ABSTRACT
Background: Lichen planus (LP) is an inflammatory disorder believed to result from CD8+ cytotoxic T-cell (CTL) mediated autoimmune reactions against basal keratinocytes. We present a review of LP following COVID-19 infection and vaccination. Method(s): Literature searches were conducted on PubMed and Google Scholar from 2019 to 7/2022. 35 articles were selected based on subject relevance, and references within articles were also screened. Result(s): 39 cases of post-vaccination LP and 6 cases of post-infection LP were found among case reports and case series. 150 cases of postvaccination LP and 12 cases of post-infection LP were found in retrospective and prospective studies. Conclusion(s): LP is a rare complication of COVID-19 infection and vaccination that may be mediated by overstimulation of T-cell responses and proinflammatory cytokine production. However, it does not represent a limitation against COVID-19 vaccination, and the benefits of vaccination considerably outweigh the risks.
ABSTRACT
BackgroundThe presence of antiphospholipid antibodies (aPL) has been observed in patients with COVID-19 (1,2), suggesting that they may be associated with deep vein thrombosis, pulmonary embolism, or stroke in severe cases (3). Antiphospholipid syndrome (APS) is a systemic autoimmune disorder and the most common form of acquired thrombophilia globally. At least one clinical criterion, vascular thrombosis (arterial, venous or microthrombosis) or pregnancy morbidity and at least one laboratory criterion- positive aPL two times at least 12 weeks apart: lupus anticoagulant (LA), anticardiolipin (aCL), anti-β2-glycoprotein 1 (anti-β2GPI) antibody, have to be met for international APS classification criteria(4). Several reports also associate anti-phosphatidylserine/prothrombin antibodies (aPS/PT) with APS.ObjectivesTo combine clinical data on arterial/venous thrombosis and pregnancy complications before and during hospitalisation with aPL laboratory findings at 4 time points (hospital admission, worsening of COVID-19, hospital discharge, and follow-up) in patients with the most severe forms of COVID-19 infection.MethodsPatients with COVID-19 pneumonia were consequetively enrolled, as they were admitted to the General hospital Pancevo. Exclusion criteria were previous diagnosis of inflammatory rheumatic disease and diagnosis of APS. Clinical data were obtained from the medical records. Laboratory results, including LA, aCL, anti-β2GPI, and aPS/PT antibodies were taken at hospital admission, worsening (defined as cytokine storm, connection of the patient to the respirator, use of the anti-IL-6 drug- Tocilizumab), at hospital discharge and at 3-months follow-up and sent to University Medical Centre Ljubljana, Slovenia for analysis. Statistics was performed by using SPSS 21.Results111 patients with COVID-19 pneumonia were recruited;7 patients died during hospitalisation (none were aPL-positive on admission and at the time of worsening), 3 due to pulmonary artery embolism. All patients were treated according to a predefined protocol which included antibiotics, corticosteroids, anticoagulation therapy and specific comorbidity drugs;patients with hypoxia were supported with oxygen. During hospitalisation, pulmonary artery thrombosis occurred in 5 patients, one was aPL-positive at all time points (was diagnosed with APS), others were negative. In addition, 9/101 patients had a history of thrombosis (5 arterial thrombosis (coronary and cerebral arteries), none of whom was aPL-positive on admission and at follow-up, and 4 venous thrombosis, one of which was aPL-positive at all time points and received an APS diagnosis). Among 9/101 patients with a history of thrombosis, 55.6% were transiently positive at the time of discharge, compared to patients without prior thrombosis, in whom 26.1% were transiently positive at the hospital release (p=0.074). Two patients had a history of pregnancy complications (both had miscarriage after 10th week of gestation), but did not have aPL positivity at any time point.ConclusionAlthough aPL was expected to be associated with vascular disease in the most severe forms of COVID-19, all patients that have died in our cohort were aPL negative. At hospital discharge, 56% of patients with a history of arterial or venous thrombosis had positive aPL that became negative at the 3-months follow-up (were transienlty positive), which should be considered when prescribing therapy after hospitalisation.References[1]Trahtemberg U, Rottapel R, Dos Santos CC, et al. Anticardiolipin and other antiphospholipid antibodies in critically ill COVID-19 positive and negative patients. Annals of the Rheumatic Diseases 2021;80:1236-1240.[2]Stelzer M, Henes J, Saur S. The Role of Antiphospholipid Antibodies in COVID-19. Curr Rheumatol Rep. 2021;23(9):72-4.[3]Xie Y, Wang X, Yang P, Zhang S. COVID-19 complicated by acute pulmonary embolism. Radiology: Cardiothoracic Imaging 2020: 2: e200067.[4]Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, et al. J.Thromb.Haemost. 2006;4: 295-306.Acknowledgements:NIL.Disclosure of nterestsNone Declared.
ABSTRACT
Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy
ABSTRACT
Background/Objectives: The broad spectrum of clinical manifestations from SARS-COV-2 infection and observed risk factors for severe disease highlight the importance of understanding molecular mechanisms underlying SARS-CoV-2 associated disease pathogenesis. Research studies have identified a large number of host proteins that play roles in viral entry, innate immune response, or immune signalling during infection. The ability to interrogate subsets of these genes simultaneously within SARSCOV-2 infected samples is critical to understanding how their expression contribute to phenotypic variability of the disease caused by the pathogen. Method(s): 30 Nasopharyngeal swab were obtained and included SARS-CoV-2 infected and control samples. RNA was extracted, reverse transcribed and loaded onto flexible TaqMan array panels designed specifically for targeting the most cited genes related to SARS-COV-2 entry and restriction factors as well as cytokines, chemokines, and growth factors involved in the pathogenesis. Result(s): Our data indicated that not only were the levels of several of these host factors differentially modulated between the two study groups, but also that SARS-CoV-2 infected subjects presented with greater frequency of several important inflammatory cytokines and chemokines such as CCL2, CCL3, IFNG, entry receptors such as ACE2, TMRPS11A, and host restriction factors including LY6E and ZBP1. Conclusion(s): TaqMan array plates provide a fast, midthroughput solution to determine the levels of several virus and host-associated factors in various cell types and add to our understanding of how the pathogenesis may vary depending on gender, age, infection site etc.
ABSTRACT
Bivalent COVID-19 vaccines that contain two mRNAs encoding Wuhan-1 and Omicron BA.4/5 spike proteins are successful in preventing infection from the original strain and Omicron variants, but the quality of adaptive immune responses is still not well documented. This study aims at characterizing adaptive immune responses to the bivalent booster vaccination in 46 healthy participants. Plasma and PBMC were collected prior and three weeks after bivalent booster. We measured anti-N, anti-S, and RBD IgM, IgA, IgG plasma titers against original, Omicron BA.1, and BA.5 variants (pending) as well as total anti-S IgG titers and surrogate Virus Neutralization capacity against the Alpha, Delta, and BA.1 variant. With spectral flow-cytometry we identified peripheral blood B-cells specific for the RBD of the S-protein of the original and BA.1 variants. T-cell-specific responses were assessed by cytokine release assay after stimulation with SARS-CoV-2 peptides from the original, BA.1, BA.4, and BA.5 variants (pending). Finally, we performed TRB and IGH repertoire studies on sorted CD4+, CD8+, CD19+ lymphocytes, to study breadth of SARS-CoV-2 specific clonotypes (pending). 27/46 participants were analyzed;9 had SARS-CoV-2 infection (COVID+), while 18 are infection naive (COVID-). In both groups, median time since last dose of SARS-CoV-2 vaccine (3rd or 4th) was 11 months. All subjects were positive for anti-S IgG prior to bivalent booster. The COVID + group displayed anti-S IgG pre-booster levels and neutralization against BA.1 higher than the COVID- group. Significant increase post-boost of total anti-S IgG and BA.1 neutralizing activity was detected in the COVID- but not in the COVID+ group;however, no difference in neutralization activity post-boost was detected between the two groups. Furthermore, the COVIDgroup showed significant increase in the frequency of CD19+ and CD27+ switched memory B-cells specific for BA.1 RBD in post-boost compared to pre-boost samples. However, post-boost frequencies of the same B-cells were higher in the COVID+ compared to the COVID- group. These preliminary findings confirm that among individual immunized with the original COVID-19 mRNAvaccine, prior COVID infection provides increased protection against SARS-CoV-2 variants. They also demonstrate that booster immunization with the bivalent vaccine induces robust adaptive immune responses against Omicron variant.[Formula presented][Formula presented]Copyright © 2023 Elsevier Inc.
ABSTRACT
Background: High-titer neutralizing anti-cytokine autoantibodies have been shown to be involved in several acquired diseases, including pulmonary alveolar proteinosis, cryptococcal meningitis, and disseminated/extrapulmonary Nocardia infections (anti-GM-CSF autoantibodies), disseminated mycobacterial disease (anti-IFN-gamma autoantibodies), and some cases of severe COVID-19 infection (anti-type 1 interferons). Currently, patient blood samples are shipped via courier and require temperaturecontrolled conditions for transfer. This method is expensive and requires patients to have access to medical personnel to draw the blood. However, the well-established technique of collecting blood on a paper card as a dried blood spot (DBS) for diagnosis offers a point of care alternative which can be performed with a simple finger prick. This method is less invasive, cheaper, and allows for easy transport of patient samples. Method(s): 30 uL of whole blood from patients was blotted on filter paper and stored at 4C until use. The filter paper was hole punched and each punched spot was eluted with 150 uL of a 0.05% Tween PBS solution at room temperature overnight. The eluate was screened for anti-cytokine autoantibodies using a particle-based approach. Patient plasma was also screened in conjunction for comparison. Result(s): We confirmed the presence of autoantibodies in the DBS eluate from 4 previously diagnosed patients with anti-GM-CSF autoantibodies and 2 patients with anti-IFN-gamma autoantibodies. Functional studies showed the DBS eluate from a patient with anti-GM-CSF autoantibodies was able to block GM-CSF-induced STAT-5 phosphorylation in normal PBMC. As a proof of concept and to increase the number of patients evaluated, we also confirmed the presence of anti-cytokine autoantibodies using dried plasma eluate from 9 patients with known anti-GM-CSF autoantibodies and 9 patients with anti-IFN-gamma autoantibodies. Levels detected in DBS analyses were comparable to the levels found in plasma from the same patients not subjected to blotting and elution. Temperature studies showed that the autoantibodies were detected at similar levels when stored at 4C, 25C, and 40C for a week. Conclusion(s): The diagnosis of pathogenic anti-cytokine autoantibodies should be considered in the context of unusual or adult-onset infections, and screening for this diagnosis can be performed with dried blood spot testing.Copyright © 2023 Elsevier Inc.
ABSTRACT
Background: Nurses and other first responders are at high risk of exposure to the SARS-CoV2 virus, and many have developed severe COVID-19 infection. A better understanding of the factors that increase the risk of infection after exposure to the virus could help to address this. Although several risk factors such as obesity, diabetes, and hypertension have been associated with an increased risk of infection, many first responders develop severe COVID-19 without established risk factors. As inflammation and cytokine storm are the primary mechanisms in severe COVID-19, other factors that promote an inflammatory state could increase the risk of COVID-19 in exposed individuals. Alcohol misuse and shift work with subsequent misaligned circadian rhythms are known to promote a pro-inflammatory state and thus could increase susceptibility to COVID-19. To test this hypothesis, we conducted a prospective, cross-sectional observational survey-based study in nurses using the American Nursing Association network. Method(s): We used validated structured questionnaires to assess alcohol consumption (the Alcohol Use Disorders Identification Test) and circadian typology or chronotype (the Munich Chronotype Questionnaire Shift -MCTQ-Shift). Result(s): By latent class analysis (LCA), high-risk features of alcohol misuse were associated with a later chronotype, and binge drinking was greater in night shift workers. The night shift was associated with more than double the odds of COVID-19 infection of the standard shift (OR 2.67, 95% CI: 1.18 to 6.07). Binge drinkers had twice the odds of COVID-19 infection of those with low-risk features by LCA (OR: 2.08, 95% CI: 0.75 to 5.79). Conclusion(s): Working night shifts or binge drinking may be risk factors for COVID-19 infection among nurses. Understanding the mechanisms underlying these risk factors could help to mitigate the impact of COVID-19 on our at-risk healthcare workforce.Copyright © 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.
ABSTRACT
COVID-19 due to severe acute respiratory syndrome coronavirus 2, which has become a global pandemic, produces elevated liver enzymes, especially in severe cases. The mechanism suggests involvement of an administrated drug, cytokine storm, or hypoxia, etc., as opposed to virus-induced direct damage. If liver enzymes are elevated in COVID-19, we should evaluate for the presence of other liver diseases, and strictly follow-up liver enzyme values. In patients with COVID-19 complicated by chronic liver disease, we will use telemedicine/visits by phone, so as not to interrupt the treatment of the underlying disease, avoid unnecessary outpatient visits, and strive to halt the spread of the infection. Metabolism-associated fatty liver disease, which is often related to obesity, diabetes, and hypertension, may be a risk factor for COVID-19 severity. International academic societies have recommended guidance outlining the evidence to date regarding the management of patients with COVID-19 and liver disorders, and chronic liver disease under the COVID-19 pandemic.Copyright 2020 The Japan Society of Hepatology.
ABSTRACT
Background and Aim: It is important to understand how inflammation caused by COVID-19 affects patients and leads to more complications and diseases. According to the importance of controlling COVID-19 related complications, the current study was designed to evaluate the inflammation caused by COVID-19 and its related complications. Materials and Methods: The present study is a review study. Studies were retrieved from PubMed, Web of science, Scopus and Google scholar databases. Finally, according to the purpose of the study, the relevant resources were selected by the researchers and a summary of their results was presented in this study. Results: The present study showed that SARS-CoV-2 viruses enter their genome into the host cell after entering to the cell by the spike protein (S) and the important receptor of coronavirus, angiotensin converting enzyme 2 (ACE - 2), and causes the onset of cytokine storms and consequently increase of primary cytokines involved in inflammation. IL-6, IL-8, TNF-α and IL-1 cytokines are key factors;These factors in turn activate macrophages, dendritic cells (DC) and other immune cells. Studies revealed that the inflammation caused by SARS-CoV-2 in the liver by inducing IL-6 activates the JAKs/STAT3 pathway, whose receptor is only found in the liver and immune cells, and causes cytokine release syndrome. Cytokines also cause the release of reactive oxygen species (ROS), superoxide anion, and nitric oxide, so that all of them can damage myocardial cells and cause insulin resistance and diabetes. In addition, the increase of inflammatory cytokines such as IL4, IL10 and IL6 and immune cells lead to cardiac disorders such as arrhythmia. The entry of the virus into the digestive system reduces the bacteria secreting butyrate (with anti-inflammatory effects) and leads to the induction of severe inflammation. Also, corona virus causes obsessive compulsive disorder, depression and other neurological disorders by increasing pro-inflammatory cytokines and increasing the activity of indoleamine 2,3 dioxygenase (IDO). Conclusion: Studies have shown that the inflammation caused by COVID-19 plays an important role in the development of the related complications such as disorders in the digestive, hepatic, cardiac, neurologic, pancreas systems and other organs. Therefore, targeting cytokines can potentially improve survival and reduce mortality. © 2022 the Authors. Published by Tehran University of Medical Sciences.
ABSTRACT
Introduction: Combination of daratumumab (Dara) and lenalidomide (Len) may enhance the function of teclistamab (Tec), potentially resulting in improved antimyeloma activity in a broader population. We present initial safety and efficacy data of Tec-Dara- Len combination in patients with multiple myeloma (MM) in a phase 1b study (MajesTEC-2;NCT04722146). Method(s): Eligible patients who received 1-3 prior lines of therapy (LOT), including a proteasome inhibitor and immune-modulatory drug, were given weekly doses of Tec (0.72-or- 1.5 mg/kg with step-up dosing) + Dara 1800 mg + Len 25 mg. Responses per International Myeloma Working Group criteria, adverse events (Aes) per CTCAE v5.0, and for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT guidelines, were assessed. Result(s): 32 patients received Tec-Dara- Len (0.72 mg/kg, n = 13;1.5 mg/kg, n = 19). At data cut-off (11 July 2022), median follow-up (range) was 5.78 months (1.0-10.4) and median treatment duration was 4.98 months (0.10-10.35). Median age was 62 years (38-75);87.5% were male. Median prior LOT was 2 (1-3), 18.8% were refractory to Dara and 28.1% refractory to Len. CRS was most frequent AE (81.3% [n = 26], all grade 1/2), 95% occurred during cycle1. Median time to onset was 2 days (1-8), median duration was 2 days (1-22). No ICANS were reported. Frequent Aes (>=25.0% across both dose levels) were neutropenia (75.0% [n = 24];grade 3/4: 68.8% [n = 22]), fatigue (43.8% [n = 14];grade 3/4: 6.3% [n = 2]), diarrhoea (37.5% [n = 12];all grade 1/2), insomnia (31.3% [n = 10];grade 3/4: 3.1% [n = 1]), cough (28.1% [n = 9];all grade 1/2), hypophosphatemia (25.0% [n = 8];all grade 1/2), and pyrexia (25% [n = 8];grade 3/4: 6.3% [n = 2]). Febrile neutropenia frequency was 12.5% (n = 4). Infections occurred in 24 patients (75.0%;grade 3/4: 28.1% [n = 9]). Most common were upper respiratory infection (21.9% [n = 7]), COVID-19 (21.9% [n = 7]), and pneumonia (21.9% [n = 7]). Three (9.4%) had COVID-19 pneumonia. One (3.1%) discontinued due to COVID-19 infection and this patient subsequently died of this infection. Overall response rate (ORR, median follow-up) was 13/13 (8.61 months) at 0.72 mg/kg and 13/16 evaluable patients (less mature at 4.17 months) at 1.5 mg/kg. 12 patients attained very good/better partial response at 0.72 mg/kg dose, and response was not mature for 1.5 mg/kg group. Median time to first response was 1.0 month (0.7-2.0). Preliminary pharmacokinetic concentrations of Tec-Dara- Len were similar as seen with Tec monotherapy. Tec-Dara- Len- treatment led to proinflammatory cytokine production and T-cell activation. Conclusion(s): The combination of Tec-Dara- Len has no new safety signals beyond those seen with Tec or Dara-Len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of Tec. These data warrant further investigation.
ABSTRACT
Introduction: Mastocytosis encompasses a heterogeneous group of diseases characterized by an accumulation of clonal mast cells (MC) in the skin and/or internal organs, and symptoms of MC activation. This MC activation can be elucidated by several factors, including infections or vaccination. Objective(s): We present our experience with COVID infection and vaccination in a series of 133 patients with pediatric mastocytosis. Method(s): Between January 1998 and December 2022, 133 pediatric patients have been referred to our hospital owing to clinically suspected MC disorder, mainly with mastocytosis in the skin. The final diagnoses of mastocytosis were established by the presence of typical skin lesions together with an increase of MC numbers in a biopsy from lesional skin or activating KIT mutations in lesional skin tissue. Serum baseline tryptase and total immunoglobulin E levels were measured, and patients underwent a comprehensive allergy workup to confirm atopic status and history of anaphylaxis. Regarding vaccination, REMA's (Spanish Network on Mastocytosis) protocol was followed. Result(s): 13 patients with COVID infection were identified, of which 25 (56,8%) were female and 0% had symptoms of MC activation. All of them had an asymptomatic or mild course of COVID infection. None of the patients experimented MC activation symptoms during viral illness. Regarding COVID vaccination, all patients received premedication with antihistamine 60 minutes prior vaccination. No one experimented immediate reactions and only one patient (0,75%) referred worsening of MC activation symptoms (baseline pruritus, urtication and brain fog) only after the first doses, recovering without changes in his treatment (oral cromoglycate and antihistamine) in two months. Discussion(s): Although MC have been implicated in the pathogenesis of cytokine storm in COVID19, there is no clinical evidence of SARSCoV- 2-induced MC activation, perhaps related to the fact that bone marrow MC lack angiotensin-converting enzyme 2 receptors.
ABSTRACT
Red bone marrow samples investigation in deceased COVID-19 patients enabled to identify the phenomena of secondary hemophagocytosis. Analysis of the data showed that phagocytic reactions during infection of patients with SARS-CoV-2 are manifested both in relation to erythrocytes and leukocytes. The data obtained make it possible to expand the strategy of therapeutic measures, taking into account the new data on the mechanisms of the pathogenesis of COVID-19 in severe viral infection based on morphological findings and additional information on the involvement of young erythrocytes and lymphocytes in the structure of the red bone marrow in the cascade of pathological reactions. The results obtained confirm a wide range of aggressive damaging effects of SARS-CoV-2 in the development of multiple organ failure against the background of COVID-19 and the involvement of the red bone marrow in the pathological process. The authors supplemented information about the mechanisms of hypoxia in COVID-19, which is not only a consequence of damage to the respiratory epithelium, but also the result of damage to erythrocyte differons both at the level of red bone marrow and in peripheral blood. This fact must be taken into account in the development of a treatment strategy and in the creation of new drugs for the treatment of infected patients with various strains of SARS-CoV-2.
ABSTRACT
Background: Several pro- and anti-inflammatory cytokines involved in COVID-19 and it is reasonable to speculate that their removal from blood might limit organ damage. Hemoperfusion with CytoSorb is a technique developed to adsorb molecules in the middle molecular weight range (up to 55 kDa). Studies in vitro and in vivo have shown that HP is highly effective in clearing blood from a number of cytokines. Method(s): We report a case series of 9 consecutive COVID-patients admitted to our COVID Intensive Care Unit (ICU). Five of them were treated with HP using CytoSorb (T), due to the heavy emergency overload it was impossible to deliver blood purification in the other 4 patients (C), who were also considered as potential candidates by the attending medical team. All patients had pneumonia and respiratory failure requiring continuous positive airway pressure. Different antibacterial prophylaxes, antiviral, and anti-inflammatory therapies including steroids were delivered. Result(s): Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. CRP decreased in both groups, but to a greater extent after HP. Lymphocytopenia worsened in control patient but not in treated patient after HP. Procalcitonin increased in 2 of the not treated patients. In all survived patients (n = 4) HP reduced pro-inflammatory cytokines, as IL-6, TNF-alpha, and IL-8. Notably, a striking effect was observed on IL-6 levels that at the end of the second session were decreased by a 40% than before the first treatment. Serum levels of IL-8 and TNF-alpha were lowered within normal range. In all patients the treatment was safe and there were no complications. Conclusion(s): Our study suggests a potential efficacy of HP in an early phase of viral infection not only for improving survival in the treated patients but also by the remodeling treatment-associated cytokine levels.
ABSTRACT
Background: Tocilizumab, an interleukin-6 (IL-6) antagonist, is being evaluated for the management of covid-19 pneumonia. The objective of this study was to assess the effectiveness of Tocilizumab in severe covid-19 pneumonia. Method(s): This was a retrospective, observational, single centre study performed in 121 patients diagnosed with severe covid-19 pneumonia. 83 patients received standard of care treatment whereas 38 patients received tocilizumab along with standard of care. Tocilizumab was administered intravenously at 8mg/kg (upto a maximum of 800mg). The second dose of Tocilizumab was given 12 to 24 hours apart. The primary outcome measure was ICU related and hospital related mortality. The secondary outcome measures were change in clinical status of patients measured by WHO (World Health Organisation) 7 category ordinary scale, changes in interleukin-6 (IL-6) levels, secondary infections and duration of ICU stay. Result(s): Tocilizumab was administered between 3-27 days after the patient reported symptoms ( a median of 10.9 days ) and between the 1st to 3rd day of ICU admission (median of 2.1 days) . In Tocilizumab group, 16(42.1%) of 38 patients died in ICU whereas in standard of care group, 27(32.53%) of 83 patients died. The difference in clinical status assessed using WHO (World Health Organisation) 7 category ordinary scale at 28 days between Tocilizumab group and standard of care group was not statistically significant (odds ratio 1.35, 95% confidence interval 0.61 to 2.97, p = 0.44). Conclusion(s): Tocilizumab plus standard care was not superior to standard care alone in reducing mortality and improving clinical outcomes at day 28.Copyright © RJPT All right reserved.
ABSTRACT
Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.
ABSTRACT
Several studies have suggested that "cytokine storms" are significant causes of the severity of COVID-19. Controlling and inhibiting the cytokine storm in COVID-19 could prevent the spread of COVID-19 and saves patient lives. Soybean (Glycine max L.) is known to have various biological activities. This study aims to examine bioactive compounds in SSE and the effect of SSE on the ARDS rats model. A total of 25 Sprague Dawley Lipopolysaccharide-induced rats were used. Determination of serum IL-1β, IL-12, and lung TNF-α levels was performed by ELISA method. NF-κB and IFN-γ expression were determined by the qRTPCR method. IL-6 expressions were analyzed by immunohistochemistry assay. The bleeding, inflammation, and alveolus collapse score were analyzed using the HE staining method. The results showed that SSE could decrease the level of IL-1β, IL-12, TNF-α, IL-6, NF-kB, and IFN-γ and improve the bleeding, inflammation, and alveolus score in the lung. SSE could decrease the pro-inflammatory cytokines and improve lung condition in ARDS rats model. © 2023, Bogor Agricultural University. All rights reserved.
ABSTRACT
This study systematically review knowledge about the mechanisms of formation of an inflammatory reaction under the influence of biological, physical, and chemical factors, their similarities and differences, and possible methods of pharmacological correction of pathological conditions associated with excessive activation. The effect of adverse environmental factors, such as biological, physical, and chemical factors, causes a systemic response, which is aimed at maintaining homeostasis and is caused, among other things, by a coordinated reaction of the immune system. Phlogogenic agents result in the activation and regulation of the inflammatory response, which is formed by cellular and humoral components of innate immunity. The activation of innate immunity is characterized by a rapid host response, which diminishes following the elimination of "foreign” invaders, endogenous killer cells, and neogenesis. Depending on the nature of the active factors (biopathogens, allergens, toxins, ionizing radiation, etc.), the mechanisms of immune response arousal have unique features mainly originating from the differences in the recognition of specific molecular patterns and "danger signals” by different receptors. However, inflammatory mediators and inflammatory response patterns at the systemic level are largely similar even under widely different triggers. Inflammation, having evolved as an adaptive reaction directed at the immune response, can lead to the development of chronic inflammation and autoimmune diseases due to a mismatch in mechanisms of its control. A "failure” in the regulation of the inflammatory process is the excessive activation of the immune system, which leads to the cytokine release syndrome (hypercytokinemia, or "cytokine storm”) and can cause self-damage (destruction) of tissues, multiple-organ failure, sepsis, and even death. Modern advances in the study of the pathogenetic bases of the inflammatory response are suggested, such as pharmacological correction using pattern recognition receptor antagonists, pro-inflammatory cytokine inhibitors, or blocking of key control genes or signaling pathways. All rights reserved © Eco-Vector, 2022.
ABSTRACT
In addition to the classical functions of the musculoskeletal system and calcium homeostasis, the function of vitamin D as an immune modulator is well established. The vitamin D receptors and enzymes that metabolize vitamin D are ubiquitously expressed in most cells in the body, including T and B lymphocytes, antigen-presenting cells, monocytes, macrophages and natural killer cells that trigger immune and antimicrobial responses. Many in vitro and in vivo studies revealed that vitamin D promotes tolerogenic immunological action and immune modulation. Vitamin D adequacy positively influences the expression and release of antimicrobial peptides, such as cathelicidin, defensin, and anti-inflammatory cytokines, and reduces the expression of proinflammatory cytokines. Evidence suggestss that vitamin D's protective immunogenic actions reduce the risk, complications, and death from COVID-19. On the contrary, vitamin D deficiency worsened the clinical outcomes of viral respiratory diseases and the COVID-19-related cytokine storm, acute respiratory distress syndrome, and death. The study revealed the need for more preclinical studies and focused on well-designed clinical trials with adequate sizes to understand the role of vitamin D on the pathophysiology of immune disorders and mechanisms of subduing microbial infections, including COVID-19.Copyright © 2023 Bentham Science Publishers.
ABSTRACT
Introduction: Critical care patients commonly have disrupted sleep patterns, with reduction of REM sleep, duration of sleep, increased fragmentation and loss of circadian rhythm.1 Causes include the patients' pathophysiology, medications administered and the busy critical care environment. Data collection showed that our patients were sleeping, on average, for a single block of sleep of 3.5 hours. Delirium rates and its known deleterious effects are highly associated with poor sleep, as well as an impairment of psychomotor performance and neurocognitive dysfunction. Sleep deprivation in the healthy population impairs lymphocyte action, cytokine production and pro-inflammatory balance, as well as a reduction in respiratory function and prolongation of respiratory support.2 Objectives: To firstly measure the sleep quality and explore the reasons behind poor sleep from the patients themselves and to gauge the MDT knowledge and interest in sleep, as a fundamental component of patient management. Then using the results we aimed to improve the duration and quality of the patients sleep on high dependency unit. Method(s): The Adapted Richard Campbell Sleep Questionnaire was given to all patients in the HDU over a 4 week period. Results were analysed, then stored for post intervention comparison. The duration of sleep was documented for all patients and a staff questionnaire was done to assess knowledge and concern of staff. Interventions included a staff sleep awareness week with education and prompts attached to the charting tables promoting sleep. Face masks and ear plugs were freely available to be distributed at the evening ward round. The critical care pharmacist identified medications that could alter the patients ability to achieve REM sleep - e.g. evening administered PPIs, and melatonin was commenced early when sleep was troublesome. Estates fixed soft close doors and soft closed bins supplied for clinical areas. After interventions, there was a further 4 week study period where the above factors were repeated. The need for natural light was highlighted and thus this was optimized in the ward environment and those physiologically able were offered trips outdoors to facilitate normal day night wake cycle. With the COVID pandemic ongoing we also endeavored to limit movement overnight of venerable patients. Result(s): The original data collection was of 45 patients with multiple data points, and the second of 27 patients with multiple data points. Results from the Adapted Richard Campbell Sleep Questionnaire were compared using a one tailed students t test. There were significant increases in the subjective quality of sleep (p=0.046) and quantity of sleep (p=0.00018). Reasons given as to improvement of sleep were reduction in discomfort from monitoring and the bed (p=0.026), reduced ambient light (p=0.031) and reduced impact from the presence of other patients (p=0.002). Conclusion(s): There was marked improvement in the awareness of the importance of sleep within the critical care team after education promoting a change in attitude and culture towards sleep. We are planning a second iteration targeting sedation, noise from monitors and staff and overnight interventions. Although this has been done with level 2 patients, extension to level 3 areas would be beneficial.
ABSTRACT
RAG mutations cause various phenotypes: SCID, Omenn syndrome (OS), leaky SCID (LS) and combined immunodeficiency (CID). We had previously reported autoantibodies targeting IFN-alpha, IFN-omega in patients with RAG deficiency. However, how the presence of such antibodies correlated with the severity of the clinical phenotype and with the recombination activity of the mutant proteins was unknown. To address this, we have studied anti-cytokine antibodies in 118 patients with RAG defects (SCID, n = 28;OS, n = 29;LS, n = 29;CID, n = 32), and in 42 controls (protocols NCT03394053 and NCT03610802). RAG mutant proteins associated with CID and LS retained 35.6 +/- 4.3 (mean +/- SE) and 29.8 +/- 5.1% recombination activity respectively, compared to wildtype protein, which was significantly higher than the recombination activity of the mutant RAG proteins associated with OS (4.1 +/- 1.5%) and SCID (5.7 +/- 2.1%) (p < 0.0001). Among 32 CID patients, 24 tested positive for anti-IFN-alpha and 21 for anti-IFN-omega antibodies. Among 29 LS patients, 15 had high levels of anti-IFN-alpha and 13 of anti-IFN-omega antibodies. A minority of the CID and LS patients had also high levels of anti-IFN-beta and anti-IL-22 antibodies. By contrast, none of the OS patients tested positive for anti-cytokine antibodies. High levels of anti-IFN-alpha and anti-IFN-omega antibodies correlated with their neutralizing activity as demonstrated in vitro by analysis of STAT1 phosphorylation upon stimulation of healthy donor monocytes in the presence of the appropriate cytokine and patient's or control plasma. Severe viral infections were recorded in 26/41 patients with CID and LS who tested positive and in 7/20 who tested negative for anti-IFN-alpha and/or anti-IFN-omega antibodies (p <0.05). Among those with anti-IFN antibodies, EBV (n = 8), CMV (n = 6), HSV (n = 5), VZV (n = 4) and adenovirus (n = 4) infections were more common. Two patients had COVID-19, which was fatal in one. Presence of the rubella virus was documented in 5 patients with anti-type I IFN antibodies. These results demonstrate that high levels of neutralizing anti-IFN-alpha and anti-IFN-omega antibodies are common in patients with RAG mutations manifesting as CID and LS, but not in those with OS, and that their presence is associated with a high risk of serious viral infections.Copyright © 2023 Elsevier Inc.