hypertension, atherosclerosis, diabetes, and atrial fibrillation, and COVID-19 is also explored, revealing that individuals with such conditions are at heightened risk for both severe acute illness and long-term complications. Long-term immune activation and the persistence of viral antigens are increasingly recognized as contributors to ongoing cardiovascular damage, even in individuals with mild or asymptomatic initial infections. As the healthcare system continues to adapt to the long-term consequences of the SARS-CoV-2 pandemic, a deeper understanding of these cardiovascular manifestations is essential. This knowledge will inform the development of targeted strategies for prevention, clinical management, and rehabilitation of affected patients. Furthermore, the insights gained from the intersection of COVID-19 and cardiovascular health will be instrumental in shaping responses to future viral epidemics, highlighting the necessity for multidisciplinary approaches to patient care and public health preparedness. Full article

Respiratory viral infections trigger immune and inflammatory responses that can be associated with excessive oxidative stress, glutathione (GSH) depletion, and a cytokine storm that drives virus-induced cell/tissue damage and severe disease. Erdosteine is a thiol-based drug with proven mucolytic, anti-inflammatory, antioxidant, and antibacterial properties, but less is known about its antiviral effects. We performed in vitro studies to investigate the antiviral and anti-inflammatory activity of erdosteine in A549-hACE2 human lung epithelial cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or respiratory syncytial virus (RSV) and in Caco-2 human colon carcinoma cells infected with influenza A virus (H1N1). The cells were treated with different concentrations of erdosteine or its active metabolite 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MET-1) before and after viral infection. The viral replication/load in the cell culture supernatants was measured by real-time quantitative polymerase chain reaction (RT-qPCR) assay and digital droplet PCR. The gene expression of innate immune response signaling pathways and oxidative stress was analyzed by reverse transcription PCR custom-array. The results showed that erdosteine and its active metabolite, at concentrations consistent with an approved therapeutic human dosage, were not directly cytotoxic and had significant antiviral effects in cells pre-infected with SARS-CoV-2, RSV, and H1N1. The transcriptome analysis showed that erdosteine activated innate immune responses by stimulating overexpression of type I interferon and inflammasome pathways and modulated oxidative stress by inducing the modulation of oxidative stress and GSH pathways. These findings suggest that erdosteine may be a useful treatment for respiratory viral infections. Full article

Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome (PIMS), presents significant challenges in pediatric cardiology, due to its complex molecular pathophysiology. In this retrospective analysis of 15 cases that were managed at a single tertiary care center, we investigated the molecular contributors to myocardial dysfunction, including cytokine storms, hyperinflammation markers, and hypercoagulable states. Transient myocardial involvement was identified in 46.6% of patients, with complete recovery achieved within 2–4 weeks following treatment. Ferritin, NT-ProBNP, and troponin levels were significantly elevated in patients with ventricular dysfunction compared to those without. The neutrophil-to-lymphocyte ratio (NLR), which was previously identified as a severity marker in acute COVID-19, was also significantly higher in patients with ventricular dysfunction, suggesting its potential as a prognostic indicator in MIS-C. Notably, no coronary artery aneurysms were detected in the cohort. These findings underscore the importance of early, standardized therapeutic interventions in mitigating severe outcomes, and they provide valuable insights into the molecular mechanisms driving myocardial dysfunction in MIS-C. Incorporating NLR and ferritin into the initial diagnostic workup may improve the early triage and identification of high-risk MIS-C patients. Full article

SARS-CoV-2, first identified in December 2019, caused a global pandemic, resulting in over 6.8 million deaths by March 2023. The elderly, or individuals over 65, accounted for the majority of COVID-19 deaths, with 81% of fatalities in the US in 2020 occurring in this group. Beyond mortality, aging populations are also at higher risk of long-term cardiovascular complications and acute respiratory distress syndrome (ARDS). Although these outcomes may be influenced by comorbidities common in the elderly, age has been found to be a standalone risk factor for severe COVID-19 infection. Therefore, investigating age-related factors in COVID-19 outcomes is crucial in protecting this vulnerable group. Of particular interest is the cytokine storm phenomenon, an excessive inflammatory response that contributes to severe COVID-19 symptoms, including ARDS and cardiovascular damage. Elevated levels of multiple cytokines are common in severe cases of COVID-19. We propose that changes that occur to cytokine profiles as we age may contribute to these aberrant inflammatory responses. This review specifically explored the interleukin class cytokines IL-1, IL-6, IL-17, and IL-23 and considered the potential of biologics targeting these cytokines to alleviate severe outcomes in both COVID-19 and aging individuals. Full article

Background: Cytokine Release Syndrome (CRS) is a hyperinflammatory state triggered by immune therapies like CAR T-cell therapy and bispecific T-cell engagers (BiTEs). Characterized by excessive cytokine release, CRS often mimics infectious and inflammatory conditions, complicating diagnosis and treatment. Immunosuppressive therapies used for CRS further elevate the risk of secondary infections. Methods: A systematic search of PubMed and EMBASE was conducted using terms related to “cytokine release syndrome”, “cytokine storm”, “infections”, and “management”. Studies were included if they described infectious complications, diagnostic mimics, or therapeutic approaches related to CRS. Results: Of 19,634 studies, 2572 abstracts were reviewed. Infections occurred in up to 23% of patients post-CAR T therapy and 24% post-BiTE therapy. Pathogens included gram-positive and gram-negative bacteria, herpesviruses (e.g., CMV, HSV), fungi (e.g., Candida, Aspergillus), and parasites (e.g., Toxoplasma gondii). CRS mimics also included non-infectious inflammatory syndromes. Differentiation remains challenging, but cytokine profiling and biomarkers (e.g., ferritin, CRP, sIL-2Rα) may aid in diagnosis. Treatments included tocilizumab, corticosteroids, and empiric antimicrobials. Prophylactic strategies were inconsistently reported. Conclusions: Effective CRS management requires early recognition, differentiation from infectious mimics, and collaboration between oncology and infectious disease (ID) specialists. A multidisciplinary, collaborative, and structured approach, including dedicated ID input and pre-treatment evaluation, is essential for optimizing CRS management and patient outcomes. Full article

Background: Critically ill patients often display systemic immune dysregulation and increased inflammatory activity. Hemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome defined by the inappropriate survival of cytotoxic T cells and the occurrence of cytokine storms. Although HLH is characterized by relatively high mortality rates, little is known about the predictive value of its diagnostic criteria. Accordingly, our objective was to evaluate these properties within an unselected cohort of critically ill patients admitted to a tertiary intensive care unit (ICU). Methods: This single-center prospective observational study included 176 consecutive patients. Available HLH criteria at admission were assessed, including sCD25 measurements performed using ELISA. Results: Overall, 30-day mortality rates were significantly higher in patients exhibiting two or more criteria of HLH (21.9% vs. 43.3%, p = 0.033). Moreover, sCD25 emerged as an independent risk predictor of 30-day mortality independent of age, sex, the use of vasopressors, and mechanical ventilation (HR 2.72 for the highest tertile vs. lowest tertile, p = 0.012). Additionally, fibrinogen was significantly decreased in non-survivors (p = 0.019), and its addition to the SAPS II score significantly increased its prognostic capability (p = 0.045). In contrast, ferritin and triglyceride levels were not different in survivors versus non-survivors. Conclusions: Critically ill patients displaying two or more HLH criteria exhibit a dramatic increase in 30-day mortality, even in the absence of an established HLH diagnosis. Furthermore, elevated levels of sCD25 and decreased levels of fibrinogen were found to be significant predictors of mortality. Full article

Background: Isofraxidin is a hydroxylcoumarin derived from herbal Fraxinus and Eleutherococcus. It has been shown that isofraxidin has antioxidant, anti-inflammatory, anti-diabetic, and anti-lipidemic effects. The study aimed to examine the therapeutic effects of isofraxidin with and without methylprednisolone to ameliorate lipopolysaccharide (LPS)-induced cytokine-releasing syndrome. Methods: The study comprised two phases: preventive and therapeutic. In all the experiments that involved LPS induction, a single dose of LPS (5 mg/kg) was used. The preventive phase involved the administration of the agents before LPS induction, in which 50 mg/kg of methylprednisolone, 15 mg/kg of isofraxidin, or a combination of 7.5 mg/kg of isofraxidin plus 25 mg/kg methylprednisolone were given daily for 3 days before induction. The therapeutic phase involved the administration of the following agents after LPS induction: 50 mg/kg methylprednisolone, 15 mg/kg of isofraxidin, or a combination of 7.5 mg/kg of isofraxidin plus 25 mg/kg methylprednisolone were given once daily was given for 7 days. Results: Isofraxidin treatment with or without methylprednisolone ameliorates LPS-induced inflammatory and oxidative stress damage in mice; it reduces the inflammatory (IL-6, TNF-α, IL-1β, IL-8, Malondialdehyde, and IFN-γ) and oxidative stress markers. Additionally, isofraxidin treatment with or without methylprednisolone prevented liver and lung tissue damage induced by LPS. Conclusions: Isofraxidin exhibited preventive and therapeutic properties against lipopolysaccharide-induced cytokine storms in mice via anti-inflammatory and antioxidant pathways, and its combination with methylprednisolone demonstrated synergistic outcomes. Full article

Background/Objectives: SARS-CoV-2 provokes acute oxidative stress in the lungs via cytokines, inflammatory mediators, and apoptotic factors, which might cause alveolar injury followed by severe respiratory syndrome during COVID-19 infection. The lack of particular antivirals for SARS-CoV-2 has opened novel avenues of complementary and alternative medicine as a potential remedy. The current study explored the mechanistic role of the ultradiluted formulation of Eupatorium (UDE) against SARS-CoV-2 recombinant S protein-mediated oxidative stress and mitochondriopathy. Methods: Cell line and BALB/c mice were used to report that SARS-CoV-2 S protein caused an inflammatory response and subsequent cytokine storm via the NF-κB pathway in the lung along with oxidative damage. Morphological examination was performed using DAPI staining and histology for treated cells and lung tissues of animals, respectively. The molecular mechanism of action of UDE was investigated through qRT-PCR for the genetic expressions of various cytokines, inflammatory, and apoptotic mediators; ELISA, immunofluorescence, immunohistochemistry, and Western blot for the translational expression of the same molecules assayed for genetic expressions; and biochemical assays for various enzymes and ROS. Results: UDE treatment suppressed the inflammatory cell infiltration and tissue-level oxidative stress and safeguarded mitochondrial integrity from free radical-mediated oxidative damage. Additionally, UDE played a direct role in restoring cellular redox homeostasis and reducing the inflammatory response by suppressing NF-κB, IL-1β, IL-18, caspase-1 expression, and ROS formation. Further, a plausible mechanism of action of UDE against S protein-induced damage was proposed. Conclusions: This study described a novel therapeutic approach against S protein-mediated hyperinflammation, apoptosis, and oxidative damage. Hence, UDE may be considered as a prospective alternative to combat life-threatening consequences of SARS-CoV-2 infection. Full article