Immune System Development Processes with Special Emphasis on Relationship to Potential Mechanisms of MIS-C

Development of the mammalian immune system requires the intersection of myriad internal and external signals, from the migration of pluripotent stem cells to interactions with the vaginal microbiome during partuition to environmental factors that shape immune processes throughout life. Because the sequence of immune developmental events is fairly transcripted across time, multiple windows of susceptibility exist that can lead to immune dysfunction when these developmental events are perturbed. Additionally, early-life immune dysfunction can persist, leading to increased disease risk across the lifespan. Immune dysfunction can present functionally as suppression, hyperresponsivity, or inappropriate inflammation and molecularly, may involve multiple cells and signaling pathways. Thus, scenarios that lead to multisystem inflammatory syndrome in children (MIS-C) can be complex and multifaceted. This presentation will consider windows of susceptibility as well as external factors that may increase the risk of MIS-C.

PSYCHOLOGICAL DISTRESS OVER 12 MONTHS POST-DIAGNOSIS IN A NATIONAL EARLY INFLAMMATORY ARTHRITIS COHORT

BackgroundIn inflammatory arthritis patients, the concomitant decline of their mental wellbeing is an increasing concern[1,2]. It is important to not only describe the trajectory of psychological distress in early disease stages, but also understand which clinical outcome measures are most associated with these changes.ObjectivesUsing data from the National Early Inflammatory Arthritis Audit (NEIAA), we assessed trends in psychological wellbeing over 12 months after initial diagnosis and mapped these against clinical outcomes to identify significant associations.MethodsNEIAA collects data from patients referred with suspected early inflammatory arthritis in rheumatology services in England and Wales. We used data provided by 20,472 patients eligible for follow-up (diagnosis of inflammatory arthritis) between May 1st, 2018, and April 1st, 2022. Data items included baseline demographics e.g., age and gender, and clinical variables e.g., rheumatic disease comorbidity index (RDCI), DAS28, and patient reported outcomes.Psychological distress was measured by the sum score of Patient Health Questionnaire Anxiety and Depression Screener (PHQ4ADS). Using mixed effects regression models, we analysed the co-variability of PHQ4ADS with demographic factors and clinical outcomes over 12 months. Time was included as a dummy-coded covariant.ResultsThe analysis included 36% of patients (7,378 out of 20,472) who completed the baseline patient outcome survey. In this cohort, PHQ4ADS scores decreased from a baseline average of 4.7 (CI: [4.6, 4.8]) to 2.62 (CI: [2.5, 2.8]) at 12 months post-diagnosis. The proportion of patients screening positive decreased from 50.0% (CI: [48.9, 51.1]) at baseline to 23.8% (CI: [21.8, 25.9]) at 12 months.At baseline, psychological distress correlated significantly with age, gender, ethnicity, RDCI, prior depression diagnosis, and baseline DAS28 (Figure 1). No significant correlations were found between psychological distress and working diagnosis, seropositivity, or the assessment being recorded after the start of the COVID-19 pandemic. Younger ages were nonlinearly associated with higher distress levels (coefficient per decade: -0.006;p<0.001;CI: [-0.009, -0.003]) (Figure 1a). Distress levels in females were higher than that of males (coefficient: 0.5;p<0.001;CI: [0.4, 0.7]) (Figure 1b). White patients reported lower PHQ4ADS scores compared to non-white patients (coefficient: -0.7;p<0.001;CI: [-1.0, -0.4]) (Figure 1c). Higher distress levels were also associated with higher RDCI (coefficient: 0.2;p<0.001;CI: [0.1, 0.3]) and prior diagnosis of depression (coefficient: 1.8;p<0.001;CI: [1.5, 2.2]) (Figure 1d, 1e). Furthermore, higher baseline DAS28 scores correlated with more severe psychological distress (coefficient: 0.8;p<0.001;CI: [0.7, 0.8]) (Figure 1f).By 12-months, psychological distress decreased significantly overall, which correlated significantly with ethnicity (coefficient: 0.8;p=0.005;CI: [0.3, 1.4]) and baseline DAS28 (coefficient: -0.5;p<0.001;CI: [-0.6, -0.4]). Compared to white patients, the reduction was significantly greater for non-white patients, but the level of distress was no longer different at 12 months (Figure 1c). While those with higher baseline DAS28 showed a greater reduction in psychological distress, the distress levels remained higher at 12 months (Figure 1f).Figure 1.Changes in psychological distress correlated with age, gender, ethnicity, RDCI, prior depression diagnosis, and baseline DAS28.[Figure omitted. See PDF]ConclusionIn this early inflammatory arthritis cohort, mental health burden was high. Age, gender, ethnicity, RDCI, prior depression diagnosis and baseline DAS28 significantly correlated with psychological distress at baseline. Supporting mental health should be a focus of clinical care for this population and it may be beneficial to use an approach that is culturally valid for non-white patients and accounts for multimorbidity.References[1]Euesden, J, et al. Psychosomatic medicine 79.6 (2017): 638.[2]Lwin, MN, et al. Rheumatology and therapy 7.3 (2020): 457-471.AcknowledgementsThe authors would like to thank the Healthcare Quality Improvement Partnership (HQIP) as the commisioner of NEIAA, British Society for Rheumatology as the audit providers, Net Solving as the audit platform developers, and the Wellcome Trust (ST12406) for funding to support L.Z..Disclosure of InterestsLucy Zhao: None declared, James Galloway Speakers bureau: Has received honoraria from AbbVie Celgene, Chugai, Gillead, Janssen, Eli Lilly, Pfizer, Roche, and UCB, Jo Ledingham: None declared, Sarah Gallagher: None declared, Neena Garnavos: None declared, Paul Amlani-Hatcher: None declared, Nicky Wilson: None declared, Lewis Carpenter Consultant of: Statistical consultancy for Pfizer, Kirsty Bannister: None declared, Sam Norton Speakers bureau: Has received honoraria from Janssen and Pfizer.

Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

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

Sometimes Late Is Better Than Never: Implantation of a Cardioverter Defibrillator Years after an Acute Myocardial Infarction - Case Report

Sustained ventricular arrhythmias that occur early post-myocardial infarction (MI) are generally considered epiphenomena of the MI and are not consistently associated with long-term prognosis. The lack of association with long-term prognosis is more clearly established for early ventricular fibrillation (VF) and polymorphic ventricular tachycardia (PVT). Sustained monomorphic ventricular tachycardia (SMVT), even when it occurs early, however, may reflect a permanent arrhythmic substrate1. Patients with COVID-19 have a high risk of thromboembolic events, and the virus has also been shown to have extensive effects on the cardiovascular system2,3,4. A 62-year-old woman, recently hospitalized for COVID-19 pneumonia, was brought to the emergency department with pulseless SMVT having been successfully resuscitated in the prehospital setting. The patient has a history of an old MI treated with thrombolysis and percutaneous coronary intervention (PCI) that was complicated with early SMVT, but with preserved left ventricular function and without heart failure. The patient underwent implantation of a cardioverter defibrillator (ICD). During the hospitalization, she developed dyspnea and was diagnosed with minor pulmonary embolism. It may be appropriate to consider early SMVT as a predictor of adverse late outcomes that would necessitate rigorous follow-up and maybe an early invasive primary prevention strategy. This case also reflects the possibility of long-term cardiac involvement and increased thromboembolic risk in patients recovering from COVID-19. © 2022 Maria Zamfirescu et al., published by Sciendo.

Assessment of biventricular myocardial systolic function in COVID-19 patients: A Tissue Doppler Imaging echocardiography study

Background: The 2019 novel coronavirus disease (COVID-19) has been reported as pandemy and the number of patients continues to rise. Based on recent data, cardiac injury is a prominent feature of the disease, leading to increased morbidity and mortality. In the present study we aimed to evaluate myocardial dysfunction using transthoracic echocardiography (TTE) and tissue Doppler imaging (TDI) in hospitalized COVID-19 patients. Methods and Results: We recruited 30 patients (56.7% male, 55.80 +/- 14.949 years) who were hospitalized with the diagnosis COVID-19 infection. We analyzed left ventricular (LV) and right ventricular (RV) conventional and TDI parameters at the time of hospitalization and during the course of the disease. Patients without any cardiac disease and with preserved LV ejection fraction (EF) were included. TTE examination was performed and all the variables were recorded and analyzed retrospectively. We observed that both LV and RV conventional echocardiographic parameters were similar when the day of admission to the hospital was compared to the 5th day of the disease. Regarding TDI analysis, we demonstrated significant impairment in LV septal and lateral deformation (P < 0.001). In the correlation analysis no marked correlation was observed between impairment in LV deformation and inflammation biomarkers. Conclusion(s): Cardiac involvement is an important feature of the COVID-19 infection but the exact mechanism is still undefined. Echocardiography is an essential technique to describe myocardial injury and provide new concepts for the possible definitions of cardiac dysfunction.Copyright © 2023 The Author(s).

Progress in understanding the health promoting effect of egg yolk immunoglobulin

As an important immuneoactive component in eggs, yolk immunoglobulin (IgY) shows great competitiveness in research and production due to its good stability, high safety, low cost, easy availability, strong immune activity, and no drug resistance. This article highlights the significant advantages of IgY as a good antibiotic substitute in the prevention and treatment of viral and bacterial diseases. Also, IgY has great potential in the regulation of nutrient metabolism balance, intestinal microflora and immune homeostasis by affecting key rate-limiting enzymes, and relevant receptors and inflammatory factors specifically. Proper diet and targeted delivery of foodborne IgY may be a new perspective on inflammation regulation, disease control, nutritional balance or homeostasis, and oral microencapsulated IgY is expected to be a new approach against increasing public health emergencies (such as COVID-19 pandemic).

THE KINETICS OF HUMORAL AND CELLULAR RESPONSES AFTER THE BOOSTER DOSE OF COVID-19 VACCINE IN INFLAMMATORY ARTHRITIS PATIENTS

BackgroundImpaired immunogenicity of COVID-19 vaccinations in inflammatory arthritis (IA) patients results in diminished immunity. However, optimal booster vaccination regimens are still unknown, due to unstudied kinetics of the immune response after booster vaccinations.ObjectivesThis study aimed to assess the kinetics of humoral and cellular responses in IA patients after the COVID-19 booster.MethodsIn 29 IA patients and 16 healthy controls (HC) humoral responses (level of IgG antibodies) and cellular responses (IFN-γ production) were assessed before (T0), after 4 weeks (T1), and after more than 6 months (T2) from the booster vaccination with BNT162b2.ResultsIA patients, but not HC, showed lower anti-S-IgG concentration and IGRA fold change at T2 compared to T1 (p=0.026 and p=0.031). Furthermore, in IA patients the level of cellular response at T2 returned to the pre-booster level (T0). All immunomodulatory drugs, except IL-6 and IL-17 inhibitors for the humoral and IL-17 inhibitors for the cellular response, impaired the immunogenicity of the booster dose at T2. However, none of the immunomodulatory drugs affected the kinetics of both humoral and cellular responses (measured as the difference between response rates at T1 and T2).ConclusionOur study showed impaired kinetics of both humoral and cellular responses after the booster dose of the COVID-19 vaccine in IA patients, which, in the case of cellular response, did not allow the vaccination effect to be maintained for more than 6 months. Repetitive vaccination with subsequent booster doses seems to be necessary for IA patients.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Refractory circulatory failure in COVID-19 patients treated with veno-arterial ECMO: A retrospective single-center experience

Objectives: Data about COVID-19 patients treated with veno-arterial-ECMO (VA-ECMO) is limited. Reported survival rates range from 27.9% to 77.8%, depending on VA-ECMO indication. A subgroup of patients suffers from circulatory failure due to a COVID-19 associated hyperinflammatory state (CovHI). In these patients, differentiation between inflammation and sepsis is difficult but important. In this retrospective case series, differential diagnoses of COVID-19 associated refractory circulatory failure and survival rates in different indications for VA-ECMO are investigated. Method(s): Retrospective analysis of 28 consecutive COVID-19 patients requiring VA-ECMO at the University Hospital Regensburg between March 2020 and May 2022. Specific treatment for COVID-19 was in accordance with respective guidelines. Mycotic infections were either invasive or met current definitions of COVID19-associated-pulmonary aspergillosis. Result(s): At VA-ECMO initiation, median age was 57.3 years (IQR: 51.4 - 61.8), SOFA score 16 (IQR: 13 - 17) and norepinephrine dosing 0.53mug/kg/min (IQR: 0.32 - 0.78). Virus-variants were: 61% wild-type, 14% Alpha, 18% Delta and 7% Omicron. Survival to hospital discharge was 39%. 17 patients were primarily supported with VA-ECMO only (survival 42%), 3 patients were switched from VV to VA-ECMO (survival 0%), and 8 patients were converted from VA to VAV or VV-ECMO (survival 50%). Indications for VA-ECMO support were pulmonary embolism (PE) (n=5, survival 80%), right heart failure due to secondary pulmonary hypertension (n=5, survival 20%), cardiac arrest (n=4, survival 25%), acute left heart failure (ALHF) (n=11, survival 36%) and refractory vasoplegia (n=3, survival 0%). Inflammatory markers at VA-ECMO initiation were higher in patients with ALHF or vasoplegia;in these patients a higher rate of invasive fungal infections (10/14, 71% vs. 4/14, 29%;p=0.023) compared to the other patients was found. Conclusion(s): Survival on VA-ECMO in COVID-19 depends on VA-ECMO indication, which should be considered in further studies and clinical decisions making. Circulatory failure due to vasoplegia should be considered very carefully as indication for VA-ECMO. A high rate of mycotic infections mandates an intense microbiological workup of these patients and must be considered as an important differential diagnosis to CovHI.

ANTI-TNF TREATMENT MODIFIES PAIN MODULATION DESCENDING PATHWAYS. A PROSPECTIVE, 6 MONTHS STUDY IN ACTIVE CHRONIC INFLAMMATORY RHEUMATISM PATIENTS' NAÏVE OF BDMARD

BackgroundIn rheumatoid arthritis (RA) and spondyloarthritis (Spa), persistent pain remains challenging. In active disease, diffuse noxious inhibitory controls (assessed through conditioned pain modulation (CPM)) are impaired [1]. Little is known regarding impairment of pain pathways in patients under bMDARD.ObjectivesThe main objective of the RAPID (Rheumatism Pain Inhibitory Descending pathways) study, was to assess descending pain modulation (through CPM paradigm) in patients with active RA or Spa, after introduction of first bDMARD with anti-TNF.MethodsWe included 50 RA and 50 Spa patients with active disease, naïve of bDMARD. We assessed clinical disease variables for patients, together with responses to various psychological questionnaires. All participants underwent QST with the determination of heat and cold pain thresholds (HPT-CPT) on dominant forearm and CPM. CPM paradigm require a conditioning stimulus, here applied to the non-dominant foot (cold circulating bath at 8°C during 1min). Descending pain control was assessed as the change in HPT (in °C) following the conditioning stimulus: the higher the CPM effect, the more efficient the inhibitory control. Patients were followed at 3 and 6 months after TNF inhibitor initiation. At both follow-up visits, clinical monitoring of the rheumatism and repeated thermal QST and CPM.ResultsOne hundred patients were included, 59 women, mean age 45.8 (± 14.6) and mean disease duration 7.93 (± 7.96) years. Due to COVID surge 87 patients initiated an anti-TNF, 74 patients completed the follow-up. At 6 months, 40 patients achieved a good therapeutic response (good EULAR response or ASDAS major improvement), 19 patients had a moderate therapeutic response (moderate EULAR response or clinically important improvement) and 15 patients had no therapeutic response. At the end of follow-up, 51 patients were in remission or low disease activity and 47 patients had a pain intensity <4/10. Thermal pain thresholds did not significantly change during follow-up. Mean HPT was at beaseline 42.35°C (+/- 3.68) and at 6 months 42.17°C (+/- 3.67). Mean CPT was at baseline 13.11°C (+/- 10.04) and at 6 months 12.86°C (+/- 9.45). Conditioned pain modulation was significantly changed during follow-up. Mean CPM effect was at baseline 0.25°C (±2.57), 2.64°C (±2.12) at 3 months and 2.96°C (±2.50) at 6 months. At the end of the 6 months follow-up, mean CPM effect was significantly higher in patients with residual mean pain intensity <4/10 compared to patients with persisting pain ≥ 4/10: 3,25°C (± 2,68) vs 2,47 (± 2,11) (p=0.04).ConclusionAfter TNF inhibitor initiation in active RA or SpA, impaired diffuse noxious inhibitory controls are significantly improved. Apart from their articular efficacy, TNF inhibitor have an action on the central nervous system and pain modulation pathways. In patients with persisting pain under bDMARD, diffuse noxious inhibitory controls are not as efficient as patient without residual pain.Reference[1]Trouvin AP, Simunek A, Coste J, Medkour T, Carvès S, Bouhassira D, Perrot S. Mechanisms of chronic pain in inflammatory rheumatism: the role of descending modulation. Pain. 2022 Aug 3. doi: 10.1097/j.pain.0000000000002745.Figure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Factors affecting disease severity of multisystem inflammatory syndrome in children

Purpose: Multisystem inflammatory syndrome that occurs after SARS-Cov-2 infection with fever, cardiogenic shock and hyperinflammation in children, can be life threatening. In this study, it was aimed to investigate the effects of the complaint and duration at diagnosis on the severity of multisystem inflammatory syndrome in children. Materials and methods: The medical records of 99 pediatric patients, who were diagnosed multisystem inflammatory syndrome between September 2020 and August 2021 according to Centers for Disease Control and Prevention, were evaluated retrospectively. Demographic features, initial findings, and admission time of patients were noted. Patients were categorized according to intensive care necessity. Results: The median age of the patients was 10 (2-18) and 62 (62.6%) of patients were male. The median duration before admission was 4 (1-10) days. All patients has fever, 81.8% had gastrointestinal and 75.8% had cardiovascular involvement at admission. The patients (56.6%) who were accepted as severe and moderate MIS-C required intensive care. Prolonged fever, delayed admission, cardiovascular involvement, high inflammatory markers, lymphopenia and thrombocytopenia were found to key parameters determining the need for intensive care. Conclusion: Multisystem inflammatory syndrome in children is a new disease characterized by fever, signs of inflammation and organ dysfunction associated with SARS-CoV-2 infection. Delayed admission, high cardiac and inflammatory markers at diagnosis increase the need for intensive care. © 2022, Pamukkale University. All rights reserved.

Binge drinking alcohol and circadian misalignment in night shift nurses is associated with decreased resiliency to COVID-19 infection

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.

BERTOLOTTI SYNDROME: AN UNDER RECOGNIZED CAUSE OF INFLAMMATORY BACK PAIN?

BackgroundBertolotti syndrome describes a lumbosacral transitional vertebra (LSTV) which causes symptoms, usually low back pain. LATV is a congenital anomaly where the L5 vertebra has an unusual morphology. Bertolotti syndrome is an under-recognised condition by clinicians.ObjectivesTo clarify the presentation of Bertolotti syndrome, whether there are features of inflammatory back pain (IBP) and the effect on quality of life.MethodsIn this pilot study, 62 patients with LSTV were identified on imaging (plain x-ray). Imaging was performed for a variety of indications, predominently for back pain. In total, 34 patients agreed to take part, with 18 returning questionnaires. Questionnaires were selected for face vailidity and included: Calin IBP Questionnaire, EQ-5D Questionnaire, Visual analogue pain scale (VAS-P). In view of Covid restrictions all contact was by phone and questionnaires were completed online or returned via post.Plain X-rays visualising the lumbar spine were assessed for radiological features of LSTV.ResultsSeventeen (94%) of the participants (n=18) recorded a VAS-P score >3, indicating a clinically significant level of pain. The mean VAS-P score was 6 (range of 2-9). 89% of respondents scored at least 3/5 in the Calin questionnaire. Of the 5 features of inflammatory back pain in the Calin questionnaire, 4 out of the 5 were reported by most respondents. The exception was ‘improvement on exercise', which was only reported by 18% of respondents. Quality of life was impaired-EQ-5D (mean: 0.503, range -0.074 to 0.796).The commonest radiological abnormality was enlarged transverse process (100%) followed by pseudoarticulation with the sacrum (83%) and scoliosis (33%). Presence of sclerosis and/or osteoarthritis at the pseudoarticulation was associated with worse pain scores. Female respondents reported worse pain.ConclusionThese results suggest Bertolotti syndrome is associated with pain in the majority of patients and affects quality of life,. The character and site of the pain suggests that Bertollotti syndrome should be considered in the differential diagnosis of spondyloarthritis.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsSimon Stebbings Consultant of: Abbvie.Janssen, Ciara White: None declared, Terence Doyle: None declared.

Totally Percutaneus Veno-Venous ECMO Therapy for COVID 19 Patients. Bridge to Recovery or Lung Transplantation?

Objective: Multiple major health organisations recommend the use of extracorporeal membrane oxygenation (ECMO) support for COVID-19-related acute hypoxaemic respiratory failure. Method(s): From march 2020 to november 2021 we done 108 veno-venous ECMO therapies. 35 patients required implantation immediately in intensive care unit in place of call by mobile ECMO team. Depend from distance of call it was used medical ambulance, rescue helicopter or medical plane. Result(s): In the first analyzed period (March-December 2020), 90-day mortality was 41%. 8 (7.6%) patients were discharged from the Intensive Care Unit. The remaining 3 (4.2%) were discharged home. 7 patients (6.6%) had both lung transplants. 7 patients (6.6%) required conversion to VV-A ECMO therapy due to the development of acute heart failure. Conclusion(s): In the analyzed period of March-December 2020, the mortality was 41%. As a result, the lower effect of regression of consolidation and inflammatory lesions of lung tissue indicates that ECMO therapy remains the treatment method in high-risk patients as a bridge therapy to lung transplantation.

Role of oxidative stress in the severity of SARS-COV-2 infection

Since the World Health Organization declared SARS-CoV-2 (COVID-19) a pandemic in March 2020, serious efforts have been made to understand the epidemiology, molecular mechanisms, pathology, and clinical evolution of this disease. Oxidative stress (OX-S) has been implicated in the etiologies of many diseases, including SARS-CoV-2. Recent studies suggest that superoxide radicals and the products of lipid peroxidation, such as the electrophilic aldehyde, 4-hydroxynonenal (4-HNE), are important mediators of the pathological effects of oxidative stress during microbial and viral infections. Numerous studies have confirmed that viral infections induce inflammatory responses that generate excessive amounts of reactive oxygen species and 4-HNE protein adducts in plasma and in various tissues, including alveolar epithelium and endothelium. In this book chapter, we will highlight and discuss the apparent and plausible relationships between SARS-CoV-2 virulence and oxidative stress/lipid peroxidation, which affect cellular and DNA repair mechanisms and immune response. © 2023 Elsevier Inc. All rights reserved.

Covid-19: Is the placenta a safe space

Problem: Several large studies have demonstrated that COVID-19 pregnant individuals are at a significant risk for severe disease and adverse pregnancy outcomes. The mechanisms underlying these phenomena remain to be elucidated and are the focus of our project. Although fetal and placental infection is rare, placental abnormalities and adverse pregnancy outcomes associated with placental dysfunction in COVID-19 cases have been widely reported. In particular, placental thrombosis and lesions consistent with maternal vascular malperfusion (MVM) of the placenta are common in individuals with COVID-19. Since thrombotic complications have been associated with COVID-19, it is not surprising that pregnant individuals with COVID- 19 are at risk for placental thrombosis. Method of Study: Placentas were evaluated histologically. Extracellular vesicles were isolated by serial centrifugation. Result(s): Adverse pregnancy outcomes associated with these placental lesions, including hypertensive disorders of pregnancy (gestational hypertension and preeclampsia), small for gestational age (SGA, birthweight < 10th percentile for gestational age), and preterm birth (PTB, < 37 weeks) are significantly increased among pregnant individuals with COVID-19. Placental infection with SARSCoV- 2 is uncommon, but multiple inflammatory and metabolic factors are likely to affect the placenta, including circulating extracellular vesicles (EVs) derived from various organs that have been associated with COVID-19 pathology and disease severity.We have analyzed over 500 placentas from COVID-19 pregnancies and found marked changes in placental morphology, characterized by abnormal maternal and fetal vessels, intervillous thrombi, and fibrin deposition, even in the face of mild or asymptomatic disease. We detected increased levels of small EVs in maternal serum from COVID-19 cases compared to controls and increased levels of mitochondrial DNA in EVs from COVID-19 cases. In in vitro experiments, we found increased oxidative stress in uterine endothelial cells and primary trophoblasts. Syncytialization of trophoblast cells following exposure to EVs from pregnant COVID-19 patients was markedly reduced. RNAseq of trophoblast cells exposed to EVs from pregnant COVID-19 patients revealed disruption of multiple pathways related to mitochondria function, oxidative stress, coagulation defects, and inflammation. Timing of infection during pregnancy (first, second, and third trimester) altered EV size distribution, cargo content, and functional consequences of trophoblast EV exposure. Conclusion(s): Our studies show that COVID-19 infection during pregnancy has profound effects on placenta morphology and function. It remains to be determined what the long-term consequences are on the offspring.

A case of possible drug-induced liver injury due to COVID-19 vaccine.

The patient presented with nausea, appetite loss, and fatigue. She had received two doses of Pfizer/BioN-Tech BNT162b2 mRNA vaccine (COMIRNATY) for coronavirus disease 2019 (COVID-19). Acute liver injury was noted 14 days after the first dose of the vaccine. Re-exposure through the second dose worsened the liver injury. After liver biopsy on the third day of admission, methylprednisolone (1000 mg) was administered. Liver histology showed acute hepatitis with diffuse lobular inflammation/necrosis and lymphocyte-dominant infiltra-tion in the portal areas. The patient was diagnosed with drug-induced liver injury due to the COVID-19 vaccine based on the Digestive Disease Week Japan 2004 (DDW-J) scale, which assesses the temporal relationship, liver biopsy, and laboratory findings. With improvements in the blood test parameters, prednisolone was gradually tapered and stopped. One month later, no biochemical signs of relapse were noted. To our knowledge, this is the first report describing liver injury after the administration of the Pfizer COVID-19 vaccine in Japan.Copyright © 2022 The Japan Society of Hepatology.

The Role of Inflammation in the Development of Complications Caused by Covid-19: A Review Study

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.

Angiotensin-converting enzyme 2 (ACE2) in COVID-19 and other diseases.

The coronavirus SARS-CoV-2 was detected in isolates of pneumonia patients in January 2020. The virus cannot multiply extracellularly but requires access to the cells of a host organism. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a receptor, to which it docks with its spikes. ACE2 belongs to the renin angiotensin system (RAS), whose inhibitors have been used for years against high blood pressure. Renin is an endopeptidase that is predominantly formed in the juxtaglomerular apparatus of the kidney and cleaves the decapeptide angiotensin I (Ang I) from angiotensinogen. Through the angiotensin-converting enzyme (ACE), another 2 C-terminal amino acids are removed from Ang I, so that finally the active octapeptide angiotensin II (Ang II) is formed. The biological effect of Ang II via the angiotensin II receptor subtype 1 (AT1-R) consists of vasoconstriction, fibrosis, proliferation, inflammation, and thrombosis formation. ACE2 is a peptidase that is a homolog of ACE. ACE2 is predominantly expressed by pulmonary alveolar epithelial cells in humans and has been detected in arterial and venous endothelial cells. In contrast to the dicarboxy-peptidase ACE, ACE2 is a monocarboxypeptidase that cleaves only one amino acid from the C-terminal end of the peptides. ACE2 can hydrolyze the nonapeptide Ang-(1-9) from the decapeptide Ang I and the heptapeptide Ang-(1-7) from the octapeptide Ang II. Ang-(1-7) acts predominantly antagonistically (vasodilatory, anti-fibrotic, anti-proliferative, anti-inflammatory, anti-thrombogenetically) via the G protein-coupled Mas receptor to the AT1-R-mediated effects of Ang II. In the pathogenesis of COVID-19 infection, it is therefore assumed that there is an imbalance due to overstimulation of the AT1 receptor in conjunction with a weakening of the biological effects of the Mas receptor.Copyright © 2022 Dustri-Verlag Dr. K. Feistle.

THE EMERGENCE OF FIBROMYALGIA FOLLOWING ACUTE COVID-19 INFECTION

BackgroundThe exact pathogenesis of fibromyalgia (FM) syndrome is unclear. However, different infections including hepatitis C virus, Human immunodeficiency virus and Lyme disease have already been implicated with the development of FM after their acute phase[1]. Imbalance between pro-inflammatory and anti-inflammatory cytokines has been suggested as a possible mechanism that facilitates the neuropathic pain[2].ObjectivesTo investigate the incidence of FM syndrome among convalesced individuals following hospitalization for Acute Coronavirus Disease-2019 (COVID-19) and to identify possible risk factors.MethodsWe performed a cross-sectional study on patients who were discharged after COVID-19 hospitalization from the Sheba Medical Center, Israel, between July 2020 to November 2020. A phone interview was performed consisting of the following questionnaires: the Fibromyalgia Survey Diagnostic Criteria Questionnaire, Sense of Coherence Questionnaire to evaluate resilience, and the Subjective Traumatic Outlook Questionnaire to assess the associated psychological aspects of the trauma. The incidence of post-COVID FM was calculated and regression models were performed to identify predictors.ResultsThe study population consisted of 198 eligible patients who completed the phone interview. The median age was 64 (52-72) and 37% were women. The median follow-up was 5.2 months (IQR 4.4-5.8). The incidence of FM was 15% (30 patients) and 87% (172 patients) had at least one FM-related symptom. Female gender was significantly associated with post-COVID FM (OR 3.65, p=0.002). In addition, high median Subjective Traumatic Outlook scores and low median Sense of Coherence scores were both significantly associated with post-COVID FM (OR 1.19, p<0.001 and OR 0.92, p<0.001, respectively).ConclusionFM is highly prevalent among COVID-19 convalescent patients. Our finding suggests that a significant subjective traumatic experience and a low resilience are highly associated with post-COVID FM.References[1]Buskila D, Atzeni F, Sarzi-Puttini P. Etiology of fibromyalgia: the possible role of infection and vaccination. Autoimmun Rev. 2008;8: 41-43. https://doi.org/10.1016/j.autrev.2008.07.023[2]Amital M, Ben-Shabat N, Amital H, Buskila D, Cohen AD, Amital D. COVID-19 associated hospitalization in 571 patients with fibromyalgia—A population-based study. PLoS ONE. 2021:16: e0261772. https://doi.org/10.1371/journal.pone.0261772Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Paediatric Appendicitis: Has SARS-COV-2 Influenced the Clinical Profile and Management during the Pandemic Period?

Introduction: The Coronavirus Disease-2019 (COVID-19) had profound repercussions on routine medical practices all over the globe. There are fewer studies on the impact of the pandemic on childhood surgical conditions like Acute Appendicitis (AA), which is the most common paediatric surgical emergency. Aim: To analyse whether COVID-19 has influenced the clinical profile and management of paediatric appendicitis during the pandemic period. Materials and Methods: A retrospective study was carried out in the Department of Paediatric Surgery, SAT Hospital, Government Medical College, Thiruvananthapuram, Kerala, India, comparing AA cases during the pandemic period (group A=from February 2020 to January 2022) with AA cases during the prepandemic period (group B=from February 2018 to January 2020). Analysis of data regarding patient demographics (age, sex), duration of symptoms and hospital stay, type of appendicitis, total and differential leucocyte count, ultrasonographic findings, treatment modality and complications was done. Subgroup analysis of children in group A was done by comparing AA cases with active/recent COVID-19 infection (Subgroup A1) with the rest of AA in the group (Subgroup A2). Pearson's Chi-square test was used for the analysis of categorical variables and independent t-test was used for numerical data. p-value<0.05 was considered significant. Results: There were 826 AA cases, with 375 children in group A and 451 in group B. A significant reduction in the number of AA cases was noted during the first year of the pandemic (n=167 vs n=242, p-value=0.009) and a significantly higher number of cases were managed conservatively during the pandemic period (n=48 vs n=10, p-value <0.0001). Children with active/recent COVID-19 infection presented late (p-value=0.03), had a significantly higher incidence of complicated appendicitis (p-value=0.02), decreased total leucocyte count (p-value=0.01), decreased polymorph count (p-value=0.02) and higher incidence of the conservative modality of treatment (p-value<0.005). Conclusion: Overall, there were no significant differences in the clinical profile of AA during the pandemic period. But, children with AA who had active/recent COVID-19 infection had a longer duration of symptoms and a higher incidence of complicated appendicitis. The pandemic influenced the management protocols with an increase in the number of AA cases being managed conservatively when compared to the prepandemic period. [ FROM AUTHOR] Copyright of Journal of Clinical & Diagnostic Research is the property of JCDR Research & Publications Private Limited and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)