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Background: Metabolic dysfunction-associated fatty liver disease has been linked to negative outcomes in patients with end-stage liver disease following liver transplantation. However, the influence of immunosuppressive regimens on it has not been explored. Methods: A retrospective analysis was conducted using the preoperative and postoperative data from patients with end-stage liver disease. The study compared three different groups: tacrolimus-based group, sirolimus-based group, and combined tacrolimus- and sirolimus-based regimens. Binary logistic regression analysis was employed to identify risk factors for metabolic dysfunction-associated fatty liver disease. Results: A total of 171 patients participated in the study, consisting of 127 males and 44 females, with a mean age of 49.6 years. The prevalence of posttransplant metabolic dysfunction-associated fatty liver disease was 29.23%. Among the three groups, there were 111 liver transplant recipients in the tacrolimus-based group, 28 in the sirolimus-based group, and 32 in the combination group. A statistically significant difference was observed in the incidence of metabolic dysfunction-associated fatty liver disease (P < 0.05), whereas the other preoperative and postoperative parameters showed no significant differences. Multivariate analysis revealed that a low-calorie diet (95% confidence intervals: 0.15-0.90, P = 0.021) and a combination of tacrolimus- and sirolimus-based immunosuppressive regimen (95% confidence intervals: 1.01-2.77, P = 0.046) were associated with lower risk of posttransplant metabolic dysfunction-associated fatty liver disease. Conclusions: Our study indicates that implementing a low-calorie diet and utilizing a combination of tacrolimus- and sirolimus-based immunosuppressive regimen can effectively lower the risk of posttransplant metabolic dysfunction-associated fatty liver disease following liver transplantation.
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Mesenchymal stem/stromal cells (MSCs) are an attractive platform for cell therapy due to their safety profile and unique ability to secrete broad arrays of immunomodulatory and regenerative molecules. Yet, MSCs are well known to require preconditioning or priming to boost their therapeutic efficacy. Current priming methods offer limited control over MSC activation, yield transient effects, and often induce the expression of pro-inflammatory effectors that can potentiate immunogenicity. Here, we describe a genetic priming method that can both selectively and sustainably boost MSC potency via the controlled expression of the inflammatory-stimulus-responsive transcription factor interferon response factor 1 (IRF1). MSCs engineered to hyper-express IRF1 recapitulate many core responses that are accessed by biochemical priming using the proinflammatory cytokine interferon-γ (IFN-γ). This includes the upregulation of anti-inflammatory effector molecules and the potentiation of MSC capacities to suppress T cell activation. However, we show that IRF1-mediated genetic priming is much more persistent than biochemical priming and can circumvent IFN-γ-dependent expression of immunogenic MHC class II molecules. Together, the ability to sustainably activate and selectively tailor MSC priming responses creates the possibility of programming MSC activation more comprehensively for therapeutic applications.
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There is growing concern that some managed and wild insect pollinator populations are in decline, potentially threatening biodiversity and sustainable food production on a global scale. In recent years, there has been increasing evidence that sub-lethal exposure to neurotoxic, neonicotinoid pesticides can negatively affect pollinator immunocompetence and could amplify the effects of diseases, likely contributing to pollinator declines. However, a direct pathway connecting neonicotinoids and immune functions remains elusive. In this study we show that haemocytes and non-neural tissues of the honeybee Apis mellifera express the building blocks of the nicotinic acetylcholine receptors that are the target of neonicotinoids. In addition, we demonstrate that the haemocytes, which form the cellular arm of the innate immune system, actively express choline acetyltransferase, a key enzyme necessary to synthesize acetylcholine. In a last step, we show that the expression of this key enzyme is affected by field-realistic doses of clothianidin, a widely used neonicotinoid. These results support a potential mechanistic framework to explain the effects of sub-lethal doses of neonicotinoids on the immune function of pollinators.
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Acetilcolina , Guanidinas , Hemocitos , Insecticidas , Neonicotinoides , Animales , Abejas/efectos de los fármacos , Abejas/inmunología , Insecticidas/toxicidad , Neonicotinoides/toxicidad , Acetilcolina/metabolismo , Hemocitos/efectos de los fármacos , Hemocitos/inmunología , Hemocitos/metabolismo , Guanidinas/toxicidad , Tiazoles , Receptores Nicotínicos/metabolismo , Receptores Nicotínicos/efectos de los fármacos , Colina O-Acetiltransferasa/metabolismoRESUMEN
Lung transplantation offers a lifesaving option for patients with end-stage lung disease, but it is marred by a high risk of post-transplant infections, particularly involving multidrug-resistant bacteria, Cytomegalovirus, and fungal pathogens. This elevated infection rate, the highest among solid organ transplants, poses a significant challenge for clinicians, particularly within the first year post-transplantation, where infections are the leading cause of mortality. The direct exposure of lung allografts to the external environment exacerbates this vulnerability leading to constant immune stimulation and consequently to an elevated risk of triggering alloimmune responses to the lung allograft. The necessity of prolonged immunosuppression to prevent allograft rejection further complicates patient management by increasing susceptibility to infections and neoplasms, and complicating the differentiation between rejection and infection, which require diametrically opposed management strategies. This review explores the intricate balance between preventing allograft rejection and managing the heightened infection risk in lung transplant recipients.
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Rechazo de Injerto , Trasplante de Pulmón , Humanos , Trasplante de Pulmón/efectos adversos , Rechazo de Injerto/inmunología , Animales , Terapia de InmunosupresiónRESUMEN
Background: Nocardiosis is the systemic manifestation of Nocardia infection, often found in immunocompromised individuals. Nocardia are transmitted via inhalation or skin wounds, disseminating hematogenously to organs and rarely, joints. We present a patient with immunosuppression who developed gout of the knee with superimposed Nocardial septic arthritis and a possible subsequent systemic infection. Case Presentation: A 74-year-old man presented with left lower extremity swelling and pain. He was taking immunosuppressive medication for antineutrophilic cytoplasmic antibody-positive vasculitis. A week prior, an arthrocentesis test was positive for gout. He received prednisone without improvement. A repeat arthrocentesis was positive for Nocardia farcinica septic arthritis. Chest imaging showed subpleural nodules. After failed antibiotics, a susceptibilities test yielded results that favored linezolid. The patient exhibited acute anemia from hematomas intramuscularly above the infection, which resolved with transfusions. Immunosuppression was stopped, and the patient recovered appropriately after the correct antibiotics were administered. Conclusion: This case involves septic arthritis with possible pulmonary nodule involvement, showcasing the complexity of infections in immunocompromised individuals. Clinicians should maintain adequate suspicion for an infectious cause of arthritis in patients with immunosuppression. In our case, the hematomas are a curious finding, without known etiology. The question of when and how to reintroduce immunosuppressive agents while preventing the recurrence of nocardiosis remains a complex consideration.
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Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune response. This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation, which might result from acute-on-chronic liver failure (ACLF) and cirrhosis. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.
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Inmunidad Innata , Fallo Hepático , Humanos , Fallo Hepático/inmunología , Animales , Sistema Inmunológico/metabolismo , Sistema Inmunológico/inmunología , Inmunidad Adaptativa , Células Asesinas Naturales/inmunología , Citocinas/metabolismo , Hígado/inmunología , Hígado/metabolismo , Hígado/patologíaRESUMEN
Myocarditis is a potentially life-threatening inflammatory disease of the myocardium, often resulting from infectious and immune-mediated responses. Clinical presentation in severe cases often results in a devastating illness requiring extracorporeal membrane oxygenation support as a result of cardiogenic shock. Although endomyocardial biopsy is still considered the gold standard for diagnosis, it often reveals nonspecific lymphocytic infiltration. Because the precise cause is usually unknown, the initial treatment typically involves immunosuppression and frequent assessment of myocardial contractility. This report presents 3 rare cases of autoimmune diseases (polymyositis, immunoglobulin G4-related disease, and systemic lupus erythematosus) that require extracorporeal membrane oxygenation support as a result of fulminant myocarditis, including their follow-up periods.
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Oxigenación por Membrana Extracorpórea , Miocarditis , Humanos , Miocarditis/terapia , Miocarditis/diagnóstico , Miocarditis/fisiopatología , Miocarditis/inmunología , Oxigenación por Membrana Extracorpórea/métodos , Masculino , Femenino , Adulto , Biopsia , Persona de Mediana Edad , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/terapia , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/complicaciones , Miocardio/patología , Miocardio/inmunología , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/terapia , Choque Cardiogénico/terapia , Choque Cardiogénico/etiología , Choque Cardiogénico/diagnóstico , Resultado del Tratamiento , Enfermedad Relacionada con Inmunoglobulina G4/diagnóstico , Enfermedad Relacionada con Inmunoglobulina G4/terapia , Enfermedad Relacionada con Inmunoglobulina G4/complicacionesRESUMEN
Introduction: Accidental or intentional ingestion of paraquat leads to many local and systemic effects and the mortality rate is very high. There is limited data from North India and our objectives were to study the spectrum of presentation, treatment given, and its relation with outcome in a tertiary care setting. Materials and methods: This retrospective observational study was conducted after ethical approval and data regarding demography, clinical features, duration of presentation, organ involvement, renal replacement therapy (RRT), management, and outcome was collected. Statistical analysis was done by calculating mean and standard deviation (SD). Chi-square (χ2) test was applied to categorical variables and the Fisher exact test was used when the expected frequency was less than 5. Results: The study population consisted of 91 male (84%) and 18 female patients. Out of 109 patients, 13 survived (12%) and 88% had a fatal outcome. Nearly 92% of patients belonged to rural background, and 68% were of younger (<30 years) age group. Age, gender, occupation, and amount taken did not have any significant relation with mortality. Patients having metabolic acidosis (58.7%), altered renal (75.2%), and hepatic function (62.3%) at presentation had a statistically significant relation with mortality. Duration of presentation was significantly lesser in patients who survived (17.26 ± 17.23, median 14 hours vs 80.18 ± 90.07, median 48 hours) compared to patients who did not survive. Renal replacement therapy (n = 57) had no relation with mortality whereas 36% of the patients who received hemoperfusion (HP) survived (p = 0.03). Conclusion: Treatment should be started early as the duration of the presentation has a significant association with the outcome. Currently there is no antidote available. Supportive treatment includes oxygenation, immunosuppression, antioxidants, RRT, and HP wherever the resources are available. How to cite this article: Goyal P, Gautam PL, Sharma S, Paul G, Taneja V, Mona A. A Study of Paraquat Poisoning Presentation, Severity, Management and Outcome in a Tertiary Care Hospital: Is There a Silver Lining in the Dark Clouds? Indian J Crit Care Med 2024;28(8):741-747.
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Liver transplantation (LT) remains one of the most effective treatments for hepatocellular carcinoma (HCC) and significantly enhances patient survival. However, the application of LT for HCC faces challenges owing to advancements in cancer-specific treatment modalities and the increased burden of patients' comorbidities. This narrative review explores current controversies and advancements in LT for HCC. Key areas of focus include the management of comorbidities and patient education by advanced practice nurses, impacts of frailty on waitlists and post-LT outcomes, selection criteria for LT in the era of new downstaging tools, role of radiology in patient selection, and implications of potential immunotherapy use both before and after LT. Additionally, the importance of immunosuppression management with strategies aimed at minimizing rejection while considering the risk of HCC recurrence and the role of surveillance for HCC recurrence is highlighted. This review also underscores the importance of a multidisciplinary approach for optimizing outcomes in patients with HCC undergoing LT.
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The management of advanced cutaneous squamous cell carcinoma (CSCC) has been revolutionized by the introduction of immunotherapy. Yet, successful treatment with immunotherapy relies on an adequate antitumor immune response. Patients who are solid-organ transplant recipients (SOTRs) have a higher incidence of CSCC compared to the general population. This review discusses the current knowledge of epidemiology, pathophysiology, and management of patients with CSCC who are immunocompromised because of their chronic exposure to immunosuppressive medications to prevent allograft rejection. First, we discuss the prognostic impact of immunosuppression in patients with CSCC. Next, we review the risk of CSCC development in immunosuppressed patients due to SOT. In addition, we provide an overview of the biological immune disruption present in transplanted immunosuppressed CSCC patients. We discuss the available evidence on the use of immunotherapy and provide a framework for the management approach with SOTRs with CSCC. Finally, we discuss potential novel approaches that are being investigated for the management of immunosuppressed patients with CSCC.
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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer without effective treatments. It is characterized by activating KRAS mutations and p53 alterations. However, how these mutations dysregulate cancer-cell-intrinsic gene programs to influence the immune landscape of the tumor microenvironment (TME) remains poorly understood. Here, we show that p53R172H establishes an immunosuppressive TME, diminishes the efficacy of immune checkpoint inhibitors (ICIs), and enhances tumor growth. Our findings reveal that the upregulation of the immunosuppressive chemokine Cxcl1 mediates these pro-tumorigenic functions of p53R172H. Mechanistically, we show that p53R172H associates with the distal enhancers of the Cxcl1 gene, increasing enhancer activity and Cxcl1 expression. p53R172H occupies these enhancers in an NF-κB-pathway-dependent manner, suggesting NF-κB's role in recruiting p53R172H to the Cxcl1 enhancers. Our work uncovers how a common mutation in a tumor-suppressor transcription factor appropriates enhancers, stimulating chemokine expression and establishing an immunosuppressive TME that diminishes ICI efficacy in PDAC.
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INTRODUCTION: Monoclonal antibodies (mAbs) and other biological agents are being increasingly approved in the last years with very different indications. Their highly heterogeneous immunosuppressive effects, mechanisms of action and pharmacokinetics require comprehensive individualized vaccination schedules. AREAS COVERED: Vaccination for immunocompromised patients. Prevention and treatment with mAbs and other biological therapies. EXPERT OPINION: Current recommendations on vaccine schedules for patients under mAbs or other biological treatments are based on expert opinions and are not individualized according to each vaccine and treatment. No studies are focusing on the high heterogeneity of these agents, that are exponentially developed and used for many different indications. Recent paradigm changes in vaccine development (boosted by the COVID-19 pandemic) and in the mAbs use for prophylactic purposes (changing 'vaccination' by 'immunization' schedules) has been witnessed in the last years. We aimed at collecting all mAbs used for treatment or prevention, approved as of 1 January 2024, by the EMA. Based on available data on mAbs and vaccines, we propose a comprehensive guide for personalizing vaccination. Recent vaccine developments and current population strategies (e.g. zoster vaccination or prophylactic nirsevimab) are discussed. This review aims to be a practical guideline for professionals working in vaccine consultations for immunosuppressed patients.
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Existing on the spectrum of post-transplant lymphoproliferative disorders (PTLD), plasmablastic lymphoma (PBL) is a highly aggressive form of B-cell non-Hodgkin lymphoma. Since its discovery in 1997, fewer than 5 cases of postliver transplantation-associated PBL have been recorded. Despite increased awareness of PTLD and improvement in imaging, PBL often presents with disseminated disease at the time of diagnosis. Treatment usually involves immunosuppression reduction and the use of chemo/immunotherapy, but the prognosis remains poor, with median survival being less than 12 months. We present to you a case of Epstein-Barr virus-negative PBL occurring more than 6 years postliver transplantation.
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Presentation of metabolites by the Major Histocompatibility Complex Class-I-related protein 1 (MR1) molecule to Mucosal-Associated Invariant T (MAIT) cells is impaired during herpes simplex type 1 (HSV-1) and type 2 (HSV-2) infections. This is surprising given these viruses do not directly synthesise MR1 ligands. We have previously identified several HSV proteins responsible for rapidly downregulating the intracellular pool of immature MR1, effectively inhibiting new surface antigen presentation, while pre-existing ligand-bound mature MR1 is surprisingly upregulated by HSV-1. Using flow cytometry, immunoblotting and high throughput fluorescence microscopy we demonstrate that the endocytosis of surface MR1 is impaired during HSV infection, and that internalised molecules accumulate in EEA1-labelled early endosomes, avoiding degradation. We establish that the short MR1 cytoplasmic tail is not required for HSV-1 mediated downregulation of immature molecules, however it may play a role in the retention of mature molecules on the surface and in early endosomes. We also determine that the HSV-1 US3 protein, the shorter US3.5 kinase and the full-length HSV-2 homolog, all predominantly target mature surface rather than total MR1 levels. We propose that the downregulation of intracellular and cell surface MR1 molecules by US3 and other HSV proteins is an immune-evasive countermeasure to minimise the effect of impaired MR1 endocytosis, which might otherwise render infected cells susceptible to MR1-mediated killing by MAIT cells.
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Clostridium perfringens (C. perfringens) causes avian necrotic enteritis, leading to huge economic losses to the poultry industry. This pathogen induces host immunosuppression; however, the molecular mechanism is still unclear. Thus, we established a laying hen infection model to explore this mechanism. We randomly divided 20 one-old-day laying hens into the control and infection groups. The infection group was infected intragastrically with 1 × 109 colony-forming units of C. perfringens in 1 mL of sterile phosphate-buffered saline (PBS) once a day from d 17 to 20; the control group received the same volume of PBS without the bacterium. Twenty-four hours after the last challenge, we sacrificed the laying hens and collected the jejunum for analysis. The infection group presented alterations in blood biochemical parameters and necrotic lesion scores as well as damage to the jejunum. Proteomics revealed 427 upregulated and 291 downregulated proteins in the infection group. In the infection group, CD3, CD4, and CD8 messenger RNA expression (mRNA) expression was decreased; LAMTOR1 and mTORC1 mRNA expression was increased; CD276 protein expression was enhanced; and the PI3K/Akt/MMP pathway was activated in jejunum of laying hens. This is the first study to report CD276 expression in the jejunum related to immunosuppression in a laying hen model of necrotic enteritis. It provides some new key targets to potentially control avian necrotic enteritis.
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This updated report highlights significant developments in the field of xenotransplantation since December 2023. Over the past 6 months, there has been a notable increase in discussions regarding the feasibility of clinical trials, with particular emphasis on their progression and associated ethical considerations. This review presents the most pertinent findings from December 2023 to June 2024.
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Xenoinjertos , Trasplante Heterólogo , Trasplante Heterólogo/métodos , Animales , HumanosRESUMEN
Objective: We investigated the risk factors associated with severe or critical Coronavirus disease 2019 (COVID-19) infection due to the Omicron variant in patients with myasthenia gravis (MG) and determined the potential effect of COVID-19 on myasthenic exacerbation during the Omicron pandemic. Methods: This retrospective study included 287 patients with MG in Tianjin, China. Clinical data of the patients were collected using electronic questionnaires, databases, and clinical records. Results: The overall infection rate was 84.7%. Advanced age, comorbidities, generalized phenotype, and MG instability were drivers of COVID-19 severity, and post-COVID-19 myasthenic exacerbation. The concurrent use of a steroid-sparing agent did not affect COVID-19 susceptibility or severity. It did lower the risk of myasthenic exacerbation after COVID-19 infection. Patients with severe COVID-19 experienced myasthenic exacerbation earlier than patients with non-severe infection (p < 0.001). The severity of COVID-19 (Hazards Ratio = 3.04, 95% CI: 1.41-6.54, p = 0.004) and the clinical phenotype (Hazards Ratio = 3.29, 95% CI: 1.63-6.63, p < 0.001) emerged as independent risk factors for early MG exacerbation. Conclusion: Generally, patients with MG appear to be susceptible to the Omicron strains. Immunotherapy for MG did not increase COVID-19 susceptibility or severity. We do not advocate an immediate cessation of ongoing immunosuppressive treatments once a COVID-19 infection is diagnosed. Instead, a judicious evaluation of the risks and benefits, tailored to each individual, is recommended.
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COVID-19 , Miastenia Gravis , SARS-CoV-2 , Humanos , COVID-19/epidemiología , COVID-19/complicaciones , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , China/epidemiología , Adulto , Factores de Riesgo , Anciano , Índice de Severidad de la Enfermedad , ComorbilidadRESUMEN
BACKGROUND: Transfusion-related acute lung injury (TRALI) is a rare life-threatening complication of blood product transfusion. Intravenous immunoglobulin (IVIG)-related TRALI is scarcely reported. CASE PRESENTATION: A 63-year-old male patient suffering from multiple sclerosis treated with half-yearly rituximab infusions, was hospitalized due to dry cough, daily fever and shivering for seven days despite antibiotic therapy. Because of the history of COVID-19 one month prior without the symptoms having improved since, persistent bilateral multifocal areas of ground glass opacities in chest computed tomography and positive SARS-CoV-2 PCR from bronchoalveolar lavage with a cycling time of 30.1 COVID-19 due to long-shedding SARS-CoV-2 under immunosuppression with rituximab was diagnosed. He received treatment with nirmatrelvir und ritonavir and because of diagnosed IgG deficiency additionally a single dose of 20 g IVIG. During the IVIG infusion, the patient acutely developed tachycardia, hypotension, fever, chills, and hypoxemic respiratory failure due to pulmonary edema. TRALI was promptly diagnosed, and the patient was transferred to the intensive care unit for non-invasive ventilation for less than 24 h. The patient was discharged home from regular ward 72 h later in a good general condition and no remaining symptoms of TRALI. CONCLUSION: IVIG-related TRALI is a rare but life-threating condition and prompt recognition is lifesaving. Due to an increased use of IVIG not only in long-shedding SARS-CoV-2, an increase of TRALI incidence is expected.
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COVID-19 , Huésped Inmunocomprometido , Inmunoglobulinas Intravenosas , Rituximab , SARS-CoV-2 , Lesión Pulmonar Aguda Postransfusional , Humanos , Masculino , Persona de Mediana Edad , COVID-19/complicaciones , Rituximab/efectos adversos , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Inmunoglobulinas Intravenosas/uso terapéutico , Inmunoglobulinas Intravenosas/administración & dosificación , Inmunoglobulinas Intravenosas/efectos adversos , Lesión Pulmonar Aguda Postransfusional/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , BetacoronavirusRESUMEN
Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.